6 tal Me Lav 1967; 9: 141-196 Human toxicology of boron with special reference to boric acid poisoning Carlo Locatelli, Claudio Minoia, Marcello Tonini, Luigi Manzo V cesar c, tin ton M, Mano L Human toxeoy of boron with special reference to borie acid poisoning. G Ital Med Lav 1987; 9: 141 - 146. The improper use of boric acid containing antiseptcs is still one of the most common eauses of toxic accidents in newborns and infants, Health hazards may also arise from inadvertent absorption of inscetiides and household products containing borates as well as from occupa- tional accidents related to production and use of boranes. A variety of boronated agents with hypolipidemic, antiinflamms- tory or anticancer properties have been developed in recent years. Unfortunately, most of these compounds Were found to be highly toxic when iested at the required therapeutic dosages in animals. In this paper, recent information on human tox- icology of boron is reviewed, with special emphasis on epidemiological and clinical aspects of boric acid poisoning. Introduction Boron toxicity has been recognized since the last century as a consequence of the improper use of pharmaceuticals containing boric acid and borates. Boric acid is weakly bacteriostatic and not at all bactericidal but it is still popular and continues to be used in many Countries as a buffering, non- irritating and non-staining antiseptic (25). Boron compounds are also used in industry and agricul- ture, and are present in a variety of household pro- duets that can be hazardous in overdosage (21). A total of 4558 cases of toxic exposures to boric acid containing products has been reported in 1985 by the American Association of Poison Control Cen- ters National Data System (34). In this paper, aspects of human toxicity of boron are described with special reference to boric acid and related compounds that are significant for their impact in clinical toxicology. Uses Boric acid is frequently found in products used for application on skin and mucous membranes as Carlo Locatelli: Centro Antiveleni Ospedale Niguarda Ca’ Granda, 20162 Milano. Claudio Minoia: Fondazione Clinica del Lavoro, Via S, Boezio 26, 27100 Pavia Marcello Tonini, Luigi Manzo: Universita di Pavia, Dipar: fimento di Medicina Interna, Sezione di Famacologia ¢ Tossico- logia, Piazza Botta 10, 27100 Pavia eyewashes, gargles, ointments and skin powders. In EEC Countries, the concentration of boric acid in tales and produets for oral hygiene is limited to 5% and 0.5% respectively (39). Borates were formerly used as food preservatives but have been replaced by safer agents for this purpose. Present- ly, the primary uses of sodium borate (borax) are in soaps, detergents, fertilizers, wood preservatives, fungicides and fire-retardant paints (59). Boric acid is particularly poisonous to insects. It has been used to protect wood against insect damage and has gained considerable popularity as an effective agent for eliminating cockroach infestation (33). SPECIAL MEDICAL APPLICATIONS In recent years, considerable attention has been fo- cused on a series of boronated substances in con- nection with their use in neutron capture therapy of intracranial tumours (1). Boron penetrates the blood-brain barrier quite poorly but accumulates in neoplasms as the brain tumors have large gaps in this barrier. The stable nuclide 'B possesses an extraordinary ability to capture neutrons. The selective uptake of '°B in malingnant tissue is followed by neutron irradia- tion to produce an in situ source of alpha radiation. ‘The development of hybridoma technology has also made it possible to deliver the neutron capture agent to tumor cells by linking '°B-containing com- pounds to monoclonal antibodies against tumor associated antigens (16). Boronated analogs of sub- stances that are bound to melanin or melanin pre~ cursors such as polycyclic amines and thioamides accumulate in murine melanotic cells and are pre~ sently studied for their potential use in melanoma therapy (32). A series of trimethylamine cyanoborane and trimethylamine carboxyborane derivatives are known to possess intrinsic antineoplastic activity against a variety of experimental tumors in animais (22). In addition, boron analogs of a-aminoacids were found to exhibit hypolipidemic (24) and anti- inflammatory (23) activities in laboratory animals. Unfortunately most of these compounds appear to be toxic with a low safety index that precludes their use in medicine.tat Med Law 1987; 95 141-146 HORANES Uses and toxicology of boranes have been re- viewed in a number of excellent articles (53,56). Diborane is a colorless gas with toxic irritating effects largely involving the respiratory tract. Pen- taborane and decaborane are neurotoxic agents which decrease brain levels of norepinephrine and serotonin in experimental animals. These changes