Mercury in fish—some toxicological considerations

Mercury in fish—some toxicological considerations

Fd Cosmet. Toxicol. Vol. 10, pp. 545-556. Pergamon Press 1972. Printed in Great Britain Mercury in Fish--Some Toxicological Considerations*~ S. SKERF...

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Fd Cosmet. Toxicol. Vol. 10, pp. 545-556. Pergamon Press 1972. Printed in Great Britain

Mercury in Fish--Some Toxicological Considerations*~ S. SKERFVING+ + Department of Nutrition and Food Hygiene, Food Research Department, National Food Administration, S-I04 O1 Stockhohn 60, Sweden (Received 24 December 1971)


During the 1960s, the levels of mercury found in fish rapidly grew into one of the most distressing problems in environmental toxicology. Though many problems are still unsolved or under debate, some facts about the origin and nature of the mercury have emerged and may serve as a basis for the toxicological appraisal of the problem. The first is that the mercury in fish is present almost entirely as methylmercury (CHaHg+). Secondly, the main cause of the increase in mercury levels is industrial pollution. This seems to be true with regard to methylmercury in fish from lakes and rivers, although the cause of the levels found in tuna, in swordfish and in shark from the oceans is not known. The same is true for fish from some apparently uncontaminated lakes and rivers. Thirdly, inorganic and organic mercury disposed into lakes, rivers or the sea may be transformed into methylmercury, and fourthly, the mercury levels found in fish, even from "non-contaminated" areas, are higher than in most other foods. Animal experiments

Experimental work carried out during the last 30 years has established some of the main metabolic and toxicological properties of methylmercury compounds (Berglund, Berlin, Birke, yon Euler, Friberg, Holmstedt, Jonsson, Ramel, Skerfving, Swensson & Tejning, 1970, 1971). These compounds are almost completely absorbed from the gastro-intestinal tract. They readily pass the blood-brain barrier and, compared with inorganic and other organic mercury compounds, give high mercury levels in the brain. Only elemental mercury vapour seems to give comparable brain levels. They damage nerve cells and pass the placental barrier. They are excreted mainly in the faeces, and the over-all elimination is slow compared with that of inorganic and other organic mercury compounds. With regard to different compartments, the situation is far more complex (Nordberg & Skerfving, 1972). The experimental metabolic and toxicological work on methylmercury has of course been carried out almost entirely with methylmercury salts. According to information derived *Some of the research reported here was supported by grants from the Research Board of the National Environment Protection Board and the Expressen's Prenatal Research Fund. 1"Basedupon a paper presented at the Gordon Conference on "Toxicology and Safety Evaluations", Meriden, New Hampshire, USA, 2-6 August 1971. ~Present address : Department of Occupational Medicine, University Hospital, S-22185Lund, Sweden. 545



