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Boric acid poisoning
T h e Journal o[ P E D I A T R I C S
531
Boric acid poisoning T h r e e f a t a l cases w i t h p a n c r e a t i c i n c l u s i o n s a n d
a r e v i e w o f the l i t e r a t u r e
The autopsy findings in 3 fatal cases of boric acid poisoning are described in detail. The demonstration of intraeytoplasmic inclusion bodies in the acinar cells of the pancreas is considered to have diagnostic significance. The literature on boric acid poisoning is reviewed, and the data relative to 83 fatal and 89 nonfatal cases are tabulated. In addition, various aspects of the subject, such as minimal lethal doses, blood and tissue concentrations, procedures for toxicologic analyses, and modes of absorption and elimination of the drug, are discussed.
Marie A. Valdes-Dapena, M.D.,* and James B. Arey, M.D. PHILADELPHIA,
B o R I C
A (3 I D
PA.
(H3BO,~)
is
a
colorless,
odorless compound commercially available as crystals, granules, and as a white powder. In the crystalline form it has a characteristic greasy feel. It is usually prepared by the action of sulfuric acid on borax (sodium borate, Na2B4OT.10HzO). It was known to the ancients as a valuable cleansing agent and was used internally by Rhazes (i.D. 875) and the physicians of the Arabian school. In 1702 William Homberg first prepared boric acid by the action of mineral acids on borax. He introduced-it into the medical practice of the times as "Homberg's sedative salt." It was purported to be a sedative, anodyne, and From St. Christopher's Hospital for Children and the Department of Pathology, Temple University School of Medicine, and the Office of the Medical Examiner, Philadelphia, Pa. (Dr. Valdes-Dapena). "X'Address, St. Christopher's Hospital for Children, 2600 North Lawrence St., Philadelphia 33, Pa.
antispasmodic. Borax was originally imported from Persia, China, and J a p a n under the name of Tinical or Tankar but in 1776 a relatively pure supply of borax mixed with boric acid was found in certain warm springs in Tuscany. In 1856 borax was found in a lake in California and later enormous deposits were found in Death Valley, California, today the chief source. s6 In 1848 Binswanger won a prize for the best essay on 'the pharmacologic properties of boric acid and borax, a5 Lister first employed boric acid as an antiseptic in 1875, s7 and it enjoyed great popularity in medical practice for many years, thereafter being used as a powder or lotion, or in solution, ointment, or paste. It has been utilized by physicians ever since for gastric lavage in cases of gastric distention, for rectal and colonic irrigations in dysentery and typhoid, and even for vaginal packs in leukorrhea.
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Valdes-Dapena and Arey
Fig. l. Case 1. Pancreatic inclusion bodies.
October 1962
In the latter part of the nineteenth century it was administered orally (daily) in the management of epilepsy. Boric acid solution, usually 5 per cent, has often been employed to wash out the urinary bladder and prostatic bed, pleural cavities in cases of empyema, surgical wounds, abscesses, inflamed joints, skin ulcers, inflamed nose, throat, and eyes, and even the mouth in thrush. Boric acid has been particularly popular in the treatment of burns, skin eruptions, various dermatologic disorders, and omphalitis. There are a number of reasons for the selection of this particular agent. In the first place it does not irritate nor does it stain. In saturated solution at room temperature it is practically isotonic with body fluids. It can be incorporated into a variety of vehicles and makes the powders with which it is mixed flow more freely from their containers. It acts as a buffer against alkali. Both of these latter factors make it desirable in talcum powder. I n addition, it is keratoplastic and mildly antiseptic and antifungal. Not long after the drug was established in medicine, reports of poisonings due to its use began to appear in medical literature and these have been accumulating ever since. We have been able to find a total of 83 fatal and 89 nonfatal cases of boric acid poisoning reported in the literature, to which we add these 3. CASE
Fig. 2. Case 2. Pancreas.
REPORTS
Case 1. J. G., a 1-month-old white male infant, was born after an uncomplicated pregnancy and delivery. The weight at birth was 6 pounds, 10 ounces. He was discharged from the hospital at 7 days of age. The weight gain thereafter was satisfactory on a formula of evaporated milk, and when last seen in the well-baby clinic 2 days prior to death he appeared to be in good health. The following day, however, he began to have loose stools and regurgitated the formula. On the day Of death all of the feedings were regurgitated. During the afternoon of 'that day the respirations became irregular and the color somewhat dusky.
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Physical examination at the hospital receiving station disclosed a cyanotic, severely dehydrated infant with glazed eyes. There was a blotchy yellow-red rash on the cheeks and reddish discoloration of the arms and legs. The skin of the scrotum and buttocks was excoriated and caked with boric acid powder which the mother had been applying as a diaper powder since birth. Various therapeutic measures, including caffeine sodium benzoate and epinephrine, were administered in vain and the child died at 6:25 P.M. on Aug. 27, 1954, without having been admitted to the ward. At autopsy, performed 15 hours after death, the body was found to be poorly nourished, measuring 51 cm. in length and weighing 2,762 grams. The buttocks were severely wasted, very red, and revealed multiple circinate areas of excoriation. The entire dependent part of the scrotum was fiery red and excoriated. There was faint pink discoloration of the abdomen, especially of the right upper quadrant, the precordium, neck, throat, shoulders, and scalp. T h e lower part of the back was diffusely mottled pink and red. T h e face was mottled red with a few punctate white vesicles or pustules located especially over the chin. The ears were pink to red. There was questionable pink discoloration of both forearms; otherwise the arms, legs, inguinal and axillary regions, palms of the hands, and soles of the feet were spared. There was fine peeling of tile skin of the tips of the fingers and questionable peeling of the palms of the hands; none was seen on the feet or toes. T h e mucosa of the large and small bowel was pale. Occasional petechiae were present in the ileum and an ecchymosis of 0.5 by 1.0 cm. was noted in the mucosa of the rectum. There were no other significant macroscopic alterations. Histologic sections of the smal bowel revealed small collections of neutrophils in the glands, m a n y of which were somewhat dilated. There were decreased numbers of lymphocytes and increased numbers of large mononuclear cells, myeloid cells, and a few neutrophils in the lamina propria. The
Boric acid poisoning
Fig. 3. Case 2. Pancreas.
Fig. 4, Case 2. Larynx.
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Valdes-Dapena and Arey
acinar cells of the pancreas revealed welldefined large single vacuoles, some of which contained acidophilic spheres and others contained discrete spherical blue bodies. These bodies were each about the size of the nucleus of a normal acinar cell. Each lay in a clear vacuole within the cytoplasm of the cell and they occurred singly. The margins of the inclusions were sharply defined. T h e substance of the inclusion, whether stained red or blue, was quite homogeneous (Fig. 1). With the exception of these changes in the bowel and pancreas, there were no other findings of significance. Chemical analyses were carried out on the tissues from this autopsy by the Office of the Chief Medical Examiner of the State of Maryland under the direction of Dr. Russell Fisher. The following are their findings: Kidney (single determination), 100.1 mg. per cent boric acid. Liver (average of 2 determinations), 71.0 mg. per cent boric acid. Brain (average of 2 determinations), 10.7 mg. per cent boric acid. It was considered that acute enteritis, probably with associated metabolic changes and dehydration, and boric acid intoxication were responsible for death. Their relative importance and their relation to each other are not clear. Case 2. D. J., a white male infant, was born at term on Nov. 10, 1956, weighing 7 pounds, 7 ~ ounces. The mother had moniliasis in the first and second trimesters of the pregnancy but the third trimester was uncomplicated. Delivery was accomplished with outlet forceps. The infant's condition at birth was good. He was discharged on Nov. 17, 1956, weighing 7 pounds, 3 ounces. He was thought to be in good health until the day before death when the mother noted purplish mottling of the face. At 2 A.M. on the day of death, November 30, the baby did not take the bottle well, was "breathing very hard," and vomited. Later he became less responsive and respirations were said to be irregular. H e was dead when he arrived at the hospital. Iri general the mother's history at the time was vague and confused.
October 1962
Following completion of the autopsy the mother was questioned concerning the use of boric acid compounds. Only then did she reveal the fact that she had used pure boric acid powder freely to dust the diaper area with every change of diapers for several days before the death of the infant. She had been advised by her mother that boric acid was the best remedy, for the infant's excoriated diaper rash. Autopsy was performed on Nov. 30, 1956, approximately 6 hours after death. The body appeared poorly nourished, weighing 3,000 grams and measuring 55 cm. in length. Patchy purple discoloration of the skin was noted over the head and cheeks. There was superficial denudation just lateral to tile right eye, over the right half of the chin, and the posterolateral aspect of the right side of the neck. There was severe denudation of the skin on the posterior aspect of the scrotum and between the scrotum and the anus; this area was covered by a great deal of caked white powder. The lips were deep purple, and the mucous membranes of the mouth were gray purple. T h e inguinal lymph nodes were slightly enlarged bilaterally. The subcutaneous tissues were slightly dehydrated. Both kidneys were of normal size and shape but contained scattered dark red infarcts averaging 7 mm. in diameter with their bases against the capsular surface of the kidney and their apices near the tips of the pyramids. There were multiple petechiae in Peyer's patches and each urinary ostium presented as a red-to-purple hemispherical mound 3 mm. in diameter. The adrenals were of normal size and shape but their external surfaces were a peculiar blotchy dark purple. On section most of each gland was maroon and those portions which were not so discolored were pale tan. Histologically there were multiple fresh thrombi in veins of medium size throughout the body, including the lungs, kidneys, adrenals, and connective tissue about the thyroid. T h e venous thrombi in the kidney were Iocated at the apices of a number of infarcts. In the adrenals there were multiple areas of
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interstitial hemorrhage, and many hyaline thrombi filled the sinusoids. A single small thrombus was attached to the endothelium of the ductus arteriosus, and occasional fibrin masses were present in small branches of the pulmonary artery. There were scattered patches of neutrophilic infiltrate in the mucosa and submucosa of the small bowel, in the gastric mucosa, and in a few of the portal triads. Edema fluid and numerous red blood cells were present immediately beneath the transitional epithelium about the ureteral ostia in the urinary bladder. Sections of tt(e pancreas revealed a great deal of vacuolization of the aeinar cells. In many of these vacuoles there were distinct inclusions. Some of these were acidophilic, whereas others were faintly basophilic (Figs. 2 and 3). They were cytoplasmic in location, pushing the nucleus to one side. Some were very large, about the size of the nucleus of an acinar cell, and contained tiny black bodies resembling Howell-Jolly bodies. Others, however, were small. A few of the same type of cytoplasmic inclusions were present in the glands of the larynx (Fig. 4) where there was some degree of sloughing of the involved epithelial cells. The presence of a neutrophilic infiltrate in the lamina propria of the small bowel suggests the possibility of diarrhea during life although no history of it was obtained. It is of interest that a similar exudate was present in the mueosa of the small bowel in the preceding infant. The relationship of such an exudate to the boric acid intoxication is not cleat'. In any event, the dehydration which was present may well have contributed to the formation of multiple venous thrombi with subsequent renal infarcts and adrenal hemorrhages. Unfortunately, the tissues were lost before toxicologic surveys could be performed. The mother, however, brought the almost empty cardboard container of U.S.P. boric acid which she had been using and there seemed to be little or no doubt as to the presence of boric acid intoxication in this infant.
