Selected Case Histories and Epidemiologic ...

Clinical Toxicology Downloaded from informahealthcare.com by National Inst of Health Library on 05/01/14 For personal use only.

CLINICAL TOXICOLOGY 1 1 ( 2 ) , pp. 131-150 (1977)

Selected Case Histories and Epidemiologic Examples of Human Mercury Poisoning * It

HERBERT B. GERSTNER and JAMES EDWARD HUFF Biomedical Sciences Section Information Center Complex/Information Division Oak Ridge National Laboratory Oak Ridge, Tennessee

All beginnings a r e hard Chaim Potok, In the Beginning, Alfred A. Knopf, 1975

INTRODUCTION Depending on its chemical s t a t e , m e r c u r y in toxic concentrations c a u s e s a broad spectrum of clinical pictures [ l ] . Though s e v e r a l hund r e d c a s e histories have been described in the l i t e r a t u r e , many r e p o r t s *By acceptance of this a r t i c l e , the publisher o r recipient acknowledges the U.S. Government's right to retain a nonexclusive, royaltyfree license in and to any copyright covering the article. ?Preparation of this review manuscript was supported by the Toxicology Information Program/National L i b r a r y of Medicine. The Oak Ridge National Laboratory is operated by Union Carbide Corporation Nuclear Division f o r the Energy Research and Development Administration under Contract Number W-7405-eng-26. 131 Copyright 0 1977 hy Mdrcel Dekker, Inc All Rights Reserved Neither this work nor dny pdrt mdy he repruduLed or trdnsmitted in dny form or by any meahs. electronic or ineLhanical, including p h o t w o p y i n g . microlilming. and recording. or by dny information storage and retrieval system. without permission in writing f r o m the publisher


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suffer from inadequacies such as preexisting disease, lack of a c c u r a t e mercury assays, and failure to perform an autopsy after lethal outcome. Similar considerations apply to epidemiologic studies of largesc ale outbreaks of human poisoning by organomercurials. Moreover, the pertinent information is scattered throughout numerous journals and other publications of the world literature, often hampering easy access. To vividly depict the various types of characteristic clinical pictures and to describe actual circumstances under which they occur, highlighted excerpts have been prepared from the most illustrative literature reports. This compilation a i m s not only at alerting all members of the health team about the diverse clinical aspects of m e r cury poisoning but also at directing their continuous awareness and vigilance toward environmental pollution by mercury, i t s e a r l y recognition, and its prevention. ELEMENTAL MERCURY Because of i t s great volatility, elemental m e r c u r y vaporizes readily at room temperature and en t ers the human body through inhalation. After inadvertent spills of the metal in poorly ventilated rooms o r other enclosed working areas, concentrations in ambient air may reach such a height as to t ri g g er an acute pulmonary syndrome. In addition to great volatility, elemental mercury h a s another dangerous characteristic. When taken in by breathing, the vaporized metal swiftly pas s es through internal lung linings and enters the bloodstream, where appreciable amounts p er s i s t unchanged f o r seve r a l minutes before undergoing final oxidation to m e r c u r i c ions. In the unchanged state-sharply contrasting with the m e r c u r i c formelemental mercury rapidly penetrates the formidable physiologic b a r r i e r between blood and brain, thereby accumulating in the central nervous system (CNS). A s a consequence, this system becomes the critical target of intoxication which determines the clinical picture emerging after long-term inhalation of excessive mercury vapors. Depending on air concentration and exposure time, elemental mercury thus produces two characteristic clinical entities with lungs o r CNS as their respective centers. Acute Pulmonarv Iniurv Cas e History No. 1 Because of needed rep ai rs , a caustic soda s t o r a g e tank that had been contaminated by elemental mercury from electrodes was emptied, flushed, and ventilated through an air blower. When a 46-year-old


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worker entered the tank to e r e c t a scaffold, the floor s t i l l contained many s c a t t e r e d globules of mercury. After 2 1/2 h r , the scaffold was finished and the worker left f o r home, feeling perfectly well. During the bus ride, he suddenly s t a r t e d to cough and to shiver. Under normal circumstances, the walk from the bus stop to h i s house took 7 min. On that particular night, however, he shivered s o violently and was s o weak that he took 30 min. On reaching home, he felt v e r y cold, s a t down before a n e l e c t r i c heater, took a hot bath, and went to bed early. During a r e s t l e s s sleep, he experienced s h o r t n e s s of breath, shivering, and coughing which lasted throughout the e n t i r e night. By morning, h e was much improved but he s t i l l complained about a "sore chest" and dyspnea which lasted two m o r e days. The f i r s t urine a s s a y s f o r mercury, which w e r e performed 10 to 14 days a f t e r exposure, yielded 100 p.g/liter and 170 pg/24 h r ; one month l a t e r , the level had declined to 70 @/liter and 110 pg/24 hr. Retrospective measurements i n a s i m i l a r s t o r a g e tank under s i m i l a r conditions yielded m e r c u r y air concentrations a t face level of about 1000 gg/m3. The preceding c a s e history-described m o r e extensively in Ref. [2]-points out two important practical aspects. First, when not s u s pected, mild and moderate f o r m s of acute elemental m e r c u r y intoxication are liable to be misdiagnosed as upper r e s p i r a t o r y infections; only e a r l y m e r c u r y analysis of blood o r urine allows a definitive differential diagnosis. And second, general ventilation of confined s p a c e s initially may be insufficient because of additional m e r c u r y evaporation by the air c u r r e n t ; therefore, the wearing of personal r e s p i r a t o r s may be required during early phases of entrance. Chronic Brain Injury C a s e History No. 2 In o r d e r to extract elemental m e r c u r y , a 25-year-old man placed used batteries and mercury-zinc a m a l g a m s into a furnace which was located in a s m a l l shed heated to m o r e than 600°F. The vaporized m e r c u r y was then condensed, purified, and ladled into flasks, which led to considerable amounts of spilled metal-numerous globules cove r i n g the concrete floor of the shed. Even a t relatively low furnace temperatures (< SOO"), the m e r c u r y concentrations in air were as follows: just above ground surface, 100 to 700 pg/m3; o v e r the closed furnace door, 2200 pg/m3; and a t face level in the c e n t e r of the room, 100 pg/m3. With the furnace a t normal operating temperature, the corresponding values presumably were much higher. After working for two y e a r s under these conditions, the man became too sick to continue his occupation. Approximately one y e a r following s t a r t of employment, the patient noticed certain changes. He became not only less and less active but