were often associated with autonomic and be- havioral dysfunction similar to that produced by the antihypertensive and tranquilizer agent, reser- pine. Liver and kidney can also be affected if expo- sure is severe. In humans, symptoms of pentabor- ane or decaborane poisoning may develop follow- ing inhalation of levels as low as 25 ppm. Low level exposures were associated with drowsiness, headache, nausea and vertigo. Visual disturbances, tremors, generalized muscle spasms, thabdomy- loysis and coma have been described in severe pen- taborane intoxication (53,61). Boric acid poisoning Boric acid poisoning was a relatively common event in the past with high mortality and morbidity rates. Valdes Dapena and Arey (57) reviewed the medical literature of boric acid poisoning and tabu- lated data on 83 fatal and 89 non-fatal cases. In a study of over 100 cases reported by Goldbloom and Goldbloom (19), the overall fatality rate was 55% with 70% fatalities in infants under 1 year of age. Because of the poor safety record, medical and pharmaceutical associations recommended res- tricting the use and availability of boric acid parti. cularly in hospitals were infant formula are being prepared (2, 39, 51). Tn contrast with earlier observations, the most recent reports of boric acid poisoning in Europe (15) and United States (33) have invariably indi- cated low fatality rates (Table 1). In a series of 72 cases described by Linden et al., 57 (79%) patients remained asymptomatic, 14 (20%) developed minor symptoms and one patient died (33). Similar results were obtained from retrospective analysis of a total of 134 cases of boric acid poisoning reported from 1974-1984 to the Poison Control Center in TAB. I - Summary of Cases of Boric Acid Poisoning Year No, Patients Fatality Rate% Ref. 1953 104 55 19 1962 175 49 55, 1984 134 07 1s 1986 216 03 3B 1, . Loctelieal. Paris indicating no symptoms in 74% of patients and gastrointestinal disturbances in 20%. Cutaneous disorders and serious CNS complica- tions were noted in one patient (15). ‘A number of factors may have contributed in re- cent years to reduce the importance of boric acid as a toxic hazard, i.e., more cautious use of products containing boric acid or borates, and progresses in clinical toxicology that have led to effective preven- tion and treatment of serious complications of bo- rate overdosage. Moreover, a more realistic eva- luation of effects of human boric acid poisoning probably resulted from systematic collection of data in poison information services by recording not only serious accidents but also mild exposures. In addition to accidents due to ingestion of large doses of boric or borates, poisoning and death occurred as the result of topical application of boric acid solutions and ointments on skin burns or abraded skin (3). Severe toxicity was also produced by boric acid-soaked dressings in the treatment of dermatitis, application of undiluted boric acid pow- ders for infant diaper rash, mucosal absorption from enemas and the irrigation of body cavities with saturated boric acid solutions (44,45,50). It is generally believed that topical use of tales contain- ing 3% boric acid or less is not dangerous because ‘of both the low boric acid concentration and the chemical reaction of alkaline tale with boric acid leading to formation of a non-soluble, unabsorb- able salt (4,25) Based on data reported to the Milan Poison In- formation Service, the majority of accidents of boric acid poisoning in Italy have resulted from boric acid solutions mistaken for mineral water mainly during preparation of infant formula or from inadvertent substitution of crystalline boric acid for sugar and other edible products. A limited number of cases have resulted from mucocu- taneous absorption of boric acid formulations (10). SINGLE DOSE EXPOSURE ‘The minimum lethal dose of ingested boric acid has not been precisely determined but is approximately 2103 gin infants, 5 to 6 g in children and 15 to 20 in adults (49). Under certain instances systemic toxicity has resulted from ingestion of as little as 0.17-0.2 g boric acid/kg body weight (46). An in- travenous dose up to 20 g of sodium borate (equivalent to 2.12 g boron) which was adminis- tered to 10 patients for the purpose of neutron cap- ture therapy of malignancies produced nausea, vomiting, mild peripheral vascular collapse and occasionally seizures and respiratory depression G5). Clinical findings. Though absorption of boric acid is rapid, clinical manifestations are delayed foral Mea Lav 1987; 9; 161-146 several hours (15,33,46). The earliest symptoms are gastrointestinal irrespectively from the route of exposure, and include nausea, persistent vomiting, diarthea and colicky abdominal pain (25). CNS in: volvement is usually manifested by headache, tre- mors, restlessness and occasionally delirium