Boric acid poisoning
535
Case 3. S. D., a 26-day-old white male infant, was admitted to St. Christopher's Hospital for Children on May 28, 1957, with the chief complaint of diarrhea and vomiting. He had been in his usual good state of health until 2 ~ days prior to admission when he started to refuse his feedings. Twenty-four hours prior to admission he suddenly developed watery, frequent (6 per day) large stools and vomiting. These symptoms increased in severity to the time of admission. The vomiting was not projectile but consisted of spitting up curds of milk after feedings. A physician saw the infant and prescribed a mixture of kaolin and pectin "~ but this was not retained. At 3 A.M. on the day of admission he became very lethargic and the crying became feeble. He was afebrile throughout the course of the illness. Past medical history revealed an uneventful pregnancy, labor, and delivery. The early neonatal course was uncomplicated. At 1 week of age he developed thrush for which he was treated successfully. One week prior to admission he developed a red rash with blisters around the diaper area, followed by a rash on the face. Physical examination revealed a thin, cold, unresponsive, and semicomatose infant with chalky pallor. The pulse was slow, being 30 to 40 per minute. Respirations were 20 per minute and were shallow and irregular. Tile temperature was 94 ~ F. The head was of normal configuration; the anterior fontanelle was very small and depressed. The eyes were sunken. There was no corneal reflex. The pupils were dilated and reacted sluggishly to light. The ear drums, throat, nose, and lung fields showed no abnormalities. The abdomen was soft with no visceromegaly and no abnormal masses. The infant was severely dehydrated and was having almost continuous watery yellow stools containing mucus. The genitals were extremely edematous, and there was gangrene of the penis and scrotum. A vesiculopusmlar rash which was secondarily infected and partially covered "~Kaopcctate.
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Valdes-Dapena and Arey
with exudate was present in the diaper area. There were small ulcers on the medial aspects of the thighs and on the lower abdomen. The skin of the face was bright red and hard; this redness extended over the forehead where there was some peeling. There were small red macules over the anterior thorax and flanks. There were no Moro reflex, no grasp, and no, tendon reflexes. He was completely flaccid. On admission the following laboratory data were obtained. The pH of the serum was 6.74; carbon dioxide, 11.0 mEq. per liter; chloride, 120 mEq. per liter; sodium, 144 mEq. per liter; and potassium, 2.7 mEq. per liter. The calcium was 9.8 mg. per cent and phosphorus was 9.2 mg. per cent. A culture of the nasopharynx revealed a luxuriant growth of coagulase-positive hemolytic Staphyloccus aureus which was sensitive to novobiocin and moderately sensitive to erythromycin. Culture of the stool yielded a moderate growth of coliform organisms. Intravenous fluids were started at the time of admission; he received 3.75 Gin. of sodium bicarbonate and 80 c.c. of whole blood. The administration of tetracycline, novobiocin, and penicillin was begun. Two hours after admission he looked more responsive and the color was better. Five hours after admission, however, he began to have convulsions. Calcium gluconate and phenobarbital sodium were given, and 3 hours later the convulsions ceased. He died 12 hours after admission. At autopsy the body was undernourished, measuring 56.5 cm. in length and weighing 3,730 grams. The skin of the penis, scrotum, and medial aspect of the right thigh was bright red, swoIlen, and superficially ulcerated. Multiple similar areas of intense hyperemia with desquamation were present in both inguinal regions and over the fingers, forehead, and chin. The left side of the face, especially the cheek and left ear, was bright red, without desquamation, and there was slight reddening of perianal skin. In the right renal vein, extending not quite to the inferior vena cava and arising ap-
October I962
parently within the renal parenchyma, there was a blunt reddish brown thrombus. Multiple thrombi were visible upon the cut surface of the right kidney. An incidental finding was the presence of but a Mngle coronary ostium which gave rise to both the left and right coronary arteries. There were no other significant macroscopic alterations. The entire nervous system revealed no gross pathologic changes. Histologic sections of the pancreas revealed vacuoles which contained acidophilic or basophilic inclusions within a number of acinar cells like those described in Cases 1 and 2. There were occasional neutrophils in scattered glands of the small bowel. Brunner's glands were moderately dilated. Urine obtained from the bladder at autopsy gave a positive reaction to turmeric paper. Analysis of the brain showed boric acid 3.8 mg. per 100 Gin. ("Normal" levels may be as high as 0.7 mg. per 100 Gm.) DISCUSSION
Lethal doses of boric acid. The minimal lethal dose of boric acid for man is not known, sa According to various case reports in the literature, there is a very wide range with great individual variation. According to Caujolle, s" a man can take 4 Gm. a day orally without incident, whereas a single dose of 18 to 20 Gm. is fatal to him and 5 to 6 Gin. to an infant. McIntyre and Burke 7a referred to an adult who was given 15 Gin. as a clysis subcutaneously and developed only slight symptoms of poisoning. They also reported the case of an adult who recovered and who developed only flushing, nausea, and vomiting after the intravenous administration of 600 ml. of a 2.5 per cent solution of boric acid. This amount equals the lower limit of the often quoted "fatal oral dose for man" which according to Potter is 1 ~ ounces of pure borax (which has a boron content equivalent to 27.6 Gm. of boric acid, almost an ounce). The young infant seems to be particularly susceptible, yet infants have survived after the ingestion of 4 t o 9 Gm. a~ Acute intoxication follows large single
Volume 61 Number 4
.doses, and chronic intoxication has occurred after daily ingestion of moderate quantities such as 4 to 5 Gin. of boric acid per day for 3 to 4 weeks or 6 to 20 Gm. of borax daily for several months. Concentration of boric acid in body tissues. Blood and tissue concentrations in fatal and nonfatal cases are widely varied. Two children were described by Fisher and Freimuth 9~ who had drunk a solution of boric acid and showed no toxic symptoms whatsoever; they had blood levels of 7.44 and 7.89 mg. per cent of boric acid, respectively. Probably such levels are nontoxic2 ~ According to the experimental work of these same authors 50 to 100 rag. per cent or more in the blood is fatal, A concentration of 52 mg. per cent in any organ is considered iethal by Hallett. 4~ A figure of this magnitude may be expected when death ensues shortly after acute poisoning. Lesser quantities may be found when the patient survives 2 or 3 days, thus allowing time for elimination of much of the drug. Since boric acid is excreted rapidly, it can be assumed that concentrations had been higher previously, and tissue damage, as proved by the fatal outcome, had been severe. According to McNally and Rust, 17 the brain and liver accumulate higher percentages than other organs. Toxicologic analysis. One difficulty with any toxicologic analysis concerning this drug is the fact that it is commonly present in the blood. Most individuals ingest a certain amount of boron daily in orange juice, all vegetables, fruits (especially currants and raisins), bread, and cereals. As a result, the average concentration in the blood is 0.14 mg. per 100 ml. of blood with a range of from 0.00 to 0.72. It has long since been established that the turmeric acid paper test on urine is unreliable since it may be positive because of the presence of boron derived from the diet alone21 Fisher and Freimuth 9~ reported that if an infant takes 4 ounces of orange juice a day he will excrete 8 times the minimal amount necessary to produce a positive test in the urine.