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a l s o l e s s talkative. His m e m o r y and i n t e r e s t in life declined; his mouth and gums developed s i g n s of inflammation. After 18 months of employment, he complained of lightheadedness, d e c r e a s e d visual acuity, and impairment of night vision. Progressively, insomnia and s l u r r i n g of speech evolved as well a s a disturbance of the body equilibrium with ataxia, unsteady gait, and t r e m o r s that s e v e r e l y interf e r e d with both eating and drinking. Toward the end of the two-year employment, the disabilities had advanced to such an extent that ataxia and general weakness prevented his standing unassisted, and involuntary jerking movements o c c u r r e d even at rest. On hospital admission, the patient also displayed skin eruptions on legs and hands a s well as a blue-purple line along the margin of the upper gum. T e s t s revealed an intelligence bordering on low norm a l and a defective memory. Impairment of vision manifested in a constriction of the visual field, in poorness of c o l o r and depth p e r ception, and in difficulties with both visual fixation and the counting of objects a t low illumination. A hearing l o s s of 20 to 30 dB ranged throughout the e n t i r e frequency spectrum. Together with an inability to balance the body and t o maintain equilibrium, the patient constantly displayed b i z a r r e movements of the fingers and a sideways t r e m o r on finger-to-nose and heel-to-shin tests. As demonstrated by pneumoencephalography, the c e n t r a l nervous s y s t e m was afflicted with widespread anatomical abnormalities-enlargement of the ventric l e s , shrinkage of the frontal lobe, and reduction in size of the c e r e bellar s u p e r i o r v e r m i s . After an initial improvement in the first two weeks of hospital stay, the patient again developed s e v e r e motor disorders-periodic hyperextensions of trunk and pelvis, waves of myoclonus traveling down the limbs-which prevented walking, sitting, and the use of hands. Then, treatment was s t a r t e d with N-acetyl-D,L-penicillamine, comprising four c o u r s e s o v e r a ten-week period. During this t i m e span, disabilities gradually subsided-the gait became n o r m a l ; the right hand regained a steady grip; the acuities of both vision and hearing returned to n o r m a l levels; and the intelligence showed such an improvement that the performance approached the p a t i e n t ' s high school t e s t results. Nine months l a t e r , the only remaining motor disturbances consisted of fine jerking movements of head, right a r m , and legs. Between days 20 and 80 in the hospital, m e r c u r y concentrations showed the following changes: cerebrospinal fluid-initial values of 7.5 & l o 0 m l fell rapidly below detectable levels; blood plasmainitial values of 5 to 7 p g / l O O m l d e c r e a s e d in a n e r r a t i c c o u r s e , finally ranging from 0 to 2 pg/lOO m l ; feces-initial excretion of 1000 pg/day gradually declined t o 50 pg/day; urine-initial excretion between 2000 and 8600 pg/24 h r slowly fell to about 600 pg/24 h r . The preceding case history-described m o r e extensively in Ref. [3]-points out s e v e r a l aspects. First, s e v e r e cases of damage to



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the central nervous system s t i l l occur occasionally in rare situations where mer cur y is handled carelessly. Second, even in these e x t r e m e situations, signs of intoxication have an insidious beginning, slowly progressing throughout many months until total incapacitation is reached. And third, through removal from the toxic environment and through suitable therapy, the disabilities can be ameliorated to a l a r ge extent, and the patient can be res t o red sufficiently to lead a useful life; but s ome residual impairment remains because the central nervous system is basically unable to replace those nerve cells that have been destroyed by the toxic action of mercury. INORGANIC MERCURY COMPOUNDS Because they a r e ubiquitous components of the environment, inorganic mercury compounds daily en t er the human body through food and beverages as well as through dust in the inhaled air. T h e i r concentration and solubility, however, are generally s o s m a l l that v e r y minute amounts pass into the bloodstream with very little penetration of blood-brain and placental b arri ers . A s a consequence, these substances attain toxic levels only under rare conditions where mishaps lead to occupational overexposure and where large quantities are ingested either accidentally o r intentionally. In the l a t t e r cases, the comparatively mo re soluble m ercu ri c compounds a c t immediately upon the mucosa from mouth to stomach, causing n e c r o s i s and bleeding. Later, additional pathologic changes develop at m a j o r points of mercury excretion-the lower gastrointestinal t r a c t and the renal system. Hence, the classical picture of inorganic m e r c u r y poisoning comprises a superimposure of disturbances mainly stemming from injuries to alimentary canal and kidneys. Acute Intoxication Cas e History No. 3 In a suicide attempt, a 20-year-old woman ingested 1.5 gm of m er cur ic chloride. She vomited almost immediately and underwent gastric lavage within one hour. The next day, treatment with BAL (British anti-lewisite: 2,3-dimercapto- 1-propanol) was s t a r t e d a t a dose schedule of 125 mg every 4 hr. The patient's pharynx displayed edema and redness; vomitus now consisted mainly of blood; the stool became tar r y from bleeding into the gastrointestinal t r a c t ; abdominal distension developed as well as tenderness to touch; and urinary output fell below 500 m1/24 h r, the minimal amount required f o r elimination of all nitrogenous waste products from the body. Over a period of five days af ter poisoning, the general condition-as well as reten-