from Japanese epidemics of poisoning in Minamata and Niigata, the methylmercury found in fish and shellfish had been conveyed into the water as a methylmercury salt through industrial discharge. In Sweden the question arose as to whether there might be any toxicological or metabolic differences between simple methylmercury salts and methylmercury that had been synthesized in the lakes (e.g. by micro-organisms) and had then accumulated in fish, in other words, whether the experimental data and the data from the Japanese epidemics were relevant to the evaluation of risks. To settle this question, a feeding experiment in cats was performed in our laboratory (Albanus, Frankenberg, Grant, von Haartman, Jernel6v, Nordberg, Lyd~ilo, SchiJtz & Skerfving, 1972). Five cats in group 1 were fed fish from a lake that had earlier been heavily polluted with phenylmercury acetate discharged from a paper-pulp factory. The fish was homogenized and in the homogenate, the mercury level turned out to be 5.7 ppm, the mercury being present almost entirely as methylmercury. A small amount of methylmercury hydroxide labelled with 2°aHg was added to the homogenate. The amount of radioactive mercury accounted for less than 1 ~o of the total mercury. For group 2, fish was caught in another lake known to have a low mercury level. The level of mercury in the homogenate was 0-1 ppm. Methylmercury hydroxide labelled with 2°aHg was added to this batch to a final concentration of 5.3-5.7 ppm. Group 3 received the same 0.1 ppm homogenate but without added mercury, and served as a control group. The purpose of adding labelled methylmercury to the homogenate of group 1 was to make possible a comparison of the metabolism of a simple methylmercury salt with fish-methylmercury in the same animal. To check whether the addition of a very small quantity of methylmercury hydroxide was of any significance, two cats (group 4) were fed a homogenate offish from the polluted lake without any added mercury. The cats were fed the homogenate as their only food together with water and vitamins and iron supplements. The daily exposure was 0.45 and 0.47 mg mercury/kg body weight in groups 1 and 2, respectively. The neurological state was recorded as a score for positive findings. In both of the exposed groups, major neurological symptoms appeared within 2-3 months (Fig. 1). The main symptoms were rigidity, ataxia, tremor, salivation and cramps, without any difference between the groups. The symptoms were identical with those described in cats poisoned in Minamata. The total doses that had been administered by the time major neurological symptoms appeared were 30 and 35 mg mercury/kg body weight, respectively. The control cats remained healthy throughout the study. The animals were sacrificed by intravital perfusion and fixation with formol calcium. The organs were analysed for radioactivity, total mercury by neutron-activation analysis and atomic absorption spectrometry, and methylmercury by gas chromatography. There was excellent agreement between the two exposed groups, the brain mercury levels being about 20 ppm in each case. There was good agreement in group 1 between mercury levels obtained from chemical analyses and those calculated from radioactivity measurements. The results indicate that the mercury originating from the paper-pulp factory and that from the added methylmercury hydroxide was metabolized in the same manner. When compared with the controls, the exposed animals had average mercury levels 15-30 times higher in different organs. In both groups the mercury in brain and muscle was present completely or almost completely as methylmercury, while in liver, and especially in kidney, there was a considerable proportion of inorganic mercury. Since more than 99 ~ of the mercury in the fish homogenates consisted of methylmercury, a breakdown of methylmercury must have







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FIG. 1. Relation between score of neurological signs of poisoning and exposure time in cats ingesting about 0.45 mg mercury/kg body weight/day, as methylmercury, either (group 1) in a contaminated pike homogenate containing 5.7 ppm mercury or (group 2) in a pike homogenate to which 5'3-5"7 ppm mercury, as methylmercury hydroxide, had been added (Albanus et al. 1972).

occurred in these cats. Breakdown of methylmercury to inorganic mercury has been demonstrated in rats (Norseth & Clarkson, 1970a,b) and in mice (Norseth, 1971). Thus methylmercury is fairly stable in the body but not completely stable. T h a t is possibly an advantage, since otherwise the accumulation of methylmercury in mammals might be even higher than it is. The organs of the cats were also investigated for morphological lesions (Grant, 1972). Lesions were found in groups 1 and 2 only, no pathological changes being present in the control group. The lesions were confined to the cerebral cortex, the granular layer of parts of the cerebellum and the peripheral nerves with their dorsal roots. The changes in the peripheral nerves and cerebellum were of the type described earlier in rats and also in poisoned humans. In both the exposed groups the lesions in the cerebral cortex consisted of scattered small foci in practically all regions of the neocortex, a pattern not seen in rats, monkeys or man. It is obvious from this study, that data obtained from experiments with simple methylmercury salts are relevant to the toxicological evaluation of mercury in fish, as are the epidemiological data from Minamata and Niigata.


o f m e t h y l m e r c u r y in m a n

Most of our knowledge on the metabolism of methylmercury in man has been obtained on the one hand from two studies using tracer-doses of methylmercury labelled with 2°3Hg