Boric acid poisoning
537
In their investigations they employed the method of Smith, Goudie, and Sivertson, ~2 colorimetric determination. In the toxicologic laboratories of the Office of the Medical Examiner of the City of Philadelphia, where the determinations for Case 3 were made, Dr. Fredric Rieders has been using the same method; he considers it valuable because it is simple and gives reproducible results. It is based upon the carminic acid-boron color system. Determinations are made on the Klett colorimeter using a red filter, 600 m/,. Absorption of boric acid. Boric acid will be absorbed to a certain extent through intact skin, as was originally suggested by the work of Kahlenberg2 a, :~4 This author soaked his feet in a warm solution of boric acid for 5 minutes, following which boric acid appeared i n the urine (as indicated by a positive turmeric acid paper test). In his second publication he reported that boric acid appeared in the urine in 50 to 55 seconds in each of three men whose feet, which were in good condition, were soaked in boric acid solution. Once again the turmeric paper test was relied upon. In 1958 Freimuth and Fisher 9s found that free boric acid in aqueous solution or in solution in urine was readily absorbed through the intact skin of the rabbit; borax was similarly absorbed. Boric acid is very much more easily absorbed whenever the skin has been broken, and it will, of course, be absorbed from granulation tissue, serous cavities, and the gastrointestinal tract. With respect to baby powders containing boric acid, Mulinos, Connant, and Hauser '~(; from a study of boric acid absorption in animals gonctuded that boric acid is absorbed in sufficient quantity from talc containing boric acid to lead to toxicity. Freimuth and Fisher, 9a however, employing quantitative rather than qualitative determinations, found little or no evidence of absorption of boric acid from talc and calcium metaborate. There is, moreover, no report of boric acid poisoning in the Iiterature in which the poisoning was due to the use of commercial talcum powder containing boric
5 3 8
Valdes-Dapena
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October 1962
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acid. Vignec and Ellis 97 showed that the average borated powder which contains 5 per cent boric acid is usually harmless. They exposed a large group of babies for a number of weeks to an average of 2.33 Gm. of boric acid daily in the form of borated talc. The results obtained in both the control and test groups fell close to normal values. Johnstone, Basila, and Glaser 9s determined the concentrations of boron in blood and urine of 8 infants with intact skin and in one infant with injured skin before, during, and after application of a commercially available talcum powder containing 5 per cent boric acid. The chemical procedures used were sufficiently accurate to detect less than 5.7 parts boric acid per million in samples as small as 2 ml. The highest value for blood boron concentration did not exceed 3.4 parts per million, a value not significantly higher than was found in the controls and well within the normal range. According to Blanchard, Blanchard, and Kravtin, 8~ un-ionized boric acid is preferentially absorbed through the skin as compared with ionized boric acid. T h e mixture of wet boric acid and talc results in ionization of the boric acid and thus less absorption, since the boric acid in solution forms salts with the alkaline compbnents of the talc.. Excretion of boric acid. Excretion of boric acid is for the most part accomplished by the kidneys. It has been shown that 82 to 100 per cent of boric acid taken rapidly by mouth is excreted in the urine29 Small amounts are found in the sweat. Boric acid appears in cows' milk after ingestion and has been shown to cross the placenta of the rat? 5 Although it is absorbed rapidly, its complete elimination requires some time. After 3 Gm. has been administered each day for 10 days, or 5 Gin. per day for 3 days, complete elimination will not be accomplished until at least 18 days have passed. 35 The greatest part, however, is eliminated within the first few days. REVIEW
OF REPORTED
CASES
To date, we have been able to find a total of 172 reported cases of boric acid
October 1962
poisoning (Table I). O f these, 83 were fatal and 89 were nonfatal. Seventy-eight of these have been in adults and 94 in children. The first reported fatal cases were those of Molodenkow a of Moscow who in 1881 presented 2 instances. In the first of these he had washed out the pleural cavity of a female patient, 25 years of age, for an hour with a large quantity of 5 per cent boric acid solution. The second was a lumbar abscess in a 16-year-old boy who was similarly treated. I n the same year Gowers ~~ reported 3 cases of nonfatal poisoning in which borax had been administered orally for the treatment of epilepsy. In all 3 a skin rash or eruption appeared; this he termed psoriasis and considered it to be a toxic manifestation of the boric acid. In recent years most instances of poisoning b y boric acid have been accidental rather than from its use as a medication. A nonfatal accidental poisoning was first reported in 1915 by Willson 6s in an infant who was given boric acid solution in a milk formula instead of water. The first report of a fatal accidental !ngestion appeared in 1917 when Sinigar la presented the case of a 70-year-old woman who took the drug, mistaking it for Epsom salts; she died 46 hours thereafter. Poisoning was accidental in a total of 71 cases, 35 being fatal and 36 nonfatal. In 54 of the 71 cases accidental poisoning was the result of the use of boric acid in the preparation of infant formulas. The majority of these occurred in hospital nurseries; 28 were fatal and 26 nonfatal. The second most common accident involved subcutaneous administration by clysis; there were 8 of these, 5 of which were fatal. Boric acid has been given intravenously once and did not result in death. 7a One infant is reported to have been poisoned following the use of boric acid solution as a cleansing agent for the mother's nipples. as Today boric acid poisonings still occur fairly frequently. Jacobziner and Raybin 8~ of the Poison Control Center of New York City reported that, from 1955 to 1960, 185 accidental ingestions of boric acid were re-
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corded. The quantity ingested ranged from one tablespoonful of the powder to a "jarful" of solution. In 1949 Gold 1~176reviewed 158 cases of household poisoning seen in New York over a 5 year period. Among them was an instance in which a woman baked a cake using boric acid instead of baking soda. In 30 of the reported cases, as in our own, poisoning was due to the application of pure boric acid to the denuded diaper area; 23 of these were fatal and 7 nonfatal. The first case of fatal poisoning by this means reported was in 1948 by Fellows, Campbell, and Wadsworth a~ and the first nonfatal case of that type, by Brooke TM in 1953. Poisoning was the result of the deliberate administration of the drug as therapy in 71 cases; 25 were fatal and 46 nonfatal. In 23 of these 71 boric acid was administered orally, mostly for the treatment of epiIepsy. Only 2 of these were fatal. In 8 of the 25 fatal cases in which the drug was used therapeutically, sores, abscesses, ulcers, and wounds were washed out with it and in 6 cases burns were treated with it. Autopsy findings, more or less detailed, have been included in 55 reports of fatal cases; the majority of these leave m u c h to be desired. M a n y of them, although very lengthy, contribute little to the pathologist who seeks in them information about how to make the diagnosis morphologically. They describe such nonspecific entities as: "Congestion of all organs, . . . . enlargement and softening of t h e liver," "congestion and edema of the lungs," "splenomegaly," or "all organs normal," with the cause of death left in doubt. The skin changes are perhaps the most significant of the gross observations. In many cases, the very extensive erythema and desquamation of the skin are outstanding features of the necropsy. Histologic changes have been described in cases of boric acid poisoning since the report of Brose 2 in 1883, but even as late as 1950 they, too, were of little help, including such observations as "swollen liver cells,"
Boric acid poisoning
54 3
and "degeneration of tubular epithelium in the kidney." In 1951 Fisher a~ first reported intracytoplasmic inclusions in the pancreas due to boric acid poisoning. He had observed this lesion in 4 autopsies. He described the bodies as varying "up to 10 micra in diameter and lying within acinar cells. They were rounded, homogeneous, eosinophilic, some with deeply basophilic granules." He thought that they represented part of a degenerative process in the cells. He considered that all the other g r o s s and histologic features of the autopsies were nonspecific and that this entity alone was diagnostic of the disease. Seventeen fatal cases were reported after 1951, with autopsies on 11 of them. The pancreatic lesion was mentioned in only two of the articlesY 9' ~ Thus, the lesion has been described in only 6 recorded cases. Stowens 1~ made mention of it in his discussion of borate poisoning. It would seem that greater awareness of the occurrence and the significance of this apparently specific morphologic change would be valuable to pathologists in general and to those dealing with infants and children in particular. Boric acid is still used extensively by both the medical profession and the laity. In 1956 Fisher 1~ conducted a survey among dermatologists. Ninety-four per cent of them used the drug in their practice, 71 per cent frequently. In I943 Ross and Conway 2~ pointed out that 20 of 30 doctors questioned were not cognizant of the fact that boric acid could be toxic when taken by mouth. Apparently m a n y persons both professional and nonprofessional are not aware that this drug can be lethal. It appears that for every conceivable medical or therapeutic use of boric acid there is now a more effective and safer' agent, whether it be for the production of moist heat or antisepsis. I t has, for instance, been shown 1~ that boric acid in concentrations higher than 2 per cent inhibits phagocytosis, thereby negating primary defense mechanisms of the body against bacterial invasion. At concentrations of 4 per cent, toxicity to the tissues is greater than its
5 44
Valdes-Dapena and Arey
bactericidal activity. Thus, the organism's invasive qualities m a y actually be aided a n d abetted by the use of a too c o n c e n t r a t e d solution. T h e drug has been aptly called a "wolf in sheep's clothing. ''1~ Since it is of so little value therapeutically and since on a n u m b e r of occasions its accidental use in hospital nurseries has resulted in the poisoning of large n u m b e r s of infants, it should be removed from hospital pharmacies. T h e r e is no d o u b t that when dispensed by drug stores to lay persons the containers should be clearly labeled "poison." SUMMARY
T h e medical literature on boric acid poisoning is surveyed and 172 reported cases are reviewed briefly. T h r e e additional cases are recorded, b r i n g i n g the total to 175. P a r t i c u l a r attention is directed to the intracytoplasmic inclusions in the pancreas in this disease entity, heretofore m e n t i o n e d b u t briefly in three articles a n d in Stowen's text. T h e toxicity of boric acid should be recognized a n d it should be clearly labeled as a poison. Boric acid should not be available in hospitals.
We wish to acknowledge the kind cooperation of the personnel of the Office of the Medical Examiner of the City of Philadelphia and especially that of Dr. Fredric Rieders, chief toxicologist, and Mr. Joseph Poppel, photographer. We are most grateful to the staff of the Library of the College of Physicians for their help, and to Dr. A. Valdes-Dapena for his translations. We also thank Miss Estelle Goebber and Mrs. Freda Lebengood, tissue technicians, and Miss Ruth Shivers, secretary.
REFERENCES For fatal cases.
1. Molodenkow, S. E.: 2 F~ille yon Vergiftung durck Bors~iure, St. Petersburger reed. Wchnsehr. 6: 361, 1881 (abstract), Vrach. 3 h 509, 1881. 2. Brose, L. "D.: Death following the external use of powdered boracic acid, M. News 43: 199, 1883.