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tion of waste products and upset of electrolyte balance-deteriorated and reached finally the point that repeated hemodialysis with an a r t i ficial kidney became necessary. Gradually, the urinary output rose, surpassing normal values on the fifteenth day. Thereafter, recovery proceeded uneventfully. The preceding case history-described m o r e extensively i n Ref. [4] -points out s e v e r a l a s p e c t s of acute poisoning from inorganic m e r c u r i c salts. F i r s t , moderate f o r m s a r e dominated by signs centering around the alimentary t r a c t , primarily comprising inflammation, ulceration, and hemorrhage. Second, renal injury reveals itself in a s h a r p decline of urinary output with a corresponding rise of waste products in the blood and a disturbance of the electrolyte balance. Third, when proper treatment carries the patient through the c r i t i c a l phase of kidney failure, complete recovery ensues, leading not only to a restoration of normal renal function but a l s o to the healing of the gastrointestinal lesions. Case History No. 4 In a moment of despondency, a 35-year-old man ingested 10 gm of m e r c u r i c chloride. One hour a f t e r taking the poison, the patient was s t a r t e d on BAL treatment; subsequent to an initial dose of 350 mg, he received 125 mg every four hours. In spite of the treatment, the clinical picture grew progressively worse. Lesions of the alimentary t r a c t included massive stomatitis, ulcerative esophagitis, gastritis, and necrotizing colitis with bloody diarrhea. The abdomen became m o r e and m o r e distended and tender. Renal failure manifested in a s h a r p decline of urinary output, leading to uremia; the blood showed rising levels of waste products-urea, u r i c acid, creatinine-and a growing imbalance of electrolytes. On the eighth day, the patient's condition had deteriorated to such a d e g r e e as to require hemodialysis. After a brief temporary improvement, the patient relapsed into a gravely ill state necessitating peritoneal dialysis. Once m o r e , r e covery was only brief, followed by deterioration and death on day 17 a f t e r poison ingestion. Histologic examination of the kidneys revealed acute tubular necrosis with signs of regeneration as well as focal interstitial nephritis. Mercury a s s a y s yielded the following results: renal tissue, 19 pg Hg/gm, and hepatic tissue, 63 pg Hg/gm. The preceding c a s e history-described m o r e extensively in Ref. [4] -points out an important aspect of s e v e r e m e r c u r i c poisoning. Although lesions of the alimentary t r a c t constitute prominent components of the illness, the clinical c o u r s e and ultimate outcome are determined by renal function. When destruction of tubular epithelium in the kidneys is too widespread to be repaired through regenerative processes, renal failure leads to progressive u r e m i a and death.


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Epidemiologic Example A n epidemiologic study was performed on adult Africans suffering from the nephrotic syndrome, a s indicated by the following findings: swelling of face and legs, normal blood p r e s s u r e , high urinary protein concentrations ranging from 1 . 5 to 20 gm/liter, and c h a r a c t e r istic electrophoretic s e r u m profiles showing a marked i n c r e a s e in alpha-2 globulin together with a significant d e c r e a s e not only of albumin but a l s o of the alpha- l , beta, and gamma globulins. Compared with the general hospital population, the nephrotic group was much younger, much better educated, and predominantly female. Examination of the past history revealed that 70% of the women with renal impairment were using-or had used-skin-lightening c r e a m s containing aminomercuric chloride in amounts from 5 to 10%. In the average, about one year had elapsed between f i r s t application of the cosmetic preparation and the onset of edema i n face and legs. Among the general hospital population, urinary m e r c u r y excretion had a mean value of 6 pg/liter with an upper limit of 80 pg/liter. In those nephrotic patients who still applied skin-lightening c r e a m , urinary m e r c u r y excretion was elevated significantly, ranging from 90 to 250 pg/liter and yielding a mean value of 150 pg/liter. In nephrotic patients who had discontinued the use of such c r e a m s , urinary m e r c u r y concentrations ranged from 0 to 90 yg/liter with a mean value of 29 &liter. These epidemiologic findings strongly incriminated aminomercuric chloride as the causative agent of the nephrotic syndrome in a l a r g e number of patients. This incrimination was further strengthened by the subsequent clinical course. Within 3 to 11 months a f t e r discontinuing the u s e of suspect c r e a m s , 50% of the patients recovered spontaneously and completely-edema as well as proteinuria disappeared and the electrophoretic s e r u m pattern became normal. The preceding epidemiologic study-described m o r e extensively i n Ref. [5] -underlines the repeatedly stated fact that long-term topical application of mercury-containing preparations may not be h a r m l e s s and that their use in modern cosmetics and pharmaceuticals requires careful monitoring.

ORGANIC MERCURY COMPOUNDS Organoniercurials vary widely in molecular s t r u c t u r e , and their fate i n the human body v a r i e s accordingly. Almost all are excreted quickly, e i t h e r unchanged o r modified through metabolic p r o c e s s e s .