and convulsions followed by weakness and coma. Hyperpyrexia, cyanosis, metabolic acidosis and shock may develop in severely affected patients. Nephrotoxicity is common in boric acid poisoning as the kidney is the major route of boron excretion and high renal boron concentrations are usually attained (10). Renal lesions are manifested in the form of tubular necrosis with oliguria and albumi- nuria which may precede anu ‘The cutaneos effects are particularly striking. An extensive exfoliative dermatitis beginning as an erythema involving palms, soles and buttocks may develop as the only manifestation. Initial skin le- sions may eventually become generalized and undergo bullous formation, massive desquamation and sloughing resembling that of Ritter’s disease or scarlet fever (11,46) Death may occur within one to several days of the onset of symptoms resulting from neurological complications, shock or terminal infections (26,58). Pathological findings include gastroenter- itis, nephrosis, hepatitis and cerebral edema. CuRontc EXPOSURE In addition to poisonings from absorption of a sing- le dose, boric acid can induce toxicity as the result of repeated exposures to lower doses. Cumulative toxicity occurred in infants following multiple application of boric acid dusting powders or ingestion of commercial mixtures of borax and honey as a soother for sore gum (20,42). Chronic boric acid poisoning was also described in adults a to misuse of boric acid-based mouthwashes 21). Clinical findings. Symptoms of chronic boric acid poisoning somewhat resemble those produced by iodism. Early manifestations may develop after weeks of exposure und usually involve skin and mucous membranes with dermatitis, conjunctivitis, appearance of a red tongue, cracked lips and hair loss (52). Periorbital edema, irritability, anorexia, weight loss, persistent nausea and vomiting, di- arthea and hypoplastic anemia have been’ de- seriben as complications. Convulsions and EEG abnormalities are not infrequent, particularly in children (20, 33, 42). Symptoms are usually reversi- ble on discontinuation of exposure (27). Factors in- cluding immaturity (infants and children) and preexisting renal disease may increase individual susceptibility to chronic borate intoxication (4), aman Tovicology of Boron PHARMACOKINETICS Intestinal absorption of boron is rapid and almost complete after ingestion of boric acid or borate, peak blood concentrations being reached within 2 hours (47).. Boric acid is poorly absorbed through intact skin, but penetrates abraded skin surfaces, wounds and burned skin in amounts sufficient to cause toxicity with the usual preparations (13,17,18). Death has resulted from the use of 3% boric acid compresses for treatment of extensive eczema in a seven month old child who presented blood boric acid levels as high as 250 mg/L (29,30). Increased absorption of boric acid through damaged skin was, demonstrated in rabbits treated with different acid formulations (as shown in Table 2) (12). On the other hand, evidence has been obtained indicating, that the vehicle may be important as a factor affect- ing dermal absorption of boric acid. For example, topical application of 3% boric acid in anhydrous, emulsifying bases failed to increase blood or urine boron levels in adult volunteers while use of a wa- tet-based jelly led to increases within 2-4 hours in the same subjects (28,47). With the water- emulsifying preparation, boron excretion was un- altered even when the boric acid ointment was ap- plied on abraded skin (55). In animals, the administered boric acid is distri- buted to all tissues. Rats given a single i.p. dose of 42 mg/kg sodium borate showed the highest boron levels in kidney, liver, heart and blood. Boron con- centration in the brain was relatively low but re- mained fairly constant throughout the study (37) In fatal cases of poisoning, levels of 400-700 ppm. boric acid were measured in autopsy samples with the liver and brain showing the highest boron con- centrations (8,25). From 80 to 100 per cent of a boric acid dose is excreted by the kidney with small amounts found in, sweat and feces (25). Pharmacokinetics studies in TAB. Il- Urinary Excretion of Boron in Rabbits treated with Boric Acid by Different Routes urinary boron route of no. administration of animals pm conrol SSH 05-72 (untreated) oral 6 6-14 dermal intact skin 2 56. 3.4 abraded skin 2 £9. 