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3. Hogner, FSrgiftningsfall genom borsyreskoljningar, Eira 8: 389, 1884. 4. Fer6, C.: Th6rapeutique m6dicale. Le '%0risme" ou les accidents de la m6decation par le borax, Semaine m6d. 1'4: 497, 1894. 5. Schwyzer, F.: Ueber Bors~iurevergiftung, New Yorker me({. Monatsschr. 7: 263, 1895. 6. Hall, A.: The possible dangers of treating extensive burns with boracic ointment, Lancet 1: 993, 1896. 7. Best, C. L.: Boric acid poisoning; report of a fatal case with autopsy, Tr. Chicago Path. Soc. 6: 161, 1903. 8. Williams, V.: Unreported data, cited by Best.* 9. Dopfer: Ober einen Todesfall nach Anwendung der Offizinellen Borsalbe bei einer Brandwunde, Miinchen. med. Wchnschr. 52: 763, 1905. I0. Editorial: A case of boracic acid poisoning, Brit. M. J. 2: 1695, 1907. 11. Savariaud, A.: Serious poisoning by boric acid dressing, J. A. M. A. 63: 593, 1914. 12. Maguire, G. C.: Boric acid poisoning? Case with comments, Practitioner 97: 580, 1916. 13. Sinigar, H.: Cases of poisoning by sodium nitrite and boric acid, Lancet 2: 162, 1917. 14. Potter, C.: A case of borax poisoning, J. A. M. A. 76: 378, 1921. 15. Bazin, A. T.: Acute boracic acid poisoning (fatal), Canad. M. A. J. 14: 419, 1924. 16. Birch, J.: Fatal poisoning by borax, Brit. M. J. h 177, 1928. 17. McNally, W. D., and Rust, C. A.: The distribution of boric acid in human organs in 6 deaths due to boric acid poisoning, J. A. M. A. 90: 382, 1928. 18. Aikman, J.: Strychnine poisoning in children (Table I--Accidental poisonings of children 5 years of age and under in New York State [exclusive of greater N. Y.]). J. A. M. A. 95: 1661, 1930. 19. Cushing, E. H.: BorsSmre-Vergiftung, medizinale, Samml. Vergift. h 91, 1930. 20. Vartianen, A., and Oravainen, M.: BorsgureVergiftungen, medizinale. Zwei Fglle, ein Fall mit t6dlichen Ausgang, Samml. Vetgift. 4: 211, 1933. 2I. W61sch: Cited by Gissel.22 22. Gissel, H. A.: Contribution to the toxicity of boric acid, Zentralbl. Chir. 60" 1635, 1933. 23. Ponsold, A.: Fatal boric acid poisoning following perforation of urethra in attempted cystoscopy, Deutsche Ztschr. ges. gerichtl. Med. 34: 321, I940. 24. Ross, C. H., and Conway, J. F.: The dangers of boric acid: Its use as an irrigant and report of a case, Am. J. Surg. 60" 386, 1943. 25. Cross, R. R.: New ruling on boric acid, J. A. M. A. 126: 715, 1944. 26. Barnum, C. G., and Opper, L. S.: Boric acid poisoning of 20 newborn infants in the hospital at New London, Conn., J. A. M. A. 128" 273, 1945. 27. Bigelow: Cited by PfeifferY s
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28. Watson, E. H.: Boric acid, a dangerous drug of little value, J. A. M. A. 129" 332, 1945. 29. McNally, W. D., and Ruckstinat, G.: Two deaths due to boric acid, M. Rec. 160; 284, 1947. 30. Fellows, A. W., Campbell, J. S., and Wadsworth, R. C.: Boric acid--poison, J. Maine M. A. 39: 339, 1948. 31. Grant, R. S., and Wegner, E. S.: Fatal case of boric acid poisoning, Am. J. Dis. Child. 75: 910, 1948. 32. Abramson, H.: Poisoning in a newborn infant, Pediatrics 4: 719, 1949. 33. Lueck, W. W.: Poisoning in children, Lancet 69: 155, 1949, 34. Young, E. G., Smith, R. P., and Macintosh, O. C.: Boric acid as a poison: Report of six accidental deaths in infants, Canad. M. A. J. 61: 447, 1949. 35. Pfeiffer, C. C.: Is boric acid harmless? Mod. Hosp. 74: 106, 1950. 36. Brooke, C., and Boggs, T.: Boric acid poisoning, A, M. A. Am. J. Dis. Child. 82: 465, 1951. 37. Fisher, R. S.: Intracytoplasmic inclusions in the pancreas due to boric acid poisoning, Am. J. Path. 27: 745, 1951. 38. Bumbalo, T. S.: Boric acid poisoning, New York J. Med. 52: 1913, 1952. 39. Ducey, J., and Brooke, W. D.: Transcutaneous absorption of boric acid, J. Pediat. 43: 644, 1953. 40. Goldbloom, R. B., and Goldbloom, A.: Boric acid poisoning; report of 4 cases and a review of 109 cases from the world literature, J. PEDIAT. 43: 631, 1953. 40a. Goldbloom, R. B.: Correspondence, J. PEmAT. 44: 720, 1954. 41. Gonzales, T. A., Vance, M., Helpern, M., and Umberger, C. J.: Legal Medicine Pathology and Toxicology, ed. 2, New York, 1954, Appleton-Century-Crofts, Inc., p. 776. 42. Maxson, W. T.: Case report of boric acid poisoning from topical application, J. Kentucky M. A. 52: 423, 1954. 43. Editorial: Baby's death from boron poisoning, Brit. M. J. 1: 237, 1955. 44. Hallett, G. W., Jr.: Boric acid poisoning; case, J. Maine M. A. 46; 93, 1955. 45. Arey, J. B.: Unexpected death in early life, J. PEDIAT. 49: 523, 1956. 46. Rosen, F. S., and Haggerty, R. J.: Toxic hazards: Fatal poisoning from topical use of boric acid powder, New England J. Med. 255: 530, 1956. 47. Jordan, J. W., and Crissy, J. T.: Boric acid poisoning, A. M. A. Arch. Dermat. 75: 720, 1957. 48. -Freehette, A. L.: Unreported data. 49. Segar, W. E.: Peritoneal dialysis in the treatment of boric acid poisoning, New England J. Med. 262: 798, 1960. For nonfatal cases.
50. Gowers, W. R : On psoriasis from borax, Lancet 2: 546, 1881.
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54 5
51. Bruzelius, R.: Om borsyref6rgiftning, Hygiea 44: 548, 1883. 52. Huse, R. C.: Poisoning by boracic acid, M. News 40: 704, 1882. 53. Warfvinge, F. W.: Fall af borsyref6rgiftning, Nord. med. Ark. 15" 36, I883. Abstract, Hygiea 45: 10, 1883. 54. Johnson, E. G.: Kliniska studier 8fver borsyrans och borax' inverkan p~ m~inskliga organismen ~ifvensom deras elimination ur den samma, Nor& med. Ark. 17: 1, 1885. 55. Spencer, C. E.: Boracic acid poisoning, Lancet 8: 22, 1888. 56. Welch, G. T.: Toxicological effects of boracic acid, M. Rec. 34: 531, 1888. 57. "Fer6, C., and Lamy, H.: Deux cas d'6ruption ecz4mateuse provoqu~e par le borax, Nouv. iconog. Salp4trihre 2: 305, 1889. 58. Lemoine, G.: De la toxicit4 de l'acide borique, Gaz. m6d., Paris 7" 222, 1890. 59. Evans, J. J.: Toxic effects of boracic acid, Brit. M. J. 1: 209, 1899. 60. Wild, R. B.: Dermatitis and other toxic effects produced by boric acid and borax, Lancet 1: 23, 1899. 61. Handford, H.: Erythematous rash due to boric acid, Brit. M. J. 2: t495, t900. 62. Rinehart, J. F.: Two cases of boric acid poisoning, Therap. Gaz. 17: 662, 1901. 63. Van Dort Kroon: Boorzuur-vergiftiging, Med. Weekbl. 12: 41, i905-1906. 64. McWalter, J. C.: Note on the effects of borax on infants, Lancet 2: 369, 1907. 65. Harley, V.: Boracic acid poisoning, Brit. M. J. 1: 832, 1912. 66. Sanders, J. H.: Boracic acid poisoning, Brit. M. J. 1: 605, 1912. 67. McWalter, J. C.: Boric acid eczema, Brit. M. J. 1: 1002, 1915. 68. Willson, P.: A case of boracic acid poisoning, Washington M. Ann. 14: 329, 1915. 69. Forsyth, D.: Coeliac disease or boric acid poisoning, Lancet 2" 728, 1919. 70. Ide, M.: Inconvenients du bore, Bull. Acad. roy. m6d. Belgique 3: 111, 1923. 71. Lewin, A.: Cited by Gissel. ~ 72. Brown, W. L., Brown, C. P., and Murphy, J. L.: Toxicity of boric acid, J. A. M. A. 106: 1221, 1936. 73. McIntyre, A. R., and Burke, J. J.: Intravenous boric acid poisoning in man, J. Pharmacol. & Exper. Therap. 60: 112, 1937. 74. Pcyton, H. A., and Green, D.: Boric acid poisoning, South. M. J. 34: 1286, 1941. 75. Velarde, J.: Un easo de alopecia i toxiea o neuropatlcia? Prensa m6d. mex. 6: 157, 1941. 76. Dwek, J.: Toxic symptoms due to the use of boric acid, Acta med. orient. 4: 352, 1945. 77. Rubin, M. B., Recinos, A., Washington, J. A., and Koppanyi, T.: Ingestions of polsans in children, A survey of 250 admissions to Children's Hospital, Clin. Proc. Child. Hosp. 5: 57, 1949. 78. Brooke, C. E.: The boric acid problem, Gen. Practitioner 7: 43, 1953. 79. MacGillivray, P. C., and Fraser, M. S.:
5 46
80.
81. 82. 83. 84. 85.
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Boric acid poisoning in infancy arising from the treatment of napkin rash, Arch. Dis. Childhood 28: 484, 1953. Blanchard, M., BIanchard, M. C., and Kravtin, A. J.: A severe case of boric acid poisoning with survival, J. M. A. Georgia 44: 395, 1955. Boggs, T. R., Jr., and Anrode, H. G.: Boric acid poisoning treated by exchange transfusion, Pediatrics 16: 109, 1955. Searle, A.: Boric acid poisoning, Clin. Proc. Child. Hosp. 12: 13, 1956. Connelly, J. P., Crawford, J. D., and Soloway, A. H.: Boric acid poisoning in an infant, New England J. Med. 259: 1123, 1958. Parkkulainen, K. V.: Boric acid poisoning treated with cortisone. A case report, Ann. Paediat. Fenniae 4: 123, 1958. Jacobziner, H., and Raybin, H. W.: Boric acid poisonings from "Briefs on accidental polsonings in New York City," New York J. Med. 60: 2903, 1960.
General. 86. Soils-Cohen, S., and Statesbury, G. T.: Pharmacotherapeutics, New York, 1928, D. Appleton & Company, pp. 581-586. 87. Nesbit, R. M.: The clinical use of boric acid, Surg. Gynec. & Obst. 80: 651, 1945. 88. Negri, G.: Della tossicita lontana dall acido borico, Rass. di terap, e pat. clin. 1: 472, 1929. 89. Caujolle, F.: Le bore en th~rapeutique, Prod. Pharm. 6: 117, 1951. 90. Fisher, R. S., and Freimuth, H. C.: Blood boron levels in human infants, J. Invest. Dermat 30: 85, 1958. 91. Draize, J. H., Woodard, G., and Calvery, H. O.: Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes, J. Pharmacol. & Exper. Therap. 82: 377, 1944. 92. Smith, W. C., Goudie, A. J., and Sivertson,
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93. 94. 95.
96.
97. 98.
99.
100. 101. 102. 103.
104.