in volunteers, and on the other from studies in subjects exposed to mercury by consumption of contaminated fish. It has generally been assumed that in the metabolism of methylmercury there is a simple relationship between exposure, total body burden, levels in different organs and excretion. It has already been indicated, however, by the breakdown of methylmercury to inorganic mercury demonstrated in animal experiments, that this concept may not be completely true. Since, in the safety evaluations, extensive calculations have been based on the concept of a simple metabolism, it is essential to scrutinize whether this is in accordance with available data. Human tracer-dose experiments were published by Aberg, Ekman, Falk, Greitz, Persson & Snihs (1969) and Miettinen, Rahola, Hattula, Rissanen & Tillander (1971). Single oral doses of 10-20 tzg mercury were administered as methylmercury nitrate or methylmercury fish proteinate. In both studies, the whole-body radioactivity had a biological half-life of 70-80 days, indicating a daily excretion of about 1 ~ of the total body burden. There were, however, indications of some variations between different organs, and these differences may be of practical importance. Aberg et al. (1969) studied the distribution of mercury within the body by step scanning at different times after administration of mercury. About I0 ~ of the total body burden was localized in the head. The biological half-life for all regions together was 60-70 days in the three subjects studied. The elimination from the head, probably mainly representing the brain-mercury load, was slower than from the other regions. The biological half-lives for the head were 64, 95 and 95 days. Miettinen et al. (1971) found that the elimination of mercury from blood cells was faster than from the whole body, the biological half-life in blood cells in six persons averaging 50 days. Thus it cannot be excluded that the elimination of methylmercury from the brain is slower than the elimination from the whole body, which in turn is slower than the elimination from the blood. This may be of great importance in the use of the blood-mercury level as an indicator of the brain level. The error is probably of minor importance at steady state, but might be a serious drawback when there is an increasing or decreasing total body burden. At least in Sweden, the consumption of methylmercury-contaminated fish varies considerably during the year and thus the blood levels are seldom stationary (S. Skerfving, in preparation, 1972). The mercury exposure in the tracer-dose studies was small, corresponding to less than I00 g tuna fish containing 0.25 ppm methylmercury. It is thus important to know whether the metabolism is the same with heavy exposure. In Sweden, we have studied the decrease of mercury levels in the blood and hair of subjects who have stopped eating contaminated fish or who have changed from a high consumption of contaminated fish to consumption of "non-contaminated" fish. The elimination of mercury in subjects formerly exposed to methylmercury by consumption of contaminated fish is shown in Fig. 2. In a few subjects the elimination has been studied for more than ten biological half-lives. It can be seen that in the hair there is a considerable variation in elimination rate, the shortest biological half-life being 33 days and the longest 120 days. It is not known whether this is due to differences in the elimination of the total body burden or to different rates of hair growth. It is also important to note that the subject who suffered the heaviest mercury load, 1200 ng/g blood cells, had a biological half-life of about 120 days in hair, blood cells and plasma. A considerable variation in elimination rate has been observed also in another group of human subjects (S. Skerfving, in preparation, 1972). From this brief discussion of the methylmercury metabolism in man, it may be concluded



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that methylmercury is metabolized in a fairly regular manner. A considerable variation between individuals may exist, however, perhaps making some people more liable to accumulate methylmercury than others. Also at steady state, methylmercury or total mercury levels in blood or hair may serve as indicators of exposure, of the total body burden and of the mercury level in the nervous system. Mainly because of the accumulation of methylmercury in blood cells, we have generally preferred the blood cell-total mercury level as an indicator. It must be realized, however, that the blood level may be a less reliable index of the level of mercury in the brain when the total body burden is increasing or decreasing.

Toxic levels in man In 1968 a study group was appointed in Sweden to make an evaluation of the risks connected with consumption of methylmercury-contaminated fish. A report was published in Swedish in 1970 (Berglund et al. 1970), and in English in 1971 (Berglund et al. 1971). Some consideration will be given here to the reasoning behind this report and the conclusions reached, with special reference to the weak points and to the criticism to which they have been subjected. In connexion with the Niigata epidemic in Japan, data were collected on mercury levels in blood and hair from poisoned subjects and from exposed but clinically healthy ones. The



data have been obtained mainly from the Report on the Cases of Mercury Poisoning in Niigata Prefecture compiled in 1967 by the Ministry of Health and Welfare, Tokyo, and from the personal communications of Dr. T. Tsubaki at the University of Niigata. A major obstacle is that the samples were, for the most part, taken from the patients at varying times after the onset of the symptoms. The data on levels seemed confusing until plotted against the time that had elapsed between onset of symptoms and sampling (Fig. 3). In some of the patients repeated samples were taken. The slopes of the decay curves in these 200



