Kidney failure, also called a renal failure or end-stage renal disease, is the last stage of chronic kidney disease.
When the kidneys fail, it means they have stopped working well enough for the person to survive without dialysis or kidney transplant (1).
However, even these remedies are not without adverse side effects. For instance, researchers found an incidence of kidney stones in patients after a kidney transplant.
Calcium based stones, such as calcium oxalate and calcium phosphate, were the most common types of kidney stones found after kidney transplantation (2).
Meanwhile, studies have examined the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic kidney disease (CKD) (3).
Findings suggested that short-term NSAID use has adverse side effects on blood pressure elevation (4).
High blood pressure is the second principal cause of kidney failure in the United States after diabetes (5).
There are no studies specific to the use of CBD alone and its impact on kidney health. There are, however, limited studies that examined the effects of cannabis on kidneys, and they produced mixed results.
During the American Society of Nephrology’s Kidney Week conference in October 2018, researchers shared their findings from a recent study on medical marijuana use and its side effects on kidneys (6).
Marijuana and hemp belong to the same plant species, Cannabis sativa, but are widely different. Marijuana contains much more tetrahydrocannabinol (THC) than hemp, while hemp contains more cannabidiol (CBD).
The researchers, who studied kidney disease progression in cannabis users, found that chronic kidney disease (CKD) patients’ kidney function declined faster in those who used cannabis, compared to those who did not (7).
Joshua L. Rein, DO, who led the study, warned that kidney patients using cannabis should be aware of potential symptoms, such as nausea, lack of appetite and chronic pain, which are all valid issues for medical marijuana usage (8).
Meanwhile, researchers of a study published in the Journal of Pain and Symptom Management believe that even minor improvements in patients with difficult-to-treat CKD symptoms may be clinically meaningful (9).
In their research, they found that cannabinoids, like CBD and THC, may present a reasonable alternative to pain and symptom management.
Another study, which was published in the Journal of Pharmacology and Experimental Therapeutics showed that CBD might help reduce nephrotoxicity by decreasing oxidative stress, inflammation, and cell death (10).
Nephrotoxicity occurs when the body is exposed to a drug or toxin that causes kidney damage, which makes the body unable to eliminate excess urine and wastes.
Still, due to limited treatment options for chronic kidney disease (CKD), symptom management can be challenging.
Thus, therapeutic alternatives are in high demand, which may explain why, in recent years, medical marijuana has emerged as an attractive therapeutic option (11).
As a result, medical cannabis continues to be used for a variety of indications with minimal guidance on known risks, particularly on the altered physiological state of patients with chronic kidney disease (CKD) (12).
According to a study published in the American Journal of Physiology - Renal Physiology in 2017, the endocannabinoid system (ECS) plays a crucial role in renal homeostasis.
While data suggest cannabis and cannabinoids could have essential effects on kidney function, there is not sufficient evidence from clinical research studies to determine the dangers faced by users of these products in respect to the development of acute kidney injury (AKI) or CKD (13).
A 2016 review looked into the emerging role of the endocannabinoid system, particularly the cannabinoids and the cannabinoid receptors, in normal kidney function and other diseases, such as diabetes and obesity, that directly contribute to the development of renal diseases (14).
The authors of the said review found that the activation of the CB1 receptor regulates renal vascular blood flow. Meanwhile, the renal CB2 receptor reduces the effects of inflammation, oxidative stress and renal fibrosis.
The limited treatment options among individuals with CKD increase the demand for therapeutic alternatives.
Despite the current lack of approved CBD or cannabis therapy, some patients may still want to start experimenting with medical cannabis for symptom management.
However, although CBD has been used in many therapeutic applications, the evidence of its efficacy with chronic kidney disease has not been well-reviewed. Also, there is not enough literature accumulated to advise appropriately on consumption forms and dosage.
Before using CBD to treat CKD symptoms or as supplementary therapy, a consultation with a nephrologist experienced in cannabis use is strictly advised.
|1.1 Scientific name|
|1.3 Common name(s)|
|2.1 Main risks and target organs|
|2.2 Summary of clinical effects|
|2.4 First-aid measures and management principles|
|2.5 Poisonous parts|
|2.6 Main toxins|
|3.1 Description of the plant|
|3.1.1 Special identification features|
|3.2 Poisonous parts of the plant|
|3.3 The toxin(s)|
|3.3.2 Description, chemical structure, stability|
|3.3.3 Other physico-chemical characteristics|
|3.4 Other chemical contents of the plant|
|4. USES/CIRCUMSTANCES OF POISONING|
|4.2 High risk circumstances|
|4.3 High risk geographical areas|
|5. ROUTES OF ENTRY|
|6.1 Absorption by route of exposure|
|6.2 Distribution by route of exposure|
|6.3 Biological half-life by route of exposure|
|6.5 Elimination by route of exposure|
|7.1 Mode of action|
|7.2.1 Human data|
|7.2.2 Animal data|
|7.2.3 Relevant in vitro data|
|8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS|
|8.1 Material sampling plan|
|8.1.1 Sampling and specimen collection|
|184.108.40.206 Toxicological analyses|
|220.127.116.11 Biomedical analyses|
|18.104.22.168 Arterial blood gas analysis|
|22.214.171.124 Haematological analyses|
|126.96.36.199 Other (unspecified) analyses|
|8.1.2 Storage of laboratory samples and specimens|
|188.8.131.52 Toxicological analyses|
|184.108.40.206 Biomedical analyses|
|220.127.116.11 Arterial blood gas analysis|
|18.104.22.168 Haematological analyses|
|22.214.171.124 Other (unspecified) analyses|
|8.1.3 Transport of laboratory samples and specimens|
|126.96.36.199 Toxicological analyses|
|188.8.131.52 Biomedical analyses|
|184.108.40.206 Arterial blood gas analysis|
|220.127.116.11 Haematological analyses|
|18.104.22.168 Other (unspecified) analyses|
|8.2 Toxicological Analyses and Their Interpretation|