J. N.: Colorimetric determination of trace quantities of boron in biologic materials, Anal. Chem. 27: 295, 1955. Kahlenberg, L.: On the passage of boric acid through the skin by osmosis, J. Biol. Chem. 62: 149, 1924. Kahlenberg, L., and Barwassar, N.: On the time of absorption and excretion of boric acid in man, J. Biol. Chem. 79: 405, 1928. Freimuth, H. C., and Fisher, R. S.: The effect of p H and the presence of other elements in solution on the absorption of boron, J. Invest. Dermat. 30: 83, 1958. Mulinos, M. G., Connant, C., and Hauser, E.: The toxicity of boric acid and the clinical implications of the use of borated baby powders, Bull. New York M. Coll. 16" 92, 1953. Vignec, A. J., and Ellis, R.: Inabsorbability of boric acid in infant powder, A. M. A. Am. J. Dis. Child. 88: 72, 1954. Johnstone, D. E., Basila, N., and Glaser, J.: A study on boric acid absorption in infants from the use of baby powders, J. PEmAT. 46: 160, 1955. Kent, N. L., and MeCanee, R. A.: The absorption and excretion of "minor" elements by man. 1. Silver, gold, lithium, boron and vanadium, Biochem. J. 35: 837, 1941. Gold, I-t.: Household poisonings, Am. J. Med. 6: 237, 1949. Stowens, D.: Pediatric Pathology, Baltimore, 1959, Williams & Wilkins Company, p. 128. Fisher, R. S.: The use of boric acid in dermatologic practice, A. M. A. Arch. Dermat. 73: 336, 1956. Novak, M., and Taylor, W. I.: Phagocyticidal and anti-bacterial action of boric acid, J. Am. Pharm. A. 40" 428, 1951 (scientific editorial). Halliday, C.: Boracic acid The wolf in sheep's clothing, Canad. Nurse 55" 1093, 1959.
531
Boric acid poisoning T h r e e f a t a l cases w i t h p a n c r e a t i c i n c l u s i o n s a n d
a r e v i e w o f the l i t e r a t u r e
The autopsy findings in 3 fatal cases of boric acid poisoning are described in detail. The demonstration of intraeytoplasmic inclusion bodies in the acinar cells of the pancreas is considered to have diagnostic significance. The literature on boric acid poisoning is reviewed, and the data relative to 83 fatal and 89 nonfatal cases are tabulated. In addition, various aspects of the subject, such as minimal lethal doses, blood and tissue concentrations, procedures for toxicologic analyses, and modes of absorption and elimination of the drug, are discussed.
Marie A. Valdes-Dapena, M.D.,* and James B. Arey, M.D. PHILADELPHIA,
B o R I C
A (3 I D
PA.
(H3BO,~)
is
a
colorless,
odorless compound commercially available as crystals, granules, and as a white powder. In the crystalline form it has a characteristic greasy feel. It is usually prepared by the action of sulfuric acid on borax (sodium borate, Na2B4OT.10HzO). It was known to the ancients as a valuable cleansing agent and was used internally by Rhazes (i.D. 875) and the physicians of the Arabian school. In 1702 William Homberg first prepared boric acid by the action of mineral acids on borax. He introduced-it into the medical practice of the times as "Homberg's sedative salt." It was purported to be a sedative, anodyne, and From St. Christopher's Hospital for Children and the Department of Pathology, Temple University School of Medicine, and the Office of the Medical Examiner, Philadelphia, Pa. (Dr. Valdes-Dapena). "X'Address, St. Christopher's Hospital for Children, 2600 North Lawrence St., Philadelphia 33, Pa.
antispasmodic. Borax was originally imported from Persia, China, and J a p a n under the name of Tinical or Tankar but in 1776 a relatively pure supply of borax mixed with boric acid was found in certain warm springs in Tuscany. In 1856 borax was found in a lake in California and later enormous deposits were found in Death Valley, California, today the chief source. s6 In 1848 Binswanger won a prize for the best essay on 'the pharmacologic properties of boric acid and borax, a5 Lister first employed boric acid as an antiseptic in 1875, s7 and it enjoyed great popularity in medical practice for many years, thereafter being used as a powder or lotion, or in solution, ointment, or paste. It has been utilized by physicians ever since for gastric lavage in cases of gastric distention, for rectal and colonic irrigations in dysentery and typhoid, and even for vaginal packs in leukorrhea.
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Valdes-Dapena and Arey
Fig. l. Case 1. Pancreatic inclusion bodies.
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In the latter part of the nineteenth century it was administered orally (daily) in the management of epilepsy. Boric acid solution, usually 5 per cent, has often been employed to wash out the urinary bladder and prostatic bed, pleural cavities in cases of empyema, surgical wounds, abscesses, inflamed joints, skin ulcers, inflamed nose, throat, and eyes, and even the mouth in thrush. Boric acid has been particularly popular in the treatment of burns, skin eruptions, various dermatologic disorders, and omphalitis. There are a number of reasons for the selection of this particular agent. In the first place it does not irritate nor does it stain. In saturated solution at room temperature it is practically isotonic with body fluids. It can be incorporated into a variety of vehicles and makes the powders with which it is mixed flow more freely from their containers. It acts as a buffer against alkali. Both of these latter factors make it desirable in talcum powder. I n addition, it is keratoplastic and mildly antiseptic and antifungal. Not long after the drug was established in medicine, reports of poisonings due to its use began to appear in medical literature and these have been accumulating ever since. We have been able to find a total of 83 fatal and 89 nonfatal cases of boric acid poisoning reported in the literature, to which we add these 3. CASE
Fig. 2. Case 2. Pancreas.
REPORTS
Case 1. J. G., a 1-month-old white male infant, was born after an uncomplicated pregnancy and delivery. The weight at birth was 6 pounds, 10 ounces. He was discharged from the hospital at 7 days of age. The weight gain thereafter was satisfactory on a formula of evaporated milk, and when last seen in the well-baby clinic 2 days prior to death he appeared to be in good health. The following day, however, he began to have loose stools and regurgitated the formula. On the day Of death all of the feedings were regurgitated. During the afternoon of 'that day the respirations became irregular and the color somewhat dusky.
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Physical examination at the hospital receiving station disclosed a cyanotic, severely dehydrated infant with glazed eyes. There was a blotchy yellow-red rash on the cheeks and reddish discoloration of the arms and legs. The skin of the scrotum and buttocks was excoriated and caked with boric acid powder which the mother had been applying as a diaper powder since birth. Various therapeutic measures, including caffeine sodium benzoate and epinephrine, were administered in vain and the child died at 6:25 P.M. on Aug. 27, 1954, without having been admitted to the ward. At autopsy, performed 15 hours after death, the body was found to be poorly nourished, measuring 51 cm. in length and weighing 2,762 grams. The buttocks were severely wasted, very red, and revealed multiple circinate areas of excoriation. The entire dependent part of the scrotum was fiery red and excoriated. There was faint pink discoloration of the abdomen, especially of the right upper quadrant, the precordium, neck, throat, shoulders, and scalp. T h e lower part of the back was diffusely mottled pink and red. T h e face was mottled red with a few punctate white vesicles or pustules located especially over the chin. The ears were pink to red. There was questionable pink discoloration of both forearms; otherwise the arms, legs, inguinal and axillary regions, palms of the hands, and soles of the feet were spared. There was fine peeling of tile skin of the tips of the fingers and questionable peeling of the palms of the hands; none was seen on the feet or toes. T h e mucosa of the large and small bowel was pale. Occasional petechiae were present in the ileum and an ecchymosis of 0.5 by 1.0 cm. was noted in the mucosa of the rectum. There were no other significant macroscopic alterations. Histologic sections of the smal bowel revealed small collections of neutrophils in the glands, m a n y of which were somewhat dilated. There were decreased numbers of lymphocytes and increased numbers of large mononuclear cells, myeloid cells, and a few neutrophils in the lamina propria. The
Boric acid poisoning
Fig. 3. Case 2. Pancreas.
Fig. 4, Case 2. Larynx.
533
534
Valdes-Dapena and Arey
acinar cells of the pancreas revealed welldefined large single vacuoles, some of which contained acidophilic spheres and others contained discrete spherical blue bodies. These bodies were each about the size of the nucleus of a normal acinar cell. Each lay in a clear vacuole within the cytoplasm of the cell and they occurred singly. The margins of the inclusions were sharply defined. T h e substance of the inclusion, whether stained red or blue, was quite homogeneous (Fig. 1). With the exception of these changes in the bowel and pancreas, there were no other findings of significance. Chemical analyses were carried out on the tissues from this autopsy by the Office of the Chief Medical Examiner of the State of Maryland under the direction of Dr. Russell Fisher. The following are their findings: Kidney (single determination), 100.1 mg. per cent boric acid. Liver (average of 2 determinations), 71.0 mg. per cent boric acid. Brain (average of 2 determinations), 10.7 mg. per cent boric acid. It was considered that acute enteritis, probably with associated metabolic changes and dehydration, and boric acid intoxication were responsible for death. Their relative importance and their relation to each other are not clear. Case 2. D. J., a white male infant, was born at term on Nov. 10, 1956, weighing 7 pounds, 7 ~ ounces. The mother had moniliasis in the first and second trimesters of the pregnancy but the third trimester was uncomplicated. Delivery was accomplished with outlet forceps. The infant's condition at birth was good. He was discharged on Nov. 17, 1956, weighing 7 pounds, 3 ounces. He was thought to be in good health until the day before death when the mother noted purplish mottling of the face. At 2 A.M. on the day of death, November 30, the baby did not take the bottle well, was "breathing very hard," and vomited. Later he became less responsive and respirations were said to be irregular. H e was dead when he arrived at the hospital. Iri general the mother's history at the time was vague and confused.