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Fie. 3. Relation between mercury levels in whole blood and the time elapsing after onset of symptoms in I 7 cases of methylmercury poisoning in Niigata. [From Berglund et al. (1971).]

patients are in fair agreement with those found in Swedes who had stopped eating methylmercury-contaminated fish, and with the results from the human tracer-dose experiments. It seems, therefore, that the patients were not exposed to mercury during the period of sampling. A major problem is that we do not know for certain whether they were exposed between the onset of symptoms and the first sampling. Figure 4 shows two possible extremes in the interpretation of the diagram with regard to the patients with the lowest blood levels. Either the patients stopped consuming contaminated fish at the onset of symptoms, or they were exposed until the first sampling was made. But there is an additional problem. It is well known from cases of occupational methylmercury poisoning, and from animal experiments, that after a single heavy exposure a few weeks may elapse before symptoms appear. Berlin, Nordberg & Hellberg (1972) have recently shown in squirrel monkeys, that this latency period is shorter the heavier the exposure. In Fig. 4 it has been assumed that the latency period between the time when a toxic level is reached and the time of onset of symptoms is 20 days. On this assumption, damage to the nervous system in these eases may have been associated with blood levels somewhere between 0.1 and 0-2/~g mercury/g. In some patients, hair samples were taken closer to the onset of symptoms than were blood samples. The mercury level in the hair of these subjects decreased in a way expected in "non-exposed" subjects. Mainly on the basis of this fact, we concluded that the best way






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FIG. 4. Possible ways of interpreting the toxic blood-mercury level from data presented in Fig. 3. of estimating a toxic blood level was to extrapolate back to the time of onset of symptoms. The lowest mercury level in whole blood at the onset of symptoms was then assumed to have been about 0.2/zg/g. It is of interest, in this connexion, that Berlin et al. (1972) report that the critical whole-blood level in subacute studies in squirrel monkeys was somewhere in the range 0-8-1.2/~g/g. The metabolism of methylmercury in the squirrel monkey shows great similarities to that in man. When the mercury levels in the hair of the Niigata patients were extrapolated in a similar manner we arrived at a level of about 200 ~g/g at the onset of symptoms in a few patients. Data on tissues of Swedish fish eaters suggest that 200/~g/g hair corresponds to about 0.7/~g/g whole blood. In one exceptional Niigata case, the mercury level in hair was 50/~g/g corresponding to a level of about 0.2 tzg/g whole blood. There is thus a substantial difference between the estimation made from blood levels and that made from hair levels, in spite of the fact that many of the analyses were made in the same individual patients. It may be added that calculations made from data from the human tracer-dose experiments, indicate levels corresponding to the higher alternative. One possible explanation of the difference is that the dithizone method used for blood analyses is relatively unreliable at blood levels of this order and gave values that were too low. There is, however, no positive evidence for this assumption. For the sake of caution, Berglund et al. (1971) therefore accepted the lower alternative, especially since the lowest recorded hair level, on a single sample obtained close to the onset of symptoms, was in accordance with the lower blood level. In spite of an extensive search in Sweden, we have not found any cases of clinical methylmercury poisoning resulting from fish consumption. Studies have been carried out in Finland by Sumari, Backman, Karli & Lahti (1969) with equally negative results. Three subjects in Sweden and Finland have had mercury levels above 0.2 /zg/g whole blood the lowest level assumed to have been present in poisoned Japanese. Two Swedes had levels exceeding that concentration by a factor of three. This may seem confusing, but it can be seen not to be impossible if the distribution of sensitivity to methylmercury is considered. Figure 5 shows a tentative dose-response relationship constructed from data from Niigata on mercury levels in the hair of healthy and poisoned subjects. The diagram has several weaknesses but it is worth some consideration. The main obstacle is that probably many of






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FIG. 5. Tentative relationship between levels of mercury in hair and the risk of clinical poisoning by methylmercury. [Based upon data from the Niigata epidemic as presented by Berglund e t al. (1971, from data from T. Tsubaki; • • ) and Tsubaki (1971 ; O - - -O).]

the samples were obtained after warnings had been issued against consumption of contaminated fish. Thus, the curves are probably drawn too far to the left. It seems, however, that the risk of getting poisoned at a mercury level of 50 tLg/g in hair is considerably less than 1 in 100. At a mercury level of 250 t~g/g hair, less than half of the exposed subjects would be expected to be clinically poisoned. The probability of the two most heavily exposed Swedes remaining clinically healthy is higher than 50 %.