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Hence, in general, these compounds pose no s e r i o u s health problem. But short-chain a k y l derivatives are an exception. Methylmercury in particular is highly dangerous because of its p r e s e n c e in food, i t s low toxic threshold, its slow excretion r a t e , its r e s i s t a n c e against metabolic alteration, and its capability of penetrating both bloodbrain and placental b a r r i e r s which entails injurious action upon the c e n t r a l nervous s y s t e m not only in the adult but a l s o in the fetus. From the standpoint of public health, the problem of organomercurials thus reduces itself essentially to that of methylmercury. I n d i v i d u a l C a s e s of t h e M e t h y l m e r c u r y S y n d r o m e in Adults C a s e History No. 5 After graduating from a technical school with distinction--"a student of m o r e than average ability"-the 16-year-old adolescent s t a r t e d work as a laboratory a s s i s t a n t in a plant manufacturing m e r c u r y compounds. He handled various o r g a n o m e r c u r i a l s including methylmercury iodide, nitrate, and phosphate. While at his place of work-which had no spec i a l ventilation-he wore a mask and gloves. After about t h r e e months of employment, he experienced sensations of "funny numbness" which s t a r t e d in his fingers and toes and then s p r e a d a c r o s s h i s hands and feet. As t i m e passed, the numbness became m o r e intense, finally interfering with buttoning and unbuttoning of clothes. During the fourth month, his amiable and courteous disposition changed strikingly, giving way to irritability and abusive language. Almost simultaneously, h e encountered difficulties in speaking and a l s o in understanding o t h e r s . In addition, although he could c l e a r l y s e e printed l e t t e r s , h i s reading speed d e c r e a s e d progressively; p e r i p h e r a l vision-especially of moving objects-also declined noticeably. Toward the end of the fourth month, he became highly i r r i t a b l e and m o r o s e , walked with staggering gait, and handled knife and fork clumsily at meals. P r e s s u r e d by h i s mother, h e finally entered the hospital. On admission, the patient was a f e b r i l e and had no abnormalities of the respiratory, cardiovascular, and gastrointestinal s y s t e m s . Neurologic examination yielded the following findings: speech- slow and s l u r r e d ; hearing-diminished bone conduction with understanding of slow but not of quick speech; vision-gross peripheral constriction of visual fields; cranial nerves-sense of position sharply reduced in tongue, nose, and lips; upper extremities-moderate spasticity and marked incoordination; sensation-gross postural l o s s in fingers, toes, and face, causing an inability to distinguish between a coin and a bundle of keys by touch alone. All laboratory tests yielded n o r m a l r e s u l t s with the exception of elevated m e r c u r y levels in the urine. The patient' s condition deteriorated steadily throughout the f i r s t two months of hospitalization. Showing no i n t e r e s t in h i s surroundings,



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h e slept almost all day, lying curled up on his right s i d e , completely helpless and apathetic. Ataxia became s o s e v e r e as to prohibit the performance of even the simplest volitional movements. Attempts a t speaking produced explosive vowel sounds which r a r e l y could be understood. After this phase of deterioration, the patient improved slowly and was entered into a vigorous program aiming a t physical and speech rehabilitation. During the eighth month, he regained the ability to walk without a s s i s t a n c e ; his speech improved to such an extent that about half of h i s words were understandable; he e x p r e s s e d keen interest i n everything around him; memory and intellect showed only little clouding; and his disposition reflected again a ready s e n s e of humor and a considerable d e g r e e of charm. Toward the end of the second y e a r a f t e r s t a r t of the illness, the patient had recovered sufficiently to d r e s s and to feed himself, but all movements still showed s e v e r e ataxia; handwriting was scrawling and unsteady. Though hesitant and explosive, his speech now could be understood easily. Nevertheless, neurologic examination revealed that the original defects p e r s i s t e d undiminished. The striking improvement thus resulted from the patient' s strong motivation and from the vigorous rehabilitation program. When seen 15 y e a r s later, the patient appeared unchanged, showing neither deterioration n o r f u r t h e r improvement. The preceding c a s e history-described m o r e extensively in Ref. [6] -points out s e v e r a l a s p e c t s of the methylmercury syndrome: 1. Insidious onset. 2. Almost complete confinement to t h e central nervous system.

3. Long duration of clinical sequelae. 4. Guarded prognosis with respect to complete recovery. 5. Hunter, Bomford, and Russell' s [6] remarkable recognition and description of the clinical entity, antedating by many y e a r s the outbreak and identification of the cause of "Minamata disease.

C a s e History No. 6

For two y e a r s p r i o r to hospital admission, the 23-year-old patient had been employed in a chemical plant manufacturing m e r c u r y compounds. He f i r s t handled inorganic m a t e r i a l ; however, during the last four months of employment, he participated in the production of s e e d d r e s s i n g which involved exposure to d u s t s of both methylmercury phosphate and nitrate. Toward the end of that time, he noticed s e v e r a l bothersome developments-namely, difficulties of "seeing around c o r n e r s " and "seeing a t the sides"; feelings of numbness in the tips of tongue and fingers which s p r e a d up the a r m s ; slowness and "thickness" of speech; unsteady gait; jerky movements; and c l u m s i n e s s of hands. After hospitalization, the patient deteriorated progressively f o r five weeks, turning into a n apathetic "slobbering moron" who was neither able to walk and to feed himself n o r to speak a n intelligible


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word. Subsequently, he entered a phase of slow recovery which, however, soon ended on a static level. Even after undergoing three years of physical therapy and speech training, the patient still remained totally disabled-incapable of unaided walking and self- feeding, incapable of uttering more than a few explosive sounds that scarcely were recognizable as words. When 38 years old, the still disabled patient died of heart failure due to hypertension and myocardial infarction. Autopsy revealed that the principal pathologic changes-aside from heart disease with associated complications-were confined almost exclusively to the central nervous system. The brain showed macroscopically an atrophy of convolutions which was most pronounced on the medial aspects of both right and left occipital lobes, particularly around the anterior ends of the calcarine fissure. Small foci of atrophy were scattered widely throughout the rest of cortex including primary motor a r e a s as well as temporal and frontal lobes. Microscopically, atrophied regions appeared more o r less denuded of neurons, while surviving nerve cells often displayed a shrunken and distorted configuration. Chiefly affecting the depth of sulci rather than the summits, foci of atrophy merged quite abruptly into adjacent normal cortex. Though greatly reduced in bulk, subcortical white matter revealed no evidence of progressive degeneration. Macroscopically the cerebellum also displayed a r e a s of gross atrophy that particularly involved folia occupying the depth of sulci in both right and left lateral lobes. Microscopically, these atrophied parts appeared a s follows: severe destruction of the granule cell layer, relatively normal Purkinje cell layer, and narrowing of the molecular cell layer. Being most pronounced at the depth of sulci, these pathologic changes gradually merged into a n almost normal cortex on the cerebellar surface. The preceding case history, described more extensively in Refs, [6] and [7], presents the first portrayal of morphologic changes associated with human methylmercury poisoning, which may be summarized as follows: Far from causing a diffuse and generalized encephalopathy, methylmercury shows high selectivity in its toxic action, preferentially destroying the optical cortex a s well as certain parts of the cerebellum. Other cortical a r e a s a r e affected to a much l e s s e r degree and only in sharply localized spots. Spinal cord and peripheral nerves show no pathologic changes. These morphologic findings readily explain the main features of the clinical picture.