October 1962
Following completion of the autopsy the mother was questioned concerning the use of boric acid compounds. Only then did she reveal the fact that she had used pure boric acid powder freely to dust the diaper area with every change of diapers for several days before the death of the infant. She had been advised by her mother that boric acid was the best remedy, for the infant's excoriated diaper rash. Autopsy was performed on Nov. 30, 1956, approximately 6 hours after death. The body appeared poorly nourished, weighing 3,000 grams and measuring 55 cm. in length. Patchy purple discoloration of the skin was noted over the head and cheeks. There was superficial denudation just lateral to tile right eye, over the right half of the chin, and the posterolateral aspect of the right side of the neck. There was severe denudation of the skin on the posterior aspect of the scrotum and between the scrotum and the anus; this area was covered by a great deal of caked white powder. The lips were deep purple, and the mucous membranes of the mouth were gray purple. T h e inguinal lymph nodes were slightly enlarged bilaterally. The subcutaneous tissues were slightly dehydrated. Both kidneys were of normal size and shape but contained scattered dark red infarcts averaging 7 mm. in diameter with their bases against the capsular surface of the kidney and their apices near the tips of the pyramids. There were multiple petechiae in Peyer's patches and each urinary ostium presented as a red-to-purple hemispherical mound 3 mm. in diameter. The adrenals were of normal size and shape but their external surfaces were a peculiar blotchy dark purple. On section most of each gland was maroon and those portions which were not so discolored were pale tan. Histologically there were multiple fresh thrombi in veins of medium size throughout the body, including the lungs, kidneys, adrenals, and connective tissue about the thyroid. T h e venous thrombi in the kidney were Iocated at the apices of a number of infarcts. In the adrenals there were multiple areas of
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interstitial hemorrhage, and many hyaline thrombi filled the sinusoids. A single small thrombus was attached to the endothelium of the ductus arteriosus, and occasional fibrin masses were present in small branches of the pulmonary artery. There were scattered patches of neutrophilic infiltrate in the mucosa and submucosa of the small bowel, in the gastric mucosa, and in a few of the portal triads. Edema fluid and numerous red blood cells were present immediately beneath the transitional epithelium about the ureteral ostia in the urinary bladder. Sections of tt(e pancreas revealed a great deal of vacuolization of the aeinar cells. In many of these vacuoles there were distinct inclusions. Some of these were acidophilic, whereas others were faintly basophilic (Figs. 2 and 3). They were cytoplasmic in location, pushing the nucleus to one side. Some were very large, about the size of the nucleus of an acinar cell, and contained tiny black bodies resembling Howell-Jolly bodies. Others, however, were small. A few of the same type of cytoplasmic inclusions were present in the glands of the larynx (Fig. 4) where there was some degree of sloughing of the involved epithelial cells. The presence of a neutrophilic infiltrate in the lamina propria of the small bowel suggests the possibility of diarrhea during life although no history of it was obtained. It is of interest that a similar exudate was present in the mueosa of the small bowel in the preceding infant. The relationship of such an exudate to the boric acid intoxication is not cleat'. In any event, the dehydration which was present may well have contributed to the formation of multiple venous thrombi with subsequent renal infarcts and adrenal hemorrhages. Unfortunately, the tissues were lost before toxicologic surveys could be performed. The mother, however, brought the almost empty cardboard container of U.S.P. boric acid which she had been using and there seemed to be little or no doubt as to the presence of boric acid intoxication in this infant.
Boric acid poisoning
535
Case 3. S. D., a 26-day-old white male infant, was admitted to St. Christopher's Hospital for Children on May 28, 1957, with the chief complaint of diarrhea and vomiting. He had been in his usual good state of health until 2 ~ days prior to admission when he started to refuse his feedings. Twenty-four hours prior to admission he suddenly developed watery, frequent (6 per day) large stools and vomiting. These symptoms increased in severity to the time of admission. The vomiting was not projectile but consisted of spitting up curds of milk after feedings. A physician saw the infant and prescribed a mixture of kaolin and pectin "~ but this was not retained. At 3 A.M. on the day of admission he became very lethargic and the crying became feeble. He was afebrile throughout the course of the illness. Past medical history revealed an uneventful pregnancy, labor, and delivery. The early neonatal course was uncomplicated. At 1 week of age he developed thrush for which he was treated successfully. One week prior to admission he developed a red rash with blisters around the diaper area, followed by a rash on the face. Physical examination revealed a thin, cold, unresponsive, and semicomatose infant with chalky pallor. The pulse was slow, being 30 to 40 per minute. Respirations were 20 per minute and were shallow and irregular. Tile temperature was 94 ~ F. The head was of normal configuration; the anterior fontanelle was very small and depressed. The eyes were sunken. There was no corneal reflex. The pupils were dilated and reacted sluggishly to light. The ear drums, throat, nose, and lung fields showed no abnormalities. The abdomen was soft with no visceromegaly and no abnormal masses. The infant was severely dehydrated and was having almost continuous watery yellow stools containing mucus. The genitals were extremely edematous, and there was gangrene of the penis and scrotum. A vesiculopusmlar rash which was secondarily infected and partially covered "~Kaopcctate.
536
Valdes-Dapena and Arey
with exudate was present in the diaper area. There were small ulcers on the medial aspects of the thighs and on the lower abdomen. The skin of the face was bright red and hard; this redness extended over the forehead where there was some peeling. There were small red macules over the anterior thorax and flanks. There were no Moro reflex, no grasp, and no, tendon reflexes. He was completely flaccid. On admission the following laboratory data were obtained. The pH of the serum was 6.74; carbon dioxide, 11.0 mEq. per liter; chloride, 120 mEq. per liter; sodium, 144 mEq. per liter; and potassium, 2.7 mEq. per liter. The calcium was 9.8 mg. per cent and phosphorus was 9.2 mg. per cent. A culture of the nasopharynx revealed a luxuriant growth of coagulase-positive hemolytic Staphyloccus aureus which was sensitive to novobiocin and moderately sensitive to erythromycin. Culture of the stool yielded a moderate growth of coliform organisms. Intravenous fluids were started at the time of admission; he received 3.75 Gin. of sodium bicarbonate and 80 c.c. of whole blood. The administration of tetracycline, novobiocin, and penicillin was begun. Two hours after admission he looked more responsive and the color was better. Five hours after admission, however, he began to have convulsions. Calcium gluconate and phenobarbital sodium were given, and 3 hours later the convulsions ceased. He died 12 hours after admission. At autopsy the body was undernourished, measuring 56.5 cm. in length and weighing 3,730 grams. The skin of the penis, scrotum, and medial aspect of the right thigh was bright red, swoIlen, and superficially ulcerated. Multiple similar areas of intense hyperemia with desquamation were present in both inguinal regions and over the fingers, forehead, and chin. The left side of the face, especially the cheek and left ear, was bright red, without desquamation, and there was slight reddening of perianal skin. In the right renal vein, extending not quite to the inferior vena cava and arising ap-
October I962
parently within the renal parenchyma, there was a blunt reddish brown thrombus. Multiple thrombi were visible upon the cut surface of the right kidney. An incidental finding was the presence of but a Mngle coronary ostium which gave rise to both the left and right coronary arteries. There were no other significant macroscopic alterations. The entire nervous system revealed no gross pathologic changes. Histologic sections of the pancreas revealed vacuoles which contained acidophilic or basophilic inclusions within a number of acinar cells like those described in Cases 1 and 2. There were occasional neutrophils in scattered glands of the small bowel. Brunner's glands were moderately dilated. Urine obtained from the bladder at autopsy gave a positive reaction to turmeric paper. Analysis of the brain showed boric acid 3.8 mg. per 100 Gin. ("Normal" levels may be as high as 0.7 mg. per 100 Gm.) DISCUSSION
Lethal doses of boric acid. The minimal lethal dose of boric acid for man is not known, sa According to various case reports in the literature, there is a very wide range with great individual variation. According to Caujolle, s" a man can take 4 Gm. a day orally without incident, whereas a single dose of 18 to 20 Gm. is fatal to him and 5 to 6 Gin. to an infant. McIntyre and Burke 7a referred to an adult who was given 15 Gin. as a clysis subcutaneously and developed only slight symptoms of poisoning. They also reported the case of an adult who recovered and who developed only flushing, nausea, and vomiting after the intravenous administration of 600 ml. of a 2.5 per cent solution of boric acid. This amount equals the lower limit of the often quoted "fatal oral dose for man" which according to Potter is 1 ~ ounces of pure borax (which has a boron content equivalent to 27.6 Gm. of boric acid, almost an ounce). The young infant seems to be particularly susceptible, yet infants have survived after the ingestion of 4 t o 9 Gm. a~ Acute intoxication follows large single
Volume 61 Number 4
.doses, and chronic intoxication has occurred after daily ingestion of moderate quantities such as 4 to 5 Gin. of boric acid per day for 3 to 4 weeks or 6 to 20 Gm. of borax daily for several months. Concentration of boric acid in body tissues. Blood and tissue concentrations in fatal and nonfatal cases are widely varied. Two children were described by Fisher and Freimuth 9~ who had drunk a solution of boric acid and showed no toxic symptoms whatsoever; they had blood levels of 7.44 and 7.89 mg. per cent of boric acid, respectively. Probably such levels are nontoxic2 ~ According to the experimental work of these same authors 50 to 100 rag. per cent or more in the blood is fatal, A concentration of 52 mg. per cent in any organ is considered iethal by Hallett. 4~ A figure of this magnitude may be expected when death ensues shortly after acute poisoning. Lesser quantities may be found when the patient survives 2 or 3 days, thus allowing time for elimination of much of the drug. Since boric acid is excreted rapidly, it can be assumed that concentrations had been higher previously, and tissue damage, as proved by the fatal outcome, had been severe. According to McNally and Rust, 17 the brain and liver accumulate higher percentages than other organs. Toxicologic analysis. One difficulty with any toxicologic analysis concerning this drug is the fact that it is commonly present in the blood. Most individuals ingest a certain amount of boron daily in orange juice, all vegetables, fruits (especially currants and raisins), bread, and cereals. As a result, the average concentration in the blood is 0.14 mg. per 100 ml. of blood with a range of from 0.00 to 0.72. It has long since been established that the turmeric acid paper test on urine is unreliable since it may be positive because of the presence of boron derived from the diet alone21 Fisher and Freimuth 9~ reported that if an infant takes 4 ounces of orange juice a day he will excrete 8 times the minimal amount necessary to produce a positive test in the urine.