|8.2.1 Tests on toxic ingredient(s) of material|
|22.214.171.124 Simple Qualitative Test(s)|
|126.96.36.199 Advanced Qualitative Confirmation Test(s)|
|188.8.131.52 Simple Quantitative Method(s)|
|184.108.40.206 Advanced Quantitative Method(s)|
|8.2.2 Tests for biological specimens|
|220.127.116.11 Simple Qualitative Test(s)|
|18.104.22.168 Advanced Qualitative Confirmation Test(s)|
|22.214.171.124 Simple Quantitative Method(s)|
|126.96.36.199 Advanced Quantitative Method(s)|
|188.8.131.52 Other Dedicated Method(s)|
|8.2.3 Interpretation of toxicological analyses|
|8.3 Biomedical investigations and their interpretation|
|8.3.1 Biochemical analysis|
|184.108.40.206 Blood, plasma or serum|
|220.127.116.11 Other fluids|
|8.3.2 Arterial blood gas analyses|
|8.3.3 Haematological analyses|
|8.3.4 Interpretation of biomedical investigations|
|8.4 Other biomedical (diagnostic) investigations and their interpretation|
|8.5 Overall Interpretation of all toxicological analyses and toxicological investigations|
|9. CLINICAL EFFECTS|
|9.1 Acute poisoning|
|9.1.3 Skin exposure|
|9.1.4 Eye contact|
|9.1.5 Parenteral exposure|
|9.2 Chronic poisoning|
|9.2.3 Skin exposure|
|9.2.4 Eye contact|
|9.2.5 Parenteral exposure|
|9.3 Course, prognosis, cause of death|
|9.4 Systematic description of clinical effects|
|18.104.22.168 Peripheral nervous system|
|22.214.171.124 Autonomic nervous system|
|126.96.36.199 Skeletal and smooth muscle|
|9.4.7 Endocrine and reproductive systems|
|9.4.9 Eye, ears, nose, throat: local effects|
|188.8.131.52 Acid base disturbances|
|184.108.40.206 Fluid and electrolyte disturbances|
|9.4.13 Allergic reactions|
|9.4.14 Other clinical effects|
|9.4.15 Special risks|
|10.1 General principles|
|10.2 Relevant laboratory analyses and other investigations|
|10.2.1 Sample collection|
|10.2.2 Biomedical analysis|
|10.2.3 Toxicological/toxinological analysis|
|10.2.4 Other investigations|
|10.3 Life supportive procedures and symptomatic treatment|
|10.6 Antidote/antitoxin treatment|
|10.7 Management discussion|
|11. ILLUSTRATIVE CASES|
|11.1 Case reports from literature|
|11.2 Internally extracted data on cases|
|11.3 Internal cases|
|12. ADDITIONAL INFORMATION|
|12.1 Availability of antidotes/antitoxins|
|12.2 Specific preventive measures|
|13.1 Clinical and toxicological|
|14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)|
POISONOUS PLANTS 1. NAME 1.1 Scientific name
Senecio Vulgaris L.1.2 Family Compositae1.3 Common name(s) Common Groundsel (USA, UK) Groundsel (USA, UK)2. SUMMARY 2.1 Main risks and target organs The plant is poisonous and has been found to contain pyrrolizidine alkaloids which produce hepatic necrosis.2.2 Summary of clinical effects The target organs are the liver, kidneys, and lungs. The manifestations of acute and chronic poisoning are well described in animals: weight loss, icterus, ataxia, and symptoms of hepatic failure. In acute poisoning, death occurs within about 7 days due to severe liver damage secondary to severe veno-occlusive disease. Chronic liver damage may follow administration of single sublethal dose or repeated low doses.2.3 Diagnosis Children are particularly vulnerable to the effects of pyrrolizidine alkaloids. The clinical picture is characterized by upper abdominal discomfort that progresses to the swelling of the abdomen, oliguria and swelling of the feet. Vomiting of blood may appear in the advanced stages of poisoning. The disease progresses rapidly and mortality is high. Symptoms include upper abdominal discomfort that progresses to the swelling of the abdomen, oliguria and swelling of the feet. Vomiting of blood may occur in the advanced stages of poisoning.2.4 First-aid measures and management principles The interval between ingestion of pyrrolizidine-containing material and the development of the veno-occlusive liver disease makes sample collection difficult. However, samples of plant material must be obtained and kept in airtight containers for further identification and analyses. Methods of isolation and identification of pyrrolizidine alkaloids have been described. Mass spectrophotometry, reverse phase exchange, gas liquid, paper and thin layer chromatography methods have been used on samples including human serum, plasma and urine. Liver biopsy shows characteristic changes of centrilobular haemorrhagic necrosis with occlusion of hepatic venules. Hepatic sinusoids and central veins are congested but the hepatic architecture remains intact. Extensive portal and sinusoidal fibrosis may appear, leading to cirrhosis. Coagulopathies, hypoglycaemia, leucocytosis, hyperbilirubinaemia and grossly elevated hepatic aminotransferase levels are found. Remove any parts (leaves, flowers, fruits) still in the mouth and wash thoroughly with water or a saline solution. Induce vomiting (e.g. by giving syrup of ipecac).2.5 Poisonous parts Do not induce vomiting if the patient's consciousness is impaired or if he is having fits. The remnants of the plant and the vomitus should be collected in a clean bottle. The treatment of acute poisoning is symptomatic and supportive. Ensure patient's airway and ventilation. Supportive measures include oxygen, artificial respiration, intravenous fluids. All cases of ingestion should be closely observed in a hospital. Emesis and gastric lavage are indicated in recent ingestion. Activated charcoal should be administered in a slurry (1 g/kg) and should be repeated every four hours for 48 hours. Correction of dehydration and hypovolaemia are indicated. Since massive hepatic necrosis represents the greatest threat to life, some authors even recommend the same treatment as for Amanita phalloides poisoning (charcoal haemoperfusion, forced diuresis and presumed antidotes such as penicillin G, thioctic acid, silibinin and, in extreme cases, liver transplantation). All parts of the plants are toxic. The alkaloid content of the different parts of the plant is variable and depends on changes of climate, soil conditions, and time of harvesting.2.6 Main toxins 142 species of Senecio are known to contain pyrrolyzidine alkaloids of proved hepatotoxicity, or with a molecular structure that would make them very probably hepatotoxic. In Senecio Vulgaris the following pyrrolizidine alkaloids are found: senecionine, seneciphylline, retrorsine, riddelline, intergerrimine, spartioidine, and usaramine.3. CHARACTERISTICS 3.1 Description of the plant 3.1.1 Special identification features Perennial or annual, glabrous, more or less woody plant; branched succulent stem of 20-60 cm in height; small cylindrical heads of yellow tubular flowers with whorl