10.8 burnt skin 2 178 - 246 * 200 mg/kg Boric Acid as a 5% solution. Adapted from Draize and Kelly (12) 1G teal Med Lav 1987; 9 161 - 6 volunteers given a single 600 mg dose of boric acid by iv. infusion indicated rapid removal of boron and no tendency to accumulation. The elimination half-life of blood boron was approximately 21 hours (28). In boric acid overdose, the kinetic pro- file of boron was found to be biphasic with rapid excretion yielding about 50 per cent in the first 12 hours and the remainder excreted over a period of 5 to 7 days (36). Boric acid was still present in urine of intoxicated patients 23 days after a single inges- tion (60) In chronic intoxication, the body burden of boron declines rapidly after cessation of exposure with a large fraction of the dose being eliminated in a few days. However, as long as three weeks were required to eliminate borate completely (31), and there is evidence suggesting that boron can accumulate in the body during repeated exposures. This, for example, has been shown to occur in in- fants who had regularly been given soothers dipped in «borax and honey» products (Table 3) (20,42) or after treatment with medicated tales containing ex- cessive boric acid concentrations (15). Reduced re- nal function may promote boric and accumulation and increase toxicity after continuous absorption of otherwise tolerated doses LABORATORY INVESTIGATIONS Since boron is normally present in human blood (40), nonquantitative identification methods are not ‘suitable for use in diagnosis of boric acid poisoning In subjects with no known exposure to boric acid, blood boron levels average 0.1 mg/L with a range from 0.04 to 0.7-1 mg/L (7, 14, 17, 33, 42, 53), TAB. III - Chronic Boric Acid Intoxication in Infants case age duration of symptoms blood boron (months) exposure” (mg) (weeks) 1 6 5 convulsions, 2.6 enteritis irritability 2 15 4 convulsions, 8.5 vomiting, irritability 3 6 10 convulsions, 84 rnonexposed 2-21 - - 0.21 infants + Resulting from regular use of soothers dipped in borax- honey formulations From O'Sullivan and Taylor (42) 7 Locate Toxic manifestations usually develop at blood boron levels greater that 20 mg/L and fatalities can be anticipated at levels exceeding 200 mg/L. Levels in excess of 500 mg/L are consistently fatal (25). Analysis of blood boron may be useful in con- firming the diagnosis but the results do not appear to be predictive of the degree of toxicity following single ingestions. Severe symptoms were reported in an infant showing blood boron values as low as 3.6 mg/L, while concentrations of 13.8 mg boron/L were measured in asymptomatic children and minor manifestations were described in adults with blood boron levels up to 70 mg/L (33). Blood boric acid concentrations higher than 30 mg/L have usually been found in subjects with chronic boric acid intoxication (52). ‘TREATMENT It is generally believed that no treatment is needed if the boric acid dose is tess than 50 mg/kg (10). Gastric lavage and careful skin decontamination are recommended after ingestion and dermal expo- sure, respectively. Since boric acid is predominantly excreted by the kidney, forced diuresis is useful and should be im- mediately started following ingestion of boric acid in doses higher than 100 mg/kg even in asymptoma- tic patients. Attention to fluid and electrolyte ba- lance is particularly important in small children as severe abnormalities may result from the profound gastroenteritis. “Aggressive elimination procedures including hemodialysis are in principle indicated in severe cases (54). Unfortunately, the majority of severe boric acid poisonings occur in infants and neonates in whom hemodialysis is technically difficult. Thus, peritoneal dialysis is usually performed (5, 38, 48, 60). Exchange transfusion was found to be little or not effective (9). The role of hemoperfusion has not been conclusively defined (11) ‘Administration of antibiotics is useful for pre- venting superinfection in severe cases. Anticonvul- sant therapy should be performed using in- travenous diazepam rather than barbiturates. Sodium borate was shown to cause significant potentiation of barbiturate-induced CNS depress- ion in rats (37) No antidotes or specific treatments against boric acid toxicity are known. Gastrointestinal decon- tamination using activated charcoal has been sug- gested to reduce absorption of ingested boric acid (33), However, the efficacy of this treatment is questionable since boric acid is bound to charcoal only in small quantities (49) The reported interactions of boric acid with riboflavin (43) suggest that treatment with high doses of riboflavin may be beneficial Using a rodent model of sub-acute boric acid in- toxication, Banner et al. (6) described favorabletal Me Lay 1987; 9: 141-146 effects of N-acetyleysteine. The i.p. injection of 500 mg/Kg of this agent was effective in increasing the total amount of boric acid excreted in the urine and reversed boric acid induced oliguria. Studies are needed to establish to role of N-acetylcysteine as an antidote of boric acid in clinical situations. Locatelli C, Minoia C, Tonini M, Manzo L. Tossicologia clinica del boro. L.’avvelenamento da acido borico. G Ital Med Lav 1987; 9: 141 - 146. 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