"Minimal" neurotoxic exposure The .potentially toxic blood-mercury level must be transformed into a daily intake of methylmercury. Estimations have been made from epidemiological and experimental data. For subjects consuming varying amounts of fish contaminated with methylmercury at different levels, the daily methylmercury exposure was plotted against the mercury level in the blood cells. From the available data, we concluded that the long-term exposure needed to reach the potentially toxic mercury level of 0.2/~g/g whole blood is about 0-3 mg mercury (as methylmercury)/day in a 70-kg man, i.e. about 4 ~g/kg body weight/day. The basis of the estimation was rather weak with regard to high exposures. The relationship has since been confirmed by some additional data from exposed Swedes (S. Skerfving, in preparation, 1972). Data on American consumers of tuna fish recently reported by McDuffie (1972) indicate a relationship with about half that slope. McDuffie remarks, however, that the blood analyses were probably too low. The relation between exposure and blood levels can also be roughly estimated from the results of the human tracer-dose experiments performed by Miettinen et al. (1971). This estimation agrees fairly well with the epidemiological data. Acceptable daily intake To arrive at an acceptable daily intake of methylmercury from the figure for toxic exposure, a safety factor must be applied. This factor should cover individual differences in sensitivity and protect against lesions other than clinically evident damage to the adult



nervous system, such as foetal damage, lesions in growing individuals, possible genetic lesions, subclinical lesions of the nervous system, other possible long-term effects and possible synergistic effects with other environmental toxicants. Unfortunately, the information available on these points is far from comprehensive, but some facts may be noted. Nomura (1968) has reported data on the age distribution of the cases of poisoning in Minamata. Unfortunately, there is no information available on the age distribution of the population in the endemic area. If, however, the incidence of poisoning at different ages is compared with the age distribution in the total Japanese population in the period during which the poisoning occurred, it is obvious that there is a definite over-representation of poisoning among infants below the age of 1 year. A less pronounced peak occurred in subjects aged 40-60 years. There was no over-representation in children. According to Harada (1968) only a few of the mothers of the 22 poisoned babies had neurological symptoms or signs. Murakami (1971) stated that one of the mothers was recognized as a case of poisoning. It thus seems that foetuses or new-born babies are considerably more susceptible to methylmercury exposure than are their mothers. Only a few experimental studies on foetal lesions due to methylmercury have been published. The concept that methylmercury induces foetal brain lesions is based almost entirely on the epidemiological experience from Minamata. It is well established experimentally that methylmercury passes the placental barrier, but quantitative data are scanty. In newborns of mothers exposed to methylmercury through consumption of contaminated fish during pregnancy, increased mercury levels were found in the blood cells (S. Skerfving, in preparation, 1972). Mercury levels in breast milk were similar to plasma levels. However, less than half of the mercury in breast milk was methylmercury (S. Skerfving and G. West66, in preparation, 1972). It has been demonstrated that methylmercury induces C-mitosis, polyploidy, aneuploidy, chromosome fragmentation and non-disjunction in the roots of the onion, Allium cepa, and in Drosophila melanogaster (Ramel, 1969; Ramel & Magnusson, 1969). It is not known for certain whether similar lesions are produced by methylmercury exposure in mammals. A cytogenetic study was performed in a group of nine Swedish subjects exposed to methylmercury through fish consumption (Skerfving, Hansson & Lindsten, 1970). The blood-cell mercury levels ranged from about 20 to about 400 ng/g. There was a significant rank correlation between the number of chromosome breaks in the lymphocytes and the mercury level of the blood cells. The biological significance of chromosome breaks is not very clear, but the risk of chromosomal aberrations being transmitted into the progency, the risk of damage to somatic cells in the foetus and the possibility also of a carcinogenic effect must be considered. A few words should be said about sub-clinical lesions of nerve tissue. It has been shown recently in rats (Grant, 1972), and squirrel monkeys (Grant, 1972; Nordberg, Berlin & Grant, 1971), that morphological lesions may be present in animals that show no obvious clinical signs of poisoning. When rats were exposed orally to I m g mercury/kg body weight/day for 150-210 days, they developed neurological symptoms and morphological lesions. Another group exposed to about 0"5 mg/kg body weight/day showed only morphological lesions, while a third group exposed to 0.2 mg/kg body weight/day showed neither neurological nor morphological signs. This clearly shows that the possibility of subclinical lesions must be borne in mind. It is, of course, difficult on the basis of this scanty information to choose a suitable safety factor. Berglund et al. (1971) decided to use a factor of 10. This may seem to be very low,