of bract below; the light ribbed dark-grey fruits bear a soft, feathery tuft of hair (pappus) (Encyclopaedia Britannica, 1963).3.1.2 Habitat Senecio grows wild in fields, as a weed in gardens, and along roadsides in temperate and subtropical climates.3.1.3 Distribution Widely distributed throughout the world.3.2 Poisonous parts of the plant All parts of the plant contain the poisonous pyrrolizidine alkaloids.3.3 The toxin(s) 3.3.1 Name(s) The Toxins are:3.3.2 Description, chemical structure, stability senecionsine, seneciphylline; retrorsine; riddelline; intergerrimine; spartioidine; usarsmine. The hepatotoxic alkaloids have a 1,2-double bond in the pyrrolizidine ring and branched chain acids, esterifying a 9-hydroxyl and possibly also the 7-hydroxyl substituent. The alkaloids occur as free bases and N- oxides. The latter are reduced to free bases in the gastrointestinal tract of animals and have a similar toxicity when ingested orally.3.3.3 Other physico-chemical characteristics 3.4 Other chemical contents of the plant Senecionine: 12-Hydroxysenecionan-11, 16 dione. Formula = C18H25NO5 Molecular weight = 335.39 Melting point = 236 Practically insoluble in water; freely soluble in chloroform; slightly soluble in alcohol, either. Intergerrimine: C15-trans Isomer of senecionine. Melting point = 172 - 172.5 Seneciphylline: 13,19-Didehydro-12 Hydroxysenecionan-11, 16-dione: jacodine; alpha-longilobine; trans-15-Ethylidene- 12-ß-hydroxy-12-ý-methyl-13-methylenesenec-1-enine. CAS 480-81-9 Cancer Chemotherapy National Service Centre Number: NSC30622 (USA) Formula C18H23NO5 Melting point = 217-218 Colorless prisms, easily soluble in chloroform, ethylene chloride; less soluble in alcohol, acetone. Relatively insoluble in ether, ligroin. Volatility: low. Stability: stable at room temperature in closed containers; best stored under nitrogen at 15°C, Reactivity: readily hydrolysed with alkali; reacts readily with oxidizing agents (slowly with atmospheric oxygen) to form dihydropyrrolizine and other derivatives (IARC 1976). Retrorsine: 12,18-Dihydroxysenecionan-11, 16-dione; ß-longilobine. 3-Etherylidene-3,4,5,6,9,11,13,14,14 ý, 14 ß decahydro-6-hydroxy-6-hydroxymethyl-5-methyl (1,6) dioxycyclododeca [2,3,3-gh] pyrrolizidine-2,7-dione; trans-15-ethylidene-12-ß-hydroxy-12-ý-hydroxymethyl-13-ß- mehylsene-1-enine (IARC, 1976). CAS: 480-54-6 Formula: C18H25NO6 Molecular weight = 351.4 Melting Point = 212°C Colourless prisms readily soluble in alcohol, chloroform. Slightly soluble in water, acetone, ethyl acetate. Practically insoluble in ether. (Merck Index, 1983) Volatility: Low Stability: stable at room temperature in closed container; best stored under nitrogen at 15°C. Reactivity : readily hydrolysed with alkali: reacts with oxidizing agents to form dihydropyrrolizine and other derivatives (IARC, 1976). Riddelline: 13, 19-Didehydro-12, 18-dhydroxysenecionan-11, 16-dione; trans-15-Ethylidene-12-ß-hydroxy-12-ý- hydroxymethyl-13-metehylenesenec-1-enine; stereoisomer of 3-ethylidene-3,4,5,6,9,11,13,14,14-ý, 14-ß-decahydro-6-hydroxy-6-(Hydroxymethyl)-5-methylene (1,6)doxacyclododecino [2,3,4-gh]-pyrrolizidine- 2,7-dione; riddelline (IARC,1976). CAS : 23246-96-0 Formula: C18H23NO6 Melting point: 198°C Colourless soluble in chloroform; slightly soluble in acetone, ethanol and water; soluble in water as the hydrochloride. Volatility: low. Stability: stable at room temperature in closed containers: best stored under nitrogen -15°C. Reactivity: readily hydrolysed in aqueous alkali; reacts readily with oxidizing agents to form dihydropyrrolizidine and other derivatives (IARC, 1976). No data available.4. USES/CIRCUMSTANCES OF POISONING 4.1 Uses The plants grow wild in fields, in gardens and along roadsides. Senecio Vulgaris was used in Europe for treatment of dysmenorrhoea and amenorrhea, and in the United States as a diaphoretic, diuretic, tonic and emmenagogue (IARC, 1976).4.2 High risk circumstances Senecio vulgaris now has no known uses; there is no consumption for medicinal or dietary purposes. A pyrrolizidine alkaloid derivative, indicine-N-oxide, was tested in man as an antitumour agent (WHO, 1988a). Incidents of poisoning are reported predominantly in grazing animals. Under normal conditions, the plant is unpalatable and is avoided by grazing animals but it may be eaten during drought conditions.4.3 High risk geographical areas Animals may also ingest the plant material in hay or silage (The Merck Veterinary Manual, 1979). Consumption of contaminated grain or the use of pyrrolizidine alkaloid- containing plants as herbal medicines, beverages, or food by man, or grazing on contaminated pastures by animals may cause acute or chronic disease (WHO, 1988b). Children appear to be more susceptible than adults (Ellenhorn, 1988). All temperate and subtropical regions. Instances of human toxicity caused by pyrrolizidine alkaloid-containing plants were described in the USA, United Kingdom, USSR, Afghanistan, Hong Kong, India, South Africa, West Indies, and Ecuador (WHO, 1988).5. ROUTES OF ENTRY 5.1 Oral Oral consumption of the plant, contaminated grain or in preparations as food, herbal medicines or beverages.5.2 Inhalation No data available.5.3 Dermal May be absorbed through the skin.5.4 Eye No data available.5.5 Parenteral No data available.5.6 Others No data available.6. KINETICS 6.1 Absorption by route of exposure The absorption of pyrrolizidine alkaloids in man has been inferred from studies in animals. The alkaloids are absorbed in the ileum and jejunum, but not the stomach. After dermal application the excreted metabolites in urine amounted to 0.1- 0.4% of the dose (WHO, 1988a).6.2 Distribution by route of exposure In animal studies highest concentrations were found in the liver, lungs, kidneys and spleen.6.3 Biological half-life by route of exposure Within a few hours, only a relatively small proportion of the administered dose remains in the body. Much of this is in the form of metabolites bound to tissue contents. A pyrrolizidine N-oxide, as indicine-N-oxide, disappeared from the serum after IV administration in animals, with initial half-lives of 3 - 20 minutes (WHO, 1988a).6.4 Metabolism In animals, the major metabolic routes of pyrrolizidine alkaloids are: (a) hydrolysis of the ester groups; (b) N- oxidation; and (c) dehydrogenation of the pyrrolizidine nucleus to pyrrolic derivatives.6.5 Elimination by route of exposure Routes (a) and (b) are believed to be detoxification mechanisms. Route (c) leads to toxic metabolites. Route (a) occurs in liver and blood; routes (b) and (c) are brought about