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I n d i v i d u a l C a s e s of P r e n a t a l M e t h y l m e r c u r y In tox i cation


C a s e History No. 7 In August 1969, s i x f a r m e r s living n e a r Alamagordo, New Mexico, acquired w a s t e products f r o m a local g r a n a r y f o r u s e as a n i m a l feed. Obtained through floor sweeping and screening, the w a s t e m a t e r i a l c o m p r i s e d a mixture of chaff, sorghum, oats, and o t h e r g r a i n s that had been t r e a t e d with fungicides containing methylmercury. In late August o r e a r l y September, one of the f a r m e r s s t a r t e d t o feed this m a t e r i a l to h i s pigs. After about t h r e e weeks of feeding, a hog was slaughtered, and the f a r m e r ' s family a t e the meat f o r m o r e than t h r e e months. Fourteen f e e d e r pigs that had received s m a l l e r quantities of the waste m a t e r i a l became s e v e r e l y s i c k by the middle of October. The pigs suffered from blindness, lack of m u s c l e coordination, and p a r a l y s i s of hind legs. Within the next t h r e e weeks, 12 of the a n i m a l s died; the two s u r v i v o r s remained permanently blind and stunted, showing only p a r t i a l improvement of m u s c l e coordination and gait. When the f a r m e r slaughtered the hog, h i s 40-year-old wife was i n h e r third month of pregnancy. Consumption of contaminated m e a t thus extended throughout the second t r i m e s t e r of gestation. P r e n a t a l examinations during the seventh and eighth months of pregnancy yielded essentially n o r m a l findings: the m o t h e r suffered f r o m neither neurologic n o r visual deficiencies; however, s h e exc r e t e d significantly i n c r e a s e d amounts of m e r c u r y with the urine. At t e r m , the f a r m e r ' s wife gave b i r t h to a male infant weighing 3062 gm. Within one minute a f t e r delivery, the baby began to exhibit dusky discoloration of skin, g r o s s tremulous movement of e x t r e m i t i e s which o c c u r r e d intermittently, and weak cries of high pitch. Aside from these unusual features, the infant a p p e a r e d n o r m a l on neurologic examination, including electroencephalography and electromyography. Urinary m e r c u r y concentrations a f t e r birth w e r e as follows: f i r s t day, 2.7 pg/liter; fourth day, 2.0 pg/liter; and s i x t h week, 0.01 gg/liter. To avoid any t r a n s f e r of m e t h y l m e r c u r y through m a t e r n a l milk, b r e a s t feeding was not permitted. Starting around the third month, abnormalities e m e r g e d in the electroencephalogram that gradually p r o g r e s s e d in intensity, reaching a s e v e r e epileptoid pattern a t the eighth month of age. At that t i m e , the infant was hypotonic and i r r i t a b l e , displaying p a r o x y s m s of myoclonic jerking; nystagmoid e y e movements and lack of evidence f o r visual fixation strongly suggested blindness. Neurologic examination of the 16-month-old infant revealed that development had been a r r e s t e d on the three-month level; hypotonia, myoclonic j e r k s , and epileptoid

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electroencephalograms s t i l l persisted; visual stimuli triggered no responses a t all. The preceding case history, described m o r e extensively in Refs. [8- l o ] , underlines an important point. Though limited in time and i n effect on the mother, methylmercury ingestion during pregnancy had a devastating effect upon the c e n t r a l nervous system of the fetus, causing mental retardation, blindness, and s e v e r e motor d i s o r d e r s in the child. C a s e History No. 8 Shortly before birth of the female infant, h e r father died of "Minamata disease." With the exception of occasional feelings of numbness, h e r mother remained in good general health throughout the entire pregnancy. The child was born about one month prematurely, weighing 2250 gm. Four weeks of b r e a s t feeding were followed by seven months of bottle feeding and then by weaning. The infant never r e ceived either fish o r shellfish. At the age of one y e a r and four months, the patient appeared as a poorly nourished and underdeveloped little g i r l with a s m a l l head circumference. Her four extremities displayed spastic p a r a l y s i s and exaggerated tendon reflexes that prevented the performance of any useful volitional movements, such as turning o v e r during sleep or crawling along the floor. Even bright light triggered only barely noticeable pupillary reactions i n h e r eyes. Moreover, s h e suffered from s e v e r e mental retardation, uttering nothing but a few unintelligible sounds. At the age of two y e a r s and s i x months, the patient died in s t a t u s epilepticus with v e r y high fever. Autopsy detected no significant pathologic changes in either thor a c i c o r abdominal organs, but the brain was s m a l l , weighing only 650 gm as compared with the normal 960 gm. On g r o s s inspection, the c e r e b r a l hemispheres appeared underdeveloped; particularly conspicuous was a n atrophy of the folia; c e r e b r a l and c e r e b e l l a r white m a t t e r w e r e markedly reduced in bulk. Microscopic examination uncovered a widespread disorganization of cellular architecture, diffusely affecting virtually the e n t i r e cortex of the two hemispheres. This disorganization stemmed mainly from a s h a r p decline in the number of nerve cells and their replacement by proliferating microglia. Furthermore, many of the visible nerve c e l l s showed signs of degeneration. In the cerebellum, the atrophic folia displayed not only s e v e r e destruction of the granule cell l a y e r but a l s o narrowing of the molecular cell l a y e r and reduction of elements in the Purkinje c e l l layer. The brain s t e m and its nuclei as well as the spinal cord appeared essentially normal. The preceding case history, described m o r e extensively in Ref. [ l l ] ,elucidates two points. Above all, it underscores once m o r e the