Boric acid poisoning
537
In their investigations they employed the method of Smith, Goudie, and Sivertson, ~2 colorimetric determination. In the toxicologic laboratories of the Office of the Medical Examiner of the City of Philadelphia, where the determinations for Case 3 were made, Dr. Fredric Rieders has been using the same method; he considers it valuable because it is simple and gives reproducible results. It is based upon the carminic acid-boron color system. Determinations are made on the Klett colorimeter using a red filter, 600 m/,. Absorption of boric acid. Boric acid will be absorbed to a certain extent through intact skin, as was originally suggested by the work of Kahlenberg2 a, :~4 This author soaked his feet in a warm solution of boric acid for 5 minutes, following which boric acid appeared i n the urine (as indicated by a positive turmeric acid paper test). In his second publication he reported that boric acid appeared in the urine in 50 to 55 seconds in each of three men whose feet, which were in good condition, were soaked in boric acid solution. Once again the turmeric paper test was relied upon. In 1958 Freimuth and Fisher 9s found that free boric acid in aqueous solution or in solution in urine was readily absorbed through the intact skin of the rabbit; borax was similarly absorbed. Boric acid is very much more easily absorbed whenever the skin has been broken, and it will, of course, be absorbed from granulation tissue, serous cavities, and the gastrointestinal tract. With respect to baby powders containing boric acid, Mulinos, Connant, and Hauser '~(; from a study of boric acid absorption in animals gonctuded that boric acid is absorbed in sufficient quantity from talc containing boric acid to lead to toxicity. Freimuth and Fisher, 9a however, employing quantitative rather than qualitative determinations, found little or no evidence of absorption of boric acid from talc and calcium metaborate. There is, moreover, no report of boric acid poisoning in the Iiterature in which the poisoning was due to the use of commercial talcum powder containing boric
5 3 8
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acid. Vignec and Ellis 97 showed that the average borated powder which contains 5 per cent boric acid is usually harmless. They exposed a large group of babies for a number of weeks to an average of 2.33 Gm. of boric acid daily in the form of borated talc. The results obtained in both the control and test groups fell close to normal values. Johnstone, Basila, and Glaser 9s determined the concentrations of boron in blood and urine of 8 infants with intact skin and in one infant with injured skin before, during, and after application of a commercially available talcum powder containing 5 per cent boric acid. The chemical procedures used were sufficiently accurate to detect less than 5.7 parts boric acid per million in samples as small as 2 ml. The highest value for blood boron concentration did not exceed 3.4 parts per million, a value not significantly higher than was found in the controls and well within the normal range. According to Blanchard, Blanchard, and Kravtin, 8~ un-ionized boric acid is preferentially absorbed through the skin as compared with ionized boric acid. T h e mixture of wet boric acid and talc results in ionization of the boric acid and thus less absorption, since the boric acid in solution forms salts with the alkaline compbnents of the talc.. Excretion of boric acid. Excretion of boric acid is for the most part accomplished by the kidneys. It has been shown that 82 to 100 per cent of boric acid taken rapidly by mouth is excreted in the urine29 Small amounts are found in the sweat. Boric acid appears in cows' milk after ingestion and has been shown to cross the placenta of the rat? 5 Although it is absorbed rapidly, its complete elimination requires some time. After 3 Gm. has been administered each day for 10 days, or 5 Gin. per day for 3 days, complete elimination will not be accomplished until at least 18 days have passed. 35 The greatest part, however, is eliminated within the first few days. REVIEW
OF REPORTED
CASES
To date, we have been able to find a total of 172 reported cases of boric acid
October 1962
poisoning (Table I). O f these, 83 were fatal and 89 were nonfatal. Seventy-eight of these have been in adults and 94 in children. The first reported fatal cases were those of Molodenkow a of Moscow who in 1881 presented 2 instances. In the first of these he had washed out the pleural cavity of a female patient, 25 years of age, for an hour with a large quantity of 5 per cent boric acid solution. The second was a lumbar abscess in a 16-year-old boy who was similarly treated. I n the same year Gowers ~~ reported 3 cases of nonfatal poisoning in which borax had been administered orally for the treatment of epilepsy. In all 3 a skin rash or eruption appeared; this he termed psoriasis and considered it to be a toxic manifestation of the boric acid. In recent years most instances of poisoning b y boric acid have been accidental rather than from its use as a medication. A nonfatal accidental poisoning was first reported in 1915 by Willson 6s in an infant who was given boric acid solution in a milk formula instead of water. The first report of a fatal accidental !ngestion appeared in 1917 when Sinigar la presented the case of a 70-year-old woman who took the drug, mistaking it for Epsom salts; she died 46 hours thereafter. Poisoning was accidental in a total of 71 cases, 35 being fatal and 36 nonfatal. In 54 of the 71 cases accidental poisoning was the result of the use of boric acid in the preparation of infant formulas. The majority of these occurred in hospital nurseries; 28 were fatal and 26 nonfatal. The second most common accident involved subcutaneous administration by clysis; there were 8 of these, 5 of which were fatal. Boric acid has been given intravenously once and did not result in death. 7a One infant is reported to have been poisoned following the use of boric acid solution as a cleansing agent for the mother's nipples. as Today boric acid poisonings still occur fairly frequently. Jacobziner and Raybin 8~ of the Poison Control Center of New York City reported that, from 1955 to 1960, 185 accidental ingestions of boric acid were re-
Volume 61 Number 4
corded. The quantity ingested ranged from one tablespoonful of the powder to a "jarful" of solution. In 1949 Gold 1~176reviewed 158 cases of household poisoning seen in New York over a 5 year period. Among them was an instance in which a woman baked a cake using boric acid instead of baking soda. In 30 of the reported cases, as in our own, poisoning was due to the application of pure boric acid to the denuded diaper area; 23 of these were fatal and 7 nonfatal. The first case of fatal poisoning by this means reported was in 1948 by Fellows, Campbell, and Wadsworth a~ and the first nonfatal case of that type, by Brooke TM in 1953. Poisoning was the result of the deliberate administration of the drug as therapy in 71 cases; 25 were fatal and 46 nonfatal. In 23 of these 71 boric acid was administered orally, mostly for the treatment of epiIepsy. Only 2 of these were fatal. In 8 of the 25 fatal cases in which the drug was used therapeutically, sores, abscesses, ulcers, and wounds were washed out with it and in 6 cases burns were treated with it. Autopsy findings, more or less detailed, have been included in 55 reports of fatal cases; the majority of these leave m u c h to be desired. M a n y of them, although very lengthy, contribute little to the pathologist who seeks in them information about how to make the diagnosis morphologically. They describe such nonspecific entities as: "Congestion of all organs, . . . . enlargement and softening of t h e liver," "congestion and edema of the lungs," "splenomegaly," or "all organs normal," with the cause of death left in doubt. The skin changes are perhaps the most significant of the gross observations. In many cases, the very extensive erythema and desquamation of the skin are outstanding features of the necropsy. Histologic changes have been described in cases of boric acid poisoning since the report of Brose 2 in 1883, but even as late as 1950 they, too, were of little help, including such observations as "swollen liver cells,"
Boric acid poisoning
54 3
and "degeneration of tubular epithelium in the kidney." In 1951 Fisher a~ first reported intracytoplasmic inclusions in the pancreas due to boric acid poisoning. He had observed this lesion in 4 autopsies. He described the bodies as varying "up to 10 micra in diameter and lying within acinar cells. They were rounded, homogeneous, eosinophilic, some with deeply basophilic granules." He thought that they represented part of a degenerative process in the cells. He considered that all the other g r o s s and histologic features of the autopsies were nonspecific and that this entity alone was diagnostic of the disease. Seventeen fatal cases were reported after 1951, with autopsies on 11 of them. The pancreatic lesion was mentioned in only two of the articlesY 9' ~ Thus, the lesion has been described in only 6 recorded cases. Stowens 1~ made mention of it in his discussion of borate poisoning. It would seem that greater awareness of the occurrence and the significance of this apparently specific morphologic change would be valuable to pathologists in general and to those dealing with infants and children in particular. Boric acid is still used extensively by both the medical profession and the laity. In 1956 Fisher 1~ conducted a survey among dermatologists. Ninety-four per cent of them used the drug in their practice, 71 per cent frequently. In I943 Ross and Conway 2~ pointed out that 20 of 30 doctors questioned were not cognizant of the fact that boric acid could be toxic when taken by mouth. Apparently m a n y persons both professional and nonprofessional are not aware that this drug can be lethal. It appears that for every conceivable medical or therapeutic use of boric acid there is now a more effective and safer' agent, whether it be for the production of moist heat or antisepsis. I t has, for instance, been shown 1~ that boric acid in concentrations higher than 2 per cent inhibits phagocytosis, thereby negating primary defense mechanisms of the body against bacterial invasion. At concentrations of 4 per cent, toxicity to the tissues is greater than its
5 44
Valdes-Dapena and Arey
bactericidal activity. Thus, the organism's invasive qualities m a y actually be aided a n d abetted by the use of a too c o n c e n t r a t e d solution. T h e drug has been aptly called a "wolf in sheep's clothing. ''1~ Since it is of so little value therapeutically and since on a n u m b e r of occasions its accidental use in hospital nurseries has resulted in the poisoning of large n u m b e r s of infants, it should be removed from hospital pharmacies. T h e r e is no d o u b t that when dispensed by drug stores to lay persons the containers should be clearly labeled "poison." SUMMARY
T h e medical literature on boric acid poisoning is surveyed and 172 reported cases are reviewed briefly. T h r e e additional cases are recorded, b r i n g i n g the total to 175. P a r t i c u l a r attention is directed to the intracytoplasmic inclusions in the pancreas in this disease entity, heretofore m e n t i o n e d b u t briefly in three articles a n d in Stowen's text. T h e toxicity of boric acid should be recognized a n d it should be clearly labeled as a poison. Boric acid should not be available in hospitals.
We wish to acknowledge the kind cooperation of the personnel of the Office of the Medical Examiner of the City of Philadelphia and especially that of Dr. Fredric Rieders, chief toxicologist, and Mr. Joseph Poppel, photographer. We are most grateful to the staff of the Library of the College of Physicians for their help, and to Dr. A. Valdes-Dapena for his translations. We also thank Miss Estelle Goebber and Mrs. Freda Lebengood, tissue technicians, and Miss Ruth Shivers, secretary.
REFERENCES For fatal cases.
1. Molodenkow, S. E.: 2 F~ille yon Vergiftung durck Bors~iure, St. Petersburger reed. Wchnsehr. 6: 361, 1881 (abstract), Vrach. 3 h 509, 1881. 2. Brose, L. "D.: Death following the external use of powdered boracic acid, M. News 43: 199, 1883.