in the liver by the microsomal mixed function oxidase system (WHO 1988a). In animals, the urinary excretion of metabolites and unchanged alkaloids is rapid and almost complete within the first 24 hours (WHO, 1988a).7. TOXICOLOGY/TOXINOLOGY/PHARMACOLOGY 7.1 Mode of action The activation of the alkaloids by mixed-function oxidases leads to pyrrolic dehydro-alkaloids which are reactive alkylating agents. The liver necrosis results from binding of the metabolites with the liver cell. Some metabolites are released into the circulation and are believed to pass beyond the liver to the lung causing vascular lesions. The pyrrolic metabolites are cytotoxic and act on the hepatocytes and on the endothelium of blood vessels of the liver and lung. From evidence in experimental animals and circumstantial evidence in one human case report, the possibility of toxic pulmonary disease in man cannot be ruled out (WHO, 1988a).7.2 Toxicity 7.2.1 Human data 220.127.116.11 Adults In man, poisoning is manifested as acute veno-occlusive disease, leading to hepatomegaly, ascites, massive pleural effusion, and in many cases progressing to cirrhosis. Data are not available for Senecio vulgaris.18.104.22.168 Children There have been two cases of poisoning from riddeline and retrorsine contained in S. longilobus. The estimated daily intakes were 0.8- 0.17 mg/kg and 3 mg/kg body weight respectively, and the total doses were 12-25 mg/kg and 12 mg/kg. These levels led to the rapid development of veno-occlusive disease in infants, and in one case to death (WHO, 1988a).7.2.2 Animal data Considerable differences in LD50 values have been reported for the same alkaloids in different species.7.2.3 Relevant in vitro data LD50 for male rats after a single intraperitoneal dose (i.p.) is: Retrorsine = 34 mg/kg (time range = 4 or 7 days) One to 7 days IV LD50's in mice and rats are about 90 and 80 mg/kg body weight, respectively. In rats, 3-day i.p. LD50 doses for males and females are 77 and 83 mg/kg, respectively (IARC, 1976). Seneciphyline = 77 mg/kg (time range = 3 days) (WHO, 1988a) The LD50 varies from 34 mg/kg for male rats to 279 mg/kg for quail and over 800 mg/kg body weight for guinea pigs. There are also differences between sexes in the same species: males are more susceptible to the acute toxicity of retrorsine than females (WHO, 1988a). Riddelline LD50 IV in mice is 105 mg/kg body weight (IARC, 1976). Human embryo liver slices (not lung slices) converted some pyrrolizidine alkaloids, including retrorsine, to pyrrolic metabolites in vitro (WHO, 1988a).7.3 Carcinogenicity Most studies have examined the effects in the liver; the tumours produced are mostly of epithelial origin, but a significant number are also vascular. Possible types of tumour include: hepatomas; hepatocellular carcinoma with metastases; mammary tumours; lung carcinoma; renal carcinomas; colonic carcinoma; splenic haemangioendothelioma; osteosarcoma bone; leukaemia; "spindle cell" tumour (neck); uterine carcinoma; retroperitoneal sarcoma; and squamous cell carcinoma (of the jaw) were described for retrorsine. Epidemiological studies to assess the carcinogenic role of pyrrolizidine alkaloids for man are not available (WHO, 1988a).7.4 Teratogenicity The teratogenic potential of heliotrine and its pyrrole metabolite was demonstrated (WHO 1988a).7.5 Mutagenicity Senecionine, seneciphylline, retrorsine, and intergerrimine have been shown to be powerful dose-dependent mutagens (WHO, 1998a).7.6 Interactions No data available.8. TOXICOLOGICAL/TOXINOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 22.214.171.124 Toxicological analyses 126.96.36.199 Biomedical analyses 188.8.131.52 Arterial blood gas analysis 184.108.40.206 Haematological analyses 220.127.116.11 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 18.104.22.168 Toxicological analyses 22.214.171.124 Biomedical analyses 126.96.36.199 Arterial blood gas analysis 188.8.131.52 Haematological analyses 184.108.40.206 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 220.127.116.11 Toxicological analyses 18.104.22.168 Biomedical analyses 22.214.171.124 Arterial blood gas analysis 126.96.36.199 Haematological analyses 188.8.131.52 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 184.108.40.206 Simple Qualitative Test(s) 220.127.116.11 Advanced Qualitative Confirmation Test(s) 18.104.22.168 Simple Quantitative Method(s) 22.214.171.124 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 126.96.36.199 Simple Qualitative Test(s) 188.8.131.52 Advanced Qualitative Confirmation Test(s) 184.108.40.206 Simple Quantitative Method(s) 220.127.116.11 Advanced Quantitative Method(s) 18.104.22.168 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 22.214.171.124 Blood, plasma or serum Serum electrolytes, glucose, bilirubin, serum transaminase, and prothrombin.126.96.36.199 Urine Urinalysis188.8.131.52 Other fluids 8.3.2 Arterial blood gas analyses Requested according to patient's condition.8.3.3 Haematological analyses Full blood count.8.3.4 Interpretation of biomedical investigations There is an increase in leucocyte numbers in blood and red blood cells in urine.8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations 8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion There is an increase of blood bilirubin, transaminases, and urea. Hypoglycaemia is present. Bilirubin is detected in the urine. Progressive hyperpnoea and encephalopathy may cause disturbances in acid-base balance. Liver biopsy shows characteristic changes of centrilobular haemorrhagic necrosis with extensive portal and sinusoidal fibrosis leading to cirrhosis (Ellenhorn, 1988). In humans, symptoms are generally acute in onset and are characterized by upper abdominal discomfort that develops rapidly and progresses to swelling of abdomen resulting in so-called veno-occlusive disease. The disease progresses rapidly and the mortality is high (WHO, 1988b).9.1.2 Inhalation The acute form of the disease is rare in animals. It is characterized by sudden death due to acute haemorrhagic liver necrosis and visceral haemorrhage. In acute poisoning, death occurs within about 7 days due to severe liver damage. No data available.9.1.3 Skin exposure No clinical data available.9.1.4 Eye contact No data available.9.1.5 Parenteral exposure No data available.9.1.6 Other No data available.9.2 Chronic poisoning 9.2.1 Ingestion In man, there is generally recovery after an acute episode, but the disease may continue for a long time leading to liver cirrhosis. Some patients may have only vague symptoms. The only sign of the disease may