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fact that though methylmercury ingestion during pregnancy may produce only mild intoxication in the mother, the developing fetus may s u f f e r i r r e p a r a b l e damage. With one exception, this observation applies to 20 additional c a s e s in the Minamata series. Second, i t r e v e a l s a widespread destruction of n e r v e c e l l s , particularly afflicting the c e r e b r a l c o r t e x and the c e r e b e l l a r folia. T h e s e morphologic changes explain not only the clinical picture of prenatal methylm e r c u r y intoxication but a l s o i t s poor prognosis. E p i d e m i c O u t b r e a k s of M e t h y l m e r c u r y P o i s o n i n g Epidemiology of "Minamata Disease" Situated on the southernmost main island of Japan, Minamata is a s m a l l town with a chemical plant as i t s m a j o r industry. Effluent from the plant empties directly into Minamata Bay, a body of w a t e r that washes a shoreline settled by s e v e r a l villages. Among villagers, the majority of adult m a l e s are fishermen who mostly c a r r y out t h e i r profession a t night. On the r e t u r n of the men in the morning, the family has breakfast of r a w o r cooked fish. Often, o t h e r m e a l s d u r ing the day a l s o include freshly caught fish and shellfish from the bay. Starting in 1953, a "mysterious nervous illness" began to e m e r g e within the populations n e a r the bay; dominant f e a t u r e s of the clinical picture comprised numbness of e x t r e m i t i e s and mouth, s l u r r e d speech, unsteady gait, "tunnel 'vision," and hearing difficulties. By 1956, the outbreak reached epidemic proportions and the public health d e p a r t ment had recorded 52 patients belonging to 40 families [12]. In a l m o s t all of these c a s e s , a t l e a s t one m e m b e r of the family was a fisherman. Neighboring households, where nobody fished o r where fish was not eaten regularly, showed no s i g n s of the disease. Among the 52 originally reported c a s e s , the clinical c o u r s e proceeded a s follows: 17 patients died; the s t a t u s of 23 patients became stationary with permanent disablement; nine patients improved; and only t h r e e patients w e r e able to r e s u m e work within s i x months a f t e r onset of the illness. Distribution of the d i s e a s e and i t s relation to individual eating habits led to the conclusion, as of November 1956, that the outbreak resulted from a n unknown toxic agent in fish and that fishing should b e prohibited. By 1961, when the causative agent in fish had been identified as methylmercury, which could be t r a c e d back to the effluent from the chemical plant, the public health r e c o r d s showed 49 additional cases of the disease. Ten y e a r s after the outbreak of the illness, reexamination of 26 c a s e s yielded the following findings [ 13, 141 : visual field constriction, only a few patients showed mild improvement; hearing l o s s , 16 patients improved, particularly in the high frequency range; ataxia, the majority of patients showed m o d e r a t e recovery; numbness, five patients regained n o r m a l feeling, while the remaining 2 1 experienced


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partial return of sensation; changes in c h a r a c t e r and mentation, most patients faded markedly over the ten-year period, with almost all victims still disabled to such an extent that they could not lead an ordinary life. Among the 121 recorded Minamata c a s e s , 23 patients suffered from prenatal intoxication; of these, t h r e e died and the 20 survivors retained various degrees of permanent impairment. Between 1965 and 1970, another outbreak of methylmercury poisoning occurred among the families of fishermen in Niigata, Japan; 47 c a s e s were reported; s i x of the patients died. Epidemiology of Methylmercury Poisoning Through Dressed Seed Grain The danger of contaminating human food with methylmercury, which aroused public concern after the Japanese incidents, received even s t r o n g e r emphasis through s e v e r a l epidemics of poisoning by antifungal seed dressings. During the wheat-planting season of the y e a r s 1963, 1964, and 1965, a strange d i s e a s e afflicted f a r m e r s in Guatemala [ 151% They and memb e r s of their families suffered from visual impairment, hearing loss, locomotor d i s o r d e r s , and mental disturbances. Forty-five c a s e s , including 24 children under ten y e a r s of age, were reported; 20 of the patients died. The tentative diagnosis of v i r a l encephalitis could not be confirmed; laboratory tests yielded negative r e s u l t s f o r Venezuelan equine encephalitis, St. Louis encephalitis, and Oriental encephalitis. Finally, an autopsy revealed that the victims' t i s s u e s contained l a r g e amounts of methylmercury, which unmasked the t r u e diagnosis, organomercurial poisoning. Throughout the planting season, the f a r m e r s expanded their scarce daily food supply by the addition of s u r p l u s s e e d wheat that had been treated with methylmercury-containing antifungal preparations. During 1969, an almost identical incident o c c u r r e d in the farming d i s t r i c t s of Pakistan [ 161. In 1960, under circumstances v e r y s i m i l a r to those described in the preceding paragraph, an epidemic of methylmercury poisoning broke out among r u r a l populations of Iraq. The s p r e a d of d i s e a s e assumed disastrous proportions, involving m o r e than 1000 persons, necessitating a t least 370 hospital admissions with a mortality r a t e from 30 to 40%, and inflicting permanent injury to the majority of s u r vivors. Without exception, the households of victims baked their own bread, using flour from surplus s e e d wheat that had been treated with a n antifungal methylmercury compound. But the most catastrophic and best-documented outbreak of methylm e r c u r y poisoning occurred throughout the r u r a l d i s t r i c t s of I r a q in 1972. From October through November of the preceding year, the nation imported large quantities of seed wheat and barley that had been treated with a n antifungal methylmercury compound. This grain was distributed to g r a n a r i e s in all provinces of the country where