but it must be remembered that considerable caution was exercised in the judgements of the potentially toxic exposure. If a safety factor of 10 is applied to the assumed potentially toxic exposure of 4/~g/kg body weight/day, one arrives at an acceptable daily intake of 0.4/zg/kg body weight. The corresponding mercury levels in the blood cells are about 4 times higher than the level of 0.01 /zg/g found by Tejning (1967) in the average Swedish fish-eater, but corresponds to " n o r m a l " mercury levels in hair reported for example from Japan. Figure 6 shows the weekly intake of fish containing 1 ppm mercury, as methylmercury, that would provide the acceptable daily intake of 0-4/zg/kg/day proposed by Berglund et al. (1971). In infants this intake is about 20 g and in adults about 200 g/week.







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FIG. 6. Estimated weekly intake offish containing 1 ppm of mercury as methylmercury producing an exposure of 0-4/~g mercury/kg body weight/day at various ages. [Data on weights from Food and Nutrition Board 0968).]



Several actions have been taken by the Swedish Government. The amounts of mercury in industrial waste have been reduced through a prohibition in 1967 against the use of phenylmercury acetate in the cellulose industry and a voluntary decrease of mercury waste in other types of industry. Pressure was put on other industries, such as the chlorine industry, to reduce mercury waste. West66 & Rydfilv (1971) have since shown that the mercury levels in fish have decreased, at least in some Swedish waters, although in other areas the mercury level in fish has not decreased. Sale of fish containing mercury levels at or above 1 ppm has been prohibited since 1967, and to this prohibition was added, in 1968, official advice that fish from waters that are not "banned" but in which mercury levels are high due to pollution should be consumed no more than once a week. Japan has established another system (Berglund, 1971). If 20% of the fish in an area of water have mercury levels exceeding 1 ppm, hair sampling is performed in the fish-eating population. Persons with levels higher than 50/~g/g are examined clinically. When the levels in fish exceed 1 ppm or the levels in hair exceed 50 ~g/g, "banning" of the fish is considered. In 1970 Canada and the USA enforced action limits of 0.5 ppm. Fish containing higher levels of mercury may not be sold. Several areas of water in Finland have been heavily polluted with mercury, and recently



a c t i o n s similar to the Swedish ones have been t a k e n by the F i n n i s h g o v e r n m e n t . I n F i n l a n d , however, there is no p r o h i b i t i o n on fish c o n t a i n i n g 1 p p m m e r c u r y , b u t only an official w a r n i n g a g a i n s t c o n s u m p t i o n . D e n m a r k has only one heavily p o l l u t e d area. T h e local p o p u l a t i o n here has been w a r n e d b y letters f r o m the g o v e r n m e n t to each family. T h e g o v e r n m e n t o f the U K has d e c i d e d n o t to enforce any restrictions, as m e r c u r y in fish is not a very i m p o r t a n t p r o b l e m in t h a t c o u n t r y ( W o r k i n g P a r t y on the M o n i t o r i n g o f F o o d s t u f f s for M e r c u r y a n d O t h e r H e a v y Metals, 1971). I t a l y a n d G e r m a n y have m a x i m u m p e r m i t t e d levels o f 0-5 p p m , a n d F r a n c e one o f 0.7 p p m . T h e J o i n t F A O / W H O E x p e r t C o m mittee on F o o d A d d i t i v e s (1971) has a p t l y e m p h a s i z e d " t h e urgent need for surveys o f the levels a n d f o r m s o f m e r c u r y in f o o d s " .

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