be persistent hepatomegaly (WHO, 1988a).9.2.2 Inhalation 9.2.3 Skin exposure In animals chronic liver damage may follow administration if a single sublethal dose or of repeated doses. No data available.9.2.4 Eye contact No data available.9.2.5 Parenteral exposure No data available.9.2.6 Other No data available.9.3 Course, prognosis, cause of death Children appear to be more susceptible than adults. A dose of 70 to 140 mg of Senecio alkaloids resulted in liver cirrhosis in a 6 month-old girl (Ellenhorn, 1988). In the acute phase of the disease the dominant symptom is rapidly-filling ascites. The disease often progresses rapidly and the mortality is high. There may be haematemesis in the advanced stages. Causes of death are haemorrhagic states (such as oesophageal haemorrhage), liver failure and necrosis, progressive hyperpnoea and encephalopathy (WHO, 1988a; Ellenhorn, 1988).9.4 Systematic description of clinical effects 9.4.1 Cardiovascular Cardiac failure.9.4.2 Respiratory Progressive hyperpnoea.9.4.3 Neurological 184.108.40.206 CNS Lethargy, encephalopathy.220.127.116.11 Peripheral nervous system No data available.18.104.22.168 Autonomic nervous system No data available.22.214.171.124 Skeletal and smooth muscle No data available.9.4.4 Gastrointestinal Anorexia, nausea, vomiting, diarrhoea, abdominal cramps. Vomiting of blood in advanced stages.9.4.5 Hepatic Hepatotoxicity is a well-recognized complication. Jaundice, ascites and hepatomegaly are described. Chronic cirrhosis. The potential risk of cancer in man should be seriously considered.9.4.6 Urinary 126.96.36.199 Renal Not specific; renal effects are a consequence of the veno-occlusive disease.188.8.131.52 Others No data available.9.4.7 Endocrine and reproductive systems No data available.9.4.8 Dermatological No data available.9.4.9 Eye, ears, nose, throat: local effects Not described.9.4.10 Haematological Leucocytosis9.4.11 Immunological No data available.9.4.12 Metabolic 184.108.40.206 Acid base disturbances Acid base disturbances may occur.220.127.116.11 Fluid and electrolyte disturbances Vomiting and diarrhoea may result in loss of fluids and electrolytes.18.104.22.168 Others No data available.9.4.13 Allergic reactions No data available.9.4.14 Other clinical effects No data available.9.4.15 Special risks No data available.9.5 Others No data available.9.6 Summary 10. MANAGEMENT 10.1 General principles Maintain a clear airway and respiration; administer oxygen. Remove any parts of the plant present in the mouth and wash with water or saline solutions. Remove ingested parts of the plant by gastric lavage or emesis. Administer activated charcoal. Correct hydration. Watch for signs of gastrointestinal haemorrhage such as haematemesis. Follow- up is recommended.10.2 Relevant laboratory analyses and other investigations 10.2.1 Sample collection Plant material should be placed between sheets of paper in a plastic bag and kept for botanical identification. Vomitus or gastric aspirate should be stored in a plastic bag.10.2.2 Biomedical analysis Request full blood count, serum electrolytes, glucose, bilirubin, and transaminases. Urinalysis to detect red blood cells. Arterial 02 and CO2 concentration and acid-base balance.10.2.3 Toxicological/toxinological analysis There is no quantitative analytical method available to measure pyrrolizidine alkaloids in body fluids (Ridker & McDermott, 1989), thus diagnosis of pyrrolizidine alkaloid poisoning must be made by exclusion of other causes of veno-occlusive disease in all patients with hepatic failure; by recognition of the pathognomic histological changes in hepatic biopsy specimens; and by analytical detection of pyrrolizidine alkaloids in preparations the patient has been exposed to (Huxtable, 1979b).10.2.4 Other investigations 10.3 Life supportive procedures and symptomatic treatment Monitor pulse, respiration, and blood pressure. Maintain fluid balance. Haemorrhage, hypoglycemia and massive hepatic necrosis represent the greatest threat to life (Ellenhorn 1988).10.4 Decontamination Maintain respiration: assess ventilation and establish an adequate airway. Correct anoxia by mechanical ventilation and oxygen. Endotracheal intubation and assisted ventilation may be necessary. In case of hypotension or shock: volume expansion with normal saline or Ringer's lactate solution; monitor central venous pressure administer dopamine 200 mg in 250 or 500 ml of saline or 5% dextrose in water and titrate dose to a rate of 2-50 g/kg/minute up to the desired response. Fresh- frozen plasma or blood as needed (Noji & Kelen, 1989). Administer intravenous glucose immediately in case of hypoglycemia. Remove any parts of the plant present in the mouth and wash thoroughly with water or a saline solution. If convulsions are not imminent, induce vomiting or perform gastric lavage10.5 Elimination Gastric lavage may be performed if emesis fails. Attention to the hazard of imminent convulsion. Administer a slurry of activated charcoal. No data available.10.6 Antidote/antitoxin treatment 10.6.1 Adults No data available.10.6.2 Children No data available.10.7 Management discussion alternatives and controversies, research needs11. ILLUSTRATIVE CASES 11.1 Case reports from literature Management is mainly symptomatic. Ellenhorn (1988) states: "Since massive hepatic necrosis represents the greatest threat life, the usual measures listed under amanita poisoning for hepatic dysfunction should be administered". These measures include antidotes such as thioctic acid, silibinin, penicillin G, although their efficacy is uncertain, and also hemoperfusion and liver transplantation. Ellenhorn (1988) refers to a case of ingestion of a dose of 80 to 147 mg of Senecio alkaloids which resulted in liver cirrhosis of a 6 month-old-girl. Death resulted from acute pulmonary oedema and cardiovascular collapse, 2.5 hours after ingestion.11.2 Internally extracted data on cases WHO's Environmental Health Criteria on pyrrolizidine alkaloids (1988a) states: "The disease has an acute onset, characterized by rapidly developing and progressing symptoms of upper abdominal discomfort, dragging pain in right hypochondrium, ascites, and sometimes oliguria and oedema of the feet. Nausea and vomiting may be present. Jaundice and fever are rare. There is generally gross, tender, smooth hepatomegaly, often accompanied by massive pleural effusion and sometimes slight splenomegaly and minimal ankle oedema. The acute disease is associated with high mortality, and a subacute or chronic onset may lead to cirrhosis. Death often occurs after oesophageal haemorrhage" No data available.11.3 Internal cases 12. ADDITIONAL INFORMATION 12.1 Availability of antidotes/antitoxins There are no antidotes or antisera.12.2 Specific preventive measures Teach children never to put leaves, stems, bark, seeds, nuts or berries from any plant into their mouths.12.3 Other Keep poisonous house plants out of the reach all children. No data available.13. REFERENCES 13.1 Clinical and toxicological Ellenhorn MJ & Barceloux DG (1988). Medical Toxicology; diagnosis and treatment of human poisoning. New York: Elsevier, 151213.2 Botanical IARC. Pyrrolizidine alkaloids. In: Some naturally occurring substances. Lyon: International Agency for Research on Cancer 10: 265-342. Reynolds JEF. Martindale, The Extra Pharmacopoeia, 29th ed. London: Pharmaceutical Press, 1989, 1876 Merck Index; and encyclopedia of chemical, drugs, and biogicals, 10th ed. Rahway: Merck, 1983 10000 . Merck Veterinary Manual. 