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local f a r m e r s received sufficient amounts for spring planting. Despite official warnings, surplus grain again was ground into flour and baked into bread. After a latent period of s e v e r a l weeks, toxic effects became evident; the poisoning culminated during January 1972 when daily hospital admissions rose to s ev e r a l hundred c a s e s . From a total number of 6530 hospitalized victims, 500 died; death could be attributed solely to methylmercury poisoning in 459 patients. The still ongoing epidemiologic studies thus far yielded the following important findings [ 161 : a. The chief o r sole cause of poisoning was consumption of homemade bread that had been prepared from grain treated with a methylmercury fungicide as identified by gas chromatography. Rather reliable estimates of individual intakes became possible through the fact that all farming families employed nearly the s a m e method for baking loaves of unleavened bread that weighed approximately 200 gm with 30% moisture content; the mean mercury concentration of flour amounted to 9 pg/gm; hence, each loaf contained about 1.3 mg of mercury. For a n y person, the ingested amount of methylmercury thus could be estimated from daily bread consumption; these estimates agreed quite well with the mercury level in blood. Roughly, 1 mg of ingested methylmercury caused the blood concentration to rise by 1 pg/lOO ml. b. The clinical threshold, onset of numbness, was reached in adults a t body burdens between 25 and 40 mg; a t 200 mg, death began to occur; the mortality rat e then increased rapidly with dose. In children, the corresponding values were considerably lower, presumably depending on body weight. c . Relation between mercury concentrations in h a i r and severity of clinical pictures was as follows [17] : 10 to 120 to 200 to 400 to

300 pg/gm-no detectable clinical effects; 600 pg/gm-mild intoxication; 800 pg/gm-moderate intoxication; 1600 pg/gm-severe intoxication.

The wide overlap of ranges presumably sprang from broad variations in individual susceptibility, which was unrelated to both s e x and age. d. The latent period, extending from s t a r t of ingestion to onset of illness, differed greatly among individual persons, varying between two weeks and one month o r even longer. This deceptive interval gave a false s ens e of security, encouraging the farming families to consume contaminated bread over such a long span of time that they accumulated dangerous o r even lethal amounts of methylmercury before onset of sickness. A s a general rule, severity of intoxication increased with length of latent period. e. Methylmercury concentrations i n human milk amounted to 3%


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of the m o t h e r ' s blood level. In certain instances, b r e a s t feeding contributed significantly to the body burden of infants. f. The clearance r a t e of methylmercury from the blood a l s o showed wide individual variations. An acceleration of the p r o c e s s was attempted through o r a l administration of D-penicillamine o r N A P and through the ingestion of a thiol resin [ 181. Efficacy of these agents differed between patients; however, even those patients who reacted with a significant d r o p in methylmercury concentrations in blood did not experience any dramatic clinical change. g . Starting about two to t h r e e months a f t e r cessation of methylm e r c u r y ingestion, the clinical condition of patients improved. Bedridden victims learned to walk again, but generally, t h e r e was a persistence of numbness and ataxia as well a s of other characteristic signs. Supported by a grant from t h e Swedish International Development Authority, a conference on "Intoxication Due to Alkylmercury Treated Seed" took place at Baghdad, Iran, November 9- 13, 1974 [ 191. Individual presentations as well as general discussions reviewed the Iraqi epidemic of 1971-72, including two-year follow-up studies. Briefly summarized, the most important new findings comprised the following observations: Most of the patients who had suffered from mild o r moderate deg r e e s of intoxication improved greatly; however, it could not be ascertained whether this improvement reflected the patient' s learning to compensate f o r residual neurologic defects. The need f o r vigorous rehabilitation p r o g r a m s was s t r e s s e d repeatedly. Prenatally exposed infants, on the contrary, showed no appreciable improvement; at two y e a r s after exposure, manifestations of methylm e r c u r y poisoning became evident in many infants who previously had been classified as healthy. Jernelov and Shahristani [ 191 reported on a study involving 80 symptom-free children in which the m e r c u r y content of h a i r was compared with school performance. They found a close i n v e r s e c o r r e l a tion; the cause remained questionable, being e i t h e r subclinical methylm e r c u r y intoxication o r a d v e r s e psychosocial conditions in families that were affected s o s e v e r e l y as to offer poor opportunities f o r successful homework. Farman [19] reported on chromosomal studies comparing 65 methylmercury patients with 30 normal controls. The blood level of mercury ranged from 30 to 450 %/lo0 m l in patients and from 0.1 to 2.0 pg/lOO ml in controls. After preparation of lymphocyte cultures 5741 individual c e l l s were analyzed cytogenetically. In patients, 6.5% of the c e l l s displayed isochromatid-type a b e r r a t i o n s during metaphase; i n controls, the corresponding value amounted to 5.4%; the difference was not significant statistically. Moreover, the frequency of aneuploidy showed no difference between the two groups. Blood m e r c u r y levels and frequency of cytogenetic aberrations w e r e not correlated.



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In his summary of the conference, Skerfving 1191 included a brief statement about therapeutic experiences. Treatment with BAL led to a deterioration of patients suffering from s e v e r e degrees of the methylmercury syndrome. Treatment with D-penicillamine, Nacetyl-DL-penicillamine, unithiol, and polythiol resin caused both a slight d ecreas e in the m ercu ry level of blood and a moderate inc r e a s e i n that of urine; the presentations furnished neither data demonstrating an appreciable effect on the body burden n o r comparative studies showing a difference between clinical c o u r s e s of treated and untreated patients. Extracorporeal hemodialysis with addition of cysteine definitely reduced the body burden and seemed to be a promising method fo r hospitals possessing the necessary equipment. E p i d e m i c O u t b r e a k s of P o i s o n i n g s b y O r g a n o mercurials Other than Methylmercury Ethylmercury-p-Toluene Sulfonanilide During the planting season of 1955-1956, f a r m e r s in northern Iraq received wheat seed that had been treated with ethylmercury-p-toluene sulfoanilide. After exhaustion of their own food stocks, they ground the d res s ed grain into flour for the preparation of homemade bread constituting the major portion of their daily diet. Numerous cases of intoxication occurred; m o re than 100 patients were admitted to a large hospital where 14 died. During the planting season of 19591960, very s imil ar circumstances triggered another outbreak of poisoning in the central part of Iraq, involving a large number of persons, necessitating the admission of 221 patients to one hospital in Baghdad alone, and inflicting a high death rate. Based on the examination of 26 hospitalized patients, a clinical picture emerged with the following dominant features 1201 : kidneys, polyuria, polydipsia, and mild proteinuria; skin,pruritus often progressing to exfoliative dermatitis, especially on hands and feet.; gastrointestinal tract, epigastric o r hypogastric pain frequently associated with nausea and vomiting; heart, electrocardiographic abnormalities in sev ere cas es ; musculoskeletal system, generalized and often excruciating deep pain in muscles and bones, fasciculation and c o a r s e twitching of muscles, rarely numbness o r paresthesia; vision, impairment in 30% of the patients, often with optic nerve atrophy; central nervous system, ataxia usually without t rem o rs , difficulties in walking, s l u r r e d speech, mentation generally not affected; latent period, a few days to one o r two months, primarily depending on daily ingestion of contaminated bread. Although preexisting conditions, especially ankylostomiasis and malnutrition, possibly exerted an influence on many patients, the above outlined clinical picture of ethylmercury poisoning differs distinctly from