October 1962
3. Hogner, FSrgiftningsfall genom borsyreskoljningar, Eira 8: 389, 1884. 4. Fer6, C.: Th6rapeutique m6dicale. Le '%0risme" ou les accidents de la m6decation par le borax, Semaine m6d. 1'4: 497, 1894. 5. Schwyzer, F.: Ueber Bors~iurevergiftung, New Yorker me({. Monatsschr. 7: 263, 1895. 6. Hall, A.: The possible dangers of treating extensive burns with boracic ointment, Lancet 1: 993, 1896. 7. Best, C. L.: Boric acid poisoning; report of a fatal case with autopsy, Tr. Chicago Path. Soc. 6: 161, 1903. 8. Williams, V.: Unreported data, cited by Best.* 9. Dopfer: Ober einen Todesfall nach Anwendung der Offizinellen Borsalbe bei einer Brandwunde, Miinchen. med. Wchnschr. 52: 763, 1905. I0. Editorial: A case of boracic acid poisoning, Brit. M. J. 2: 1695, 1907. 11. Savariaud, A.: Serious poisoning by boric acid dressing, J. A. M. A. 63: 593, 1914. 12. Maguire, G. C.: Boric acid poisoning? Case with comments, Practitioner 97: 580, 1916. 13. Sinigar, H.: Cases of poisoning by sodium nitrite and boric acid, Lancet 2: 162, 1917. 14. Potter, C.: A case of borax poisoning, J. A. M. A. 76: 378, 1921. 15. Bazin, A. T.: Acute boracic acid poisoning (fatal), Canad. M. A. J. 14: 419, 1924. 16. Birch, J.: Fatal poisoning by borax, Brit. M. J. h 177, 1928. 17. McNally, W. D., and Rust, C. A.: The distribution of boric acid in human organs in 6 deaths due to boric acid poisoning, J. A. M. A. 90: 382, 1928. 18. Aikman, J.: Strychnine poisoning in children (Table I--Accidental poisonings of children 5 years of age and under in New York State [exclusive of greater N. Y.]). J. A. M. A. 95: 1661, 1930. 19. Cushing, E. H.: BorsSmre-Vergiftung, medizinale, Samml. Vergift. h 91, 1930. 20. Vartianen, A., and Oravainen, M.: BorsgureVergiftungen, medizinale. Zwei Fglle, ein Fall mit t6dlichen Ausgang, Samml. Vetgift. 4: 211, 1933. 2I. W61sch: Cited by Gissel.22 22. Gissel, H. A.: Contribution to the toxicity of boric acid, Zentralbl. Chir. 60" 1635, 1933. 23. Ponsold, A.: Fatal boric acid poisoning following perforation of urethra in attempted cystoscopy, Deutsche Ztschr. ges. gerichtl. Med. 34: 321, I940. 24. Ross, C. H., and Conway, J. F.: The dangers of boric acid: Its use as an irrigant and report of a case, Am. J. Surg. 60" 386, 1943. 25. Cross, R. R.: New ruling on boric acid, J. A. M. A. 126: 715, 1944. 26. Barnum, C. G., and Opper, L. S.: Boric acid poisoning of 20 newborn infants in the hospital at New London, Conn., J. A. M. A. 128" 273, 1945. 27. Bigelow: Cited by PfeifferY s
Volum~ 6I
Number 4
28. Watson, E. H.: Boric acid, a dangerous drug of little value, J. A. M. A. 129" 332, 1945. 29. McNally, W. D., and Ruckstinat, G.: Two deaths due to boric acid, M. Rec. 160; 284, 1947. 30. Fellows, A. W., Campbell, J. S., and Wadsworth, R. C.: Boric acid--poison, J. Maine M. A. 39: 339, 1948. 31. Grant, R. S., and Wegner, E. S.: Fatal case of boric acid poisoning, Am. J. Dis. Child. 75: 910, 1948. 32. Abramson, H.: Poisoning in a newborn infant, Pediatrics 4: 719, 1949. 33. Lueck, W. W.: Poisoning in children, Lancet 69: 155, 1949, 34. Young, E. G., Smith, R. P., and Macintosh, O. C.: Boric acid as a poison: Report of six accidental deaths in infants, Canad. M. A. J. 61: 447, 1949. 35. Pfeiffer, C. C.: Is boric acid harmless? Mod. Hosp. 74: 106, 1950. 36. Brooke, C., and Boggs, T.: Boric acid poisoning, A, M. A. Am. J. Dis. Child. 82: 465, 1951. 37. Fisher, R. S.: Intracytoplasmic inclusions in the pancreas due to boric acid poisoning, Am. J. Path. 27: 745, 1951. 38. Bumbalo, T. S.: Boric acid poisoning, New York J. Med. 52: 1913, 1952. 39. Ducey, J., and Brooke, W. D.: Transcutaneous absorption of boric acid, J. Pediat. 43: 644, 1953. 40. Goldbloom, R. B., and Goldbloom, A.: Boric acid poisoning; report of 4 cases and a review of 109 cases from the world literature, J. PEDIAT. 43: 631, 1953. 40a. Goldbloom, R. B.: Correspondence, J. PEmAT. 44: 720, 1954. 41. Gonzales, T. A., Vance, M., Helpern, M., and Umberger, C. J.: Legal Medicine Pathology and Toxicology, ed. 2, New York, 1954, Appleton-Century-Crofts, Inc., p. 776. 42. Maxson, W. T.: Case report of boric acid poisoning from topical application, J. Kentucky M. A. 52: 423, 1954. 43. Editorial: Baby's death from boron poisoning, Brit. M. J. 1: 237, 1955. 44. Hallett, G. W., Jr.: Boric acid poisoning; case, J. Maine M. A. 46; 93, 1955. 45. Arey, J. B.: Unexpected death in early life, J. PEDIAT. 49: 523, 1956. 46. Rosen, F. S., and Haggerty, R. J.: Toxic hazards: Fatal poisoning from topical use of boric acid powder, New England J. Med. 255: 530, 1956. 47. Jordan, J. W., and Crissy, J. T.: Boric acid poisoning, A. M. A. Arch. Dermat. 75: 720, 1957. 48. -Freehette, A. L.: Unreported data. 49. Segar, W. E.: Peritoneal dialysis in the treatment of boric acid poisoning, New England J. Med. 262: 798, 1960. For nonfatal cases.
50. Gowers, W. R : On psoriasis from borax, Lancet 2: 546, 1881.
Boric acid poisoning
54 5
51. Bruzelius, R.: Om borsyref6rgiftning, Hygiea 44: 548, 1883. 52. Huse, R. C.: Poisoning by boracic acid, M. News 40: 704, 1882. 53. Warfvinge, F. W.: Fall af borsyref6rgiftning, Nord. med. Ark. 15" 36, I883. Abstract, Hygiea 45: 10, 1883. 54. Johnson, E. G.: Kliniska studier 8fver borsyrans och borax' inverkan p~ m~inskliga organismen ~ifvensom deras elimination ur den samma, Nor& med. Ark. 17: 1, 1885. 55. Spencer, C. E.: Boracic acid poisoning, Lancet 8: 22, 1888. 56. Welch, G. T.: Toxicological effects of boracic acid, M. Rec. 34: 531, 1888. 57. "Fer6, C., and Lamy, H.: Deux cas d'6ruption ecz4mateuse provoqu~e par le borax, Nouv. iconog. Salp4trihre 2: 305, 1889. 58. Lemoine, G.: De la toxicit4 de l'acide borique, Gaz. m6d., Paris 7" 222, 1890. 59. Evans, J. J.: Toxic effects of boracic acid, Brit. M. J. 1: 209, 1899. 60. Wild, R. B.: Dermatitis and other toxic effects produced by boric acid and borax, Lancet 1: 23, 1899. 61. Handford, H.: Erythematous rash due to boric acid, Brit. M. J. 2: t495, t900. 62. Rinehart, J. F.: Two cases of boric acid poisoning, Therap. Gaz. 17: 662, 1901. 63. Van Dort Kroon: Boorzuur-vergiftiging, Med. Weekbl. 12: 41, i905-1906. 64. McWalter, J. C.: Note on the effects of borax on infants, Lancet 2: 369, 1907. 65. Harley, V.: Boracic acid poisoning, Brit. M. J. 1: 832, 1912. 66. Sanders, J. H.: Boracic acid poisoning, Brit. M. J. 1: 605, 1912. 67. McWalter, J. C.: Boric acid eczema, Brit. M. J. 1: 1002, 1915. 68. Willson, P.: A case of boracic acid poisoning, Washington M. Ann. 14: 329, 1915. 69. Forsyth, D.: Coeliac disease or boric acid poisoning, Lancet 2" 728, 1919. 70. Ide, M.: Inconvenients du bore, Bull. Acad. roy. m6d. Belgique 3: 111, 1923. 71. Lewin, A.: Cited by Gissel. ~ 72. Brown, W. L., Brown, C. P., and Murphy, J. L.: Toxicity of boric acid, J. A. M. A. 106: 1221, 1936. 73. McIntyre, A. R., and Burke, J. J.: Intravenous boric acid poisoning in man, J. Pharmacol. & Exper. Therap. 60: 112, 1937. 74. Pcyton, H. A., and Green, D.: Boric acid poisoning, South. M. J. 34: 1286, 1941. 75. Velarde, J.: Un easo de alopecia i toxiea o neuropatlcia? Prensa m6d. mex. 6: 157, 1941. 76. Dwek, J.: Toxic symptoms due to the use of boric acid, Acta med. orient. 4: 352, 1945. 77. Rubin, M. B., Recinos, A., Washington, J. A., and Koppanyi, T.: Ingestions of polsans in children, A survey of 250 admissions to Children's Hospital, Clin. Proc. Child. Hosp. 5: 57, 1949. 78. Brooke, C. E.: The boric acid problem, Gen. Practitioner 7: 43, 1953. 79. MacGillivray, P. C., and Fraser, M. S.:
5 46
80.
81. 82. 83. 84. 85.
Valdes-Dapena and Arey
Boric acid poisoning in infancy arising from the treatment of napkin rash, Arch. Dis. Childhood 28: 484, 1953. Blanchard, M., BIanchard, M. C., and Kravtin, A. J.: A severe case of boric acid poisoning with survival, J. M. A. Georgia 44: 395, 1955. Boggs, T. R., Jr., and Anrode, H. G.: Boric acid poisoning treated by exchange transfusion, Pediatrics 16: 109, 1955. Searle, A.: Boric acid poisoning, Clin. Proc. Child. Hosp. 12: 13, 1956. Connelly, J. P., Crawford, J. D., and Soloway, A. H.: Boric acid poisoning in an infant, New England J. Med. 259: 1123, 1958. Parkkulainen, K. V.: Boric acid poisoning treated with cortisone. A case report, Ann. Paediat. Fenniae 4: 123, 1958. Jacobziner, H., and Raybin, H. W.: Boric acid poisonings from "Briefs on accidental polsonings in New York City," New York J. Med. 60: 2903, 1960.
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