5th ed. Siegmund OH, ed. Rahway: Merck, 1979. Noji EK & Kelen GD (1989). Manual of Toxicological Emergencies, Chicago, London, Boca Raton: Year Book Medical Publishers, 850 WHO (1988a). Pyrrolixidine Alkaloids, Environmental Health Criteria 80. Geneva: World Health Organization, 345 WHO (1988b). Pyrrolizidine Alkaloids, Health and Safety Guide 26. Geneva: World Health Organization, 20 Encyclopedia Britannica (1963). Chicago, London, Toronto, Geneva: William Benton Publisher, 20: 322.14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Author: Dr A. Furtado Rahde Rua Riachuelo 677 ap 201 90010 Porto Alegre Brazil Date: September 1989 Peer review: London, United Kingdom, March 1990
ANTIDOTES FOR POISONING BY
METALS AND METALLOIDS
Completed August 2004
W Banner Jr1 & AD Woolf2
Edited by Nicola Bates MSc, MA: National Poisons Information Service (London Centre), UK
Peer-review by Dr P Dargan3, Dr L Murray4 & Dr B Groszek5
©World Health Organization 2004
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TABLE OF CONTENTS
- NAME AND CHEMICAL FORMULA
- PHYSICO-CHEMICAL PROPERTIES
- PHARMACEUTICAL FORMULATION AND SYNTHESIS
4.1 Routes of synthesis
4.2 Presentation and formulation
- ANALYTICAL METHODS
5.1 Quality control of antidote
5.2 Identification of antidote
5.3 Analysis of antidote
5.4 Analysis of toxic agents in biological samples
- GENERAL PROPERTIES
7.1 Iron toxicity
7.2 Aluminium toxicity
- ANIMAL STUDIES
8.1.1 Oral deferoxamine
8.3.1 Acute toxicity
8.3.2 Subacute and chronic toxicity
8.4 Pulmonary toxicity
8.5 Other safety data
9 VOLUNTEER STUDIES
9.5 Effect of deferoxamine on oral iron absorption
10 CLINICAL STUDIES
10.1 Use in acute iron poisoning
10.2 Use in aluminium toxicity
11 CLINICAL STUDIES - CASE REPORTS
11.1 Evidence of efficacy in iron poisoning
11.2 Assessment of severity of iron poisoning
11.3 Use in pregnancy
11.4 Evidence of acute toxicity
11.5 Evidence of chronic toxicity
11.5.1 Infectious complications
11.5.2 Ocular and auditory toxicity
11.5.3 Local reactions
11.5.4 Other side effects
11.6 Use in renal failure
11.7 Use in pregnancy
12 SUMMARY OF EVALUATION
12.2 Advised routes and dose
12.3 Other consequential or supportive therapy
12.4 Controversial issues and areas of use where there is insufficient information to make recommendations
12.5 Proposals for further study
12.6 Adverse effects
12.7 Restrictions of use
13 MODEL INFORMATION SHEET
13.2 Dosage and route
13.4 Adverse effects
13.5 Use in pregnancy and lactation
Deferoxamine (desferrioxamine B) is derived from ferrioxamine B, a sideramine isolated in 1960 from Streptomyces pilosus. It has a high binding affinity for trivalent iron which can be exploited to clinically remove excess iron from blood and tissue (Keberle, 1964).
Currently, deferoxamine is used for the treatment of acute iron poisoning and iron-overload anaemias, such as thalassaemia major, as well as aluminium poisoning associated with chronic renal dialysis (Banner and Tong, 1986; Day & Ackrill, 1993).
Acute iron intoxication is often described as progressing through four stages (Proudfoot et al., 1986; McGuigan, 1996).
The first of these is the gastrointestinal phase which may begin within minutes and last for several hours. This phase is due to the corrosive effects of iron and results in abdominal pain, vomiting and diarrhoea with fluid and electrolyte losses and in severe cases, gastrointestinal bleeding with shock and metabolic acidosis. The second stage is a quiescent period where the patient may appear to be relatively stable. In the third stage acidosis and shock occur which may lead to cardiovascular collapse. This may begin within hours but may be delayed as long as 24 hours in some cases. The fourth stage is characterised by the after effects of mucosal corrosion such as stricture formation and pyloric stenosis. These can occur even in patients treated with deferoxamine (Saviuc et al., 1992). Hepatic necrosis has been reported and normally occurs within the first 48 hours. It is the most common cause of death after shock.
In acute or chronic iron poisoning the goal of treatment is the removal of toxic iron from the body by chelation in order to avoid acute organ damage. Early treatment prior to distribution of iron into tissue and the reticulo-endothelial system has long been thought to be most effective (Whitten et al, 1966).
Deferoxamine has intrinsic toxicity (Bentur et al., 1991). Subacute effects consisting of nephrotoxicity, ototoxicity and retinal toxicity have been reported. These effects generally appear following long-term administration for chronic iron overload, however nephrotoxicity has been reported in patients treated for acute iron poisoning (Hershko and Weatherall, 1988; Koren et al., 1989). Rapid infusion of a large dose has been associated with histamine-induced hypotension (Whitten et al., 1965; Barker et al., 1974) and acute renal insufficiency (Freedman et al., 1989; Koren et al., 1989). Prolonged infusion has been associated with pulmonary toxicity (Tenenbein et al., 1992; Adamson et al., 1993).
- NAME AND CHEMICAL FORMULA
International non-proprietary name:
N-(5-C3-L (5 aminopentyl) hydroxycarbamoyl)-propionamido)pentyl)-3(5-(N-hydroxyacetoamido)-pentyl)carbamoyl)-proprionhydroxamic acid
138-14-7 (deferoxamine mesylate)
Figure 1: Deferoxamine mesylate
Relative molecular mass: 560.71 (656.8 as mesylate)
Manufacturers: Novartis Pharma AG (previously Ciba Geigy), Basel, Switzerland
- PHYSICO-CHEMICAL PROPERTIES
Solubility in vehicle of administration:
water at 20°C, 1.2%
3.5 - 5.5 in water as a 10% solution
Stability in light:
In water, stable for 1 day at room temperature (23°C or below).