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the methylmercury syndrome. Particularly with ethylmercury' s strong involvement of kidneys, skin, and gastrointestinal tract, the disease displays facets that are much m o r e characteristic of subacute poisoning by inorganic mercury.


Mixture of Phenylmercury Acetate and Ethylmercury Chloride During the planting season of 1960- 1961, f a r m e r s in s e v e r a l dist r i c t s of Pakistan received s e e d wheat that had been treated with a mixture of phenylmercury acetate and ethylmercury chloride. Starting around the middle of February, a "mysterious disease" erupted among the farming population, mimicing a v i r a l infection and afflicting at least 100 persons. By March, an epidemiologic study unequivocally identified the d i s e a s e as m e r c u r y poisoning. Based on examination of 34 patients who were hospitalized at Peshawar, the characteristic clinical picture emerged as follows [21] : Typically, patients became ill a f t e r approximately t h r e e weeks of eating contaminated wheat, first complaining about malaise, fatigue, and lethargy. Several days l a t e r , they a l s o suffered from burning sensations in mouth and stomach, epigastric pain, nausea and vomiting, l o s s of appetite, as well as from excessive thirst and fever. Throughout three weeks a f t e r onset, the d i s e a s e advanced in severity and extent, including now a progressive weakness of limbs, an impairment of both vision and speech, as well as a slowing down of mentation. Autopsy uncovered major pathologic changes only in kidneys, liver, and gastrointestinal t r a c t but not in c e r e b r u m , cerebellum, and spinal cord. The incident in Pakistan illustrates that, when ingested, the mixt u r e of phenylmercury and ethylmercury provokes clinical pictures and morphologic lesions that closely resemble those seen in subacute poisoning by inorganic m e r c u r y r a t h e r than those found within the methylmercury syndrome. This observation underlines the fact that toxic actions of organomercurials strongly depend on chemical s t r u c t u r e and that methylmercury holds an exceptional position concerning hazards to human health. SUMMARY To illustrate the various clinical pictures resulting from toxic effects of m e r c u r y and its compounds, highlighted l i t e r a t u r e excerpts have been prepared and arranged in a logical sequence. P a r t i c u l a r emphasis is placed upon e a r l y diagnosis and prevention of epidemic outbreaks involving intoxication through organomercurials.


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ACKNOWLEDGMENTS


For p r o f e s s i o n a l advice and s u p p o r t , the a u t h o r s e x p r e s s s p e c i a l thanks to H a r o l d C. Hodge, University of California; G e r a l d U. Ulrikson, Oak Ridge National L a b o r a t o r y ; and Henry M. K i s s m a n , National L i b r a r y of Medicine.

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GERSTNER AND H U F F T. Takeuchi, "Biological Reactions a n d Pathological C h a n g e s in Human Beings a n d A n i m a l s C a u s e d by O r g a n i c M e r c u r y Contamination , I ' in E n v i r o n m e n t a l M e r c u r y Con t a m inat ion (R. Hartung a n d G. Dinman, eds.), Ann A r b o r Science P u b l i s h e r s , Ann A r b o r , Michigan, 1972, pp. 247-289. J. V. Ordonez, J. A. C a r r i l l o , M. M i r a n d a , and J. L. Gale, Estudio epidemiologico d e una e n f e r m e d a d c o n s i d e r a d a c o m o e n c e f a l i t i s e n la region d e 10s Altos G u a t e m a l a , Boll. Off. Sanit. P a n a m . , 60, 510 (1966). F. B a k i r z . F. Damluji, L. Amin-Zaki, M. Mrutadha, A. Khalidi, N. Y. Al-Rawi, S. T i k r i t i , H. I. Dhahir, T. W. C l a r k s o n , J . C. Smith, and R. A. Doherty, M e t h y l m e r c u r y poisoning in Iraq: a n i n t e r u n i v e r s i t y r e p o r t , S c i e n c e , 181, 230 ( 1973). H. Al-Shahristani a n d I. K. Al-Haddad, M e r c u r y content of h a i r f r o m n o r m a l and poisoned p e r s o n s , R e p o r t No. PH- 15, N u c l e a r R e s e a r c h Institute, Tuwaitha Baghada, I r a q , 1973. T. W. C l a r k s o n , H. S m a l l , a n d T. N o r s e t h , E x c r e t i o n a n d a b s o r p tion of m e t h y l m e r c u r y a f t e r polythiol r e s i n t r e a t m e n t , Arch. Environ. Health, 26, 173 (1973). WHO (World Health Organization), C o n f e r e n c e on intoxication due t o a l k y l m e r c u r y t r e a t e d s e e d , Final R e p o r t VBC/74.7, 1975. M. A. Jalili a n d A. H. Abbasi, Poisoning by ethyl m e r c u r y toluene sulphonanilide, Brit. J. Ind. Med., 18,303 (1961). I. U. Haq, Agrosan poisoning in m a n , B r i t . Med. J., 1963-1, 1579.