Loss of weight on drying:
- PHARMACEUTICAL FORMULATION AND SYNTHESIS
4.1 Routes of synthesis
Currently available commercially produced deferoxamine is a derivative of the iron-bearing metabolite, ferrioxamine B, from Streptomyces pilosus (Keberle, 1964). Ferrioxamine is isolated and iron is then removed by chemical means. The resulting deferoxamine is then exhaustively purified.
De novo organic synthesis was attempted in 1962 leading to a 6% yield (Prelog and Walser, 1962). Since then, a de novo synthesis has been developed leading to a greater overall yield with improved purity. The synthesis is very expensive.
4.2 Presentation and formulation
Deferoxamine mesylate is available in vials of 500 mg or 2 g, as sterile powder for preparing injections or for oral use. The sterile content of a sealed container should be dissolved in the requisite amount of water for injection to form a clear pale yellow solution. The preparation should be used immediately and cloudy or discoloured solutions should be discarded.
- ANALYTICAL METHODS
5.1 Quality control of antidote
As a measure of quality control, a deferoxamine solution can be tested by adding ferrous or ferric iron at a neutral pH and measuring absorbance at 430 nm compared to a known standard.
5.2 Identification of antidote
Identification of deferoxamine and ferrioxamine in solution or plasma is based on spectrophotometric analyses and the absorption of ferrioxamine at 430 nm. In solution, ferrioxamine can be measured directly. Deferoxamine is measured as ferrioxamine after addition of iron at low pH (Pippard and Stray, 1982). In plasma, the same assay can be used after deproteinisation with trichloroacetic acid.
5.3 Analysis of antidote
Deferoxamine can be measured by atomic absorption spectroscopy (Allain et al., 1986) or by a high performance liquid chromatography (HPLC) technique which can separate deferoxamine and its metabolites, as well as the iron and aluminium chelate (Jenny and Peter, 1988).
5.4 Analysis of toxic agents in biological samples
Metals and metalloids can be analysed by sensitive standard methods, such as atomic absorption spectroscopy (AAS) or inductively coupled plasma-atomic emission spectroscopy (ICP-AES).
The shelf-life of deferoxamine is 4 years stored in an airtight container protected from light and heat. Vials of powder should be stored in a cool place (below 15°C) (Ciba-Geigy, 1994).
- GENERAL PROPERTIES
7.1 Iron toxicity
Deferoxamine appears only to chelate free iron (as the Fe3+ ion), and iron stored in the form of ferritin and haemosiderin, and to a very limited extent, transferrin; the iron of cytochromes and haemoglobin is unaffected (Keberle, 1964; Lipschitz et al., 1971; Hershko & Weatherall, 1988). One mole of deferoxamine binds one mole of iron to form the deferoxamine-iron complex, ferrioxamine. Almost all of the ferrioxamine formed is then eliminated by the kidneys within few hours, as demonstrated in studies in dogs, and the remainder is believed to be metabolised (Keberle, 1964). As such, the neutralisation of free iron by complexation and the renal excretion of the complexed iron reduces the amount of toxic iron available. This, in combination with the slower physiological movement of iron into storage compartments and the stabilisation of iron complexed to proteins, leads to an overall reduction of serum iron and decreased body burden (Bothwell et al., 1979). Ferrioxamine has a significantly lower volume of distribution (Keberle, 1964; Peters et al., 1966), is considered to be of lower toxicity than deferoxamine (Bentur et al., 1991) and complexation is important even without increased elimination of iron via ferrioxamine in the urine. Ferrioxamine can, however, be lethal if administered in the absence of free iron (Whitten et al., 1965; Adamson et al., 1993).
The failure of other chelators (e.g. diethylenetriaminepentaacetate; DTPA), which are excluded from the intracellular space, to aid in the prevention of iron-related morbidity, argues for a role for deferoxamine other than the quantitative removal of iron from serum (Whitten et al., 1965). An in vitro study of rat heart ventricular muscle cells in culture suggests a protective, in addition to a therapeutic, effect of deferoxamine. When these cells were exposed to iron concentrations of 20, 40 and 80 µg/mL (reflecting plasma concentrations in fatal intoxications) they developed arrhythmias and depression of contractility similar to that observed in terminal iron poisoning. The provision of deferoxamine was found to not only prevent the oxidative toxicity of iron but to reverse iron-induced tissue damage (Link et al., 1989). This may suggest that in both acute and chronic iron overload it is the provision of excess iron binding capacity (chelation) which prevents toxic iron damage, rather than the removal of iron as chelate.
Recently several authors have focused on the role of deferoxamine as an antioxidant and free-radical scavenger in non-iron intoxications (Hoffer et al., 1992; Van der Wal et al., 1992; Burkitt et al., 1993; Meulenbelt et al., 1993). The practical significance of this ability of deferoxamine in acute iron or other poisonings remains unproven. There is evidence that the mitochondrial respiration enzymes are the main target of acute iron toxicity (Link et al., 1998).
7.2 Aluminium toxicity
The high stability of the deferoxamine-aluminium complex (aluminoxamine) led to the use deferoxamine in dialysis-related aluminium toxicity syndromes (Day & Ackrill, 1993). Sudden decreases of aluminium concentrations do not occur because the excretion of deferoxamine is mainly renal. Aluminium appears to have some toxicity even bound to deferoxamine since the reduction of metal toxicity seems to depend on removal of the chelate complex by ambulatory peritoneal dialysis, haemodialysis, haemofiltration or haemoperfusion in patients with chronic renal failure (Allain et al., 1988; McCarthy et al., 1988). The possibility exists that the translocation of aluminium from bone may actually increase cerebral symptoms in a fashion analogous to the use of other chelators in other types of heavy metal poisoning. Our understanding of this phenomenon is limited.
Many studies have demonstrated that over relatively long intervals (weeks to months) the use of deferoxamine after dialysis at a dose not exceeding 40 mg/kg has led to a reduction in the severity of aluminium toxicity (encephalopathy, bone disease and anaemia). This improvement correlates approximately with concentrations of aluminium measured directly in tissues (bone) but not with serum concentrations (Day & Ackrill, 1993).
- ANIMAL STUDIES
Deferoxamine produces its dynamic effect by the removal of excess inorganic iron. Inorganic iron is directly toxic to rabbit myocardium exposed to increasing amounts of iron leading to loss of contractile function (Artman et al., 1984). By binding to iron, deferoxamine may cause clinical improvement even before the iron is eliminated from the body. Deferoxamine also reverses iron-induced dysfunction of isolated rat heart muscle (Link et al., 1989).
8.1.1 Oral deferoxamine
Oral administration of deferoxamine in animals receiving oral lethal doses of iron demonstrates an interesting intraspecies difference. In rodents, deferoxamine had no effect on plasma iron concentrations (Dean and Krenzelok, 1987). In swine, significant differences in plasma iron concentrations were observed (Dean et al., 1988). One could argue that the pig model more closely resembles the human situation because of the greater similarity to human gastrointestinal iron handling. In one set of canine experiments, the deferoxamine-iron complex was absorbed directly as plasma iron concentrations rose rapidly after intragastric instillation of the ferrioxamine complex, and time to death was shorter than with iron alone (Whitten et al., 1965).
In a subsequent experiment by the same group, plasma iron concentrations rose less than in control dogs when intragastric and intravenous deferoxamine were given (Whitten et al., 1966). The presence of intravenous deferoxamine complicates the data analysis, but it is unlikely that the decrease in concentrations occurred as a result of the rapid clearance of ferrioxamine alone. Another study in dogs, however, revealed a survival advantage to dogs treated simultaneously with oral iron and oral deferoxamine (Brunner et al., 1965). In view of the difficulty in interpreting these data it is not surprising that the value of administration of intragastric deferoxamine in humans is controversial (Banner and Tong, 1986).
In a study in swine, 10 pigs were given elemental iron (60 mg/kg) + deferoxamine (1 g/kg) orally, whereas 13 pigs served as controls and were given iron only (Dean et al., 1996). Although deferoxamine reduced some peak concentrations, the total absorption of iron was unchanged.
Few adequate animal studies have been performed to mimic the actual conditions for which deferoxamine is used in aluminium toxicity. In most studies, animals are acutely loaded with aluminium, thus creating toxicity that may not relate to humans undergoing chronic dialysis. These studies yield conflicting results as to the value of deferoxamine as an antidote. In one study examining subacute aluminium loading in rabbits, deferroxamine treatment appeared to reduce tissue aluminium concentrations (Melograna & Yokel, 1984).
The dog has been the principle species used to examine the pharmacokinetics of deferoxamine (as opposed to the rodent models of chronic iron overload for chemical studies). Studies in the dog revealed a significant difference in the handling of the chelated and unchelated forms of deferoxamine (Peters et al., 1966). Ferrioxamine was distributed only to the extracellular space and excreted directly into the urine by glomerular filtration (clearance ferrioxamine/clearance inulin = 1.0). There was a small component of tubular reabsorption. In contrast, deferoxamine was distributed into total body water and is renally excreted by glomerular filtration with an easily overwhelmed tubular reabsorption mechanism.
In nephrectomised dogs, deferoxamine underwent hepatic metabolism with a plasma half-life of 76 ± 10 minutes. Ferrioxamine was not metabolised and plasma concentrations fell very slowly. Some metabolites of deferoxamine, most notably the product of oxidative deamination, also chelate iron, and thus the antidotal effect of the drug appears unaffected by hepatic metabolism (Peters et al., 1966).
When dogs were injected with tritrium-labelled deferoxamine, radioactivity was highest in the bile and brain, intermediate in the spleen, kidney and plasma, and lowest in the heart and lung (Hershko and Weatherall, 1988). In bile, deferoxamine exists primarily as metabolites. Ferrioxamine in bile is most likely derived from the deferoxamine chelation of iron in the hepatocyte, except in the case of nephrectomised dogs (and humans).
Deferoxamine may further complicate the picture by directly altering renal function to increase fractional excretion of sodium and decrease insulin clearance in the dog even with volume loading (Koren et al., 1989).
The toxicity of deferoxamine has recently been extensively reviewed by Bentur et al. (1991).
8.3.1 Acute toxicity
See table 1 for information on the acute toxicity of deferoxamine.
Table 1: The acute LD50 values of deferoxamine (Ciba Laboratories, 1964).
8.3.2 Subacute and chronic toxicity
Studies in dogs showed that deferoxamine administration was associated with depressed cardiac function and hypotension (Whitten et al., 1966). A reversible acute decrease in glomerular filtration rate and renal plasma flow, accompanied by disturbances in electrolyte excretion was demonstrated in dogs given deferoxamine. The mechanism of this nephrotoxic effect is not clear (Bentur et al., 1991).
8.4 Pulmonary toxicity
Pulmonary effects have been observed with prolonged infusion of deferoxamine, but it has been argued that these effects may be to be due to iron toxicity, rather than deferoxamine itself (Shannon, 1992).
Pulmonary complications (ARDS, adult respiratory distress syndrome) associated with prolonged infusion of deferoxamine has been observed in humans (Tenenbein et al., 1992), and the same group later studied evidence of pulmonary toxicity in iron-poisoned mice (Adamson et al., 1993). Mice treated with one oral dose of iron followed by multiple doses of deferoxamine, or with ferrioxamine (the chelated complex) alone, did not develop lung lesions, even at doses which were fatal. To potentiate any possible free radical reaction some mice were also treated with oxygen (75-80% over 4 days). Ten of 12 mice receiving oxygen therapy in addition to 0.75 mg elemental iron and then deferoxamine (10 mg, 4 times/day for 4 days) died suddenly. Autopsy and electron microscopy of the lungs revealed changes as seen in ARDS. Furthermore, a free radical reaction product was demonstrated at the alveolar surface indicating that free radical formation was associated with the damages seen. Such changes were not seen in controls given deferoxamine or iron, plus hyperoxia. This study appears to confirm that the lung damage observed clinically was related to the prolonged use of deferoxamine. Although a free radical mechanism behind this toxicity may be possible, it remains unproven.
8.5 Other safety data
No evidence of a mutagenic potential has been observed in vitro with deferoxamine. Long-term carcinogenicity studies have not been performed. In rabbits exposed in utero deferoxamine caused skeletal malformations. However, these teratogenic effects were observed at doses which were toxic to the mother. In mice and rats deferoxamine appears to be free of teratogenic activity (Ciba-Geigy, 1994).
- VOLUNTEER STUDIES
Deferoxamine is rapidly absorbed after intramuscular or subcutaneous administration, but only poorly absorbed from the gastrointestinal tract in the presence of intact mucosa (Ciba-Geigy, 1994).
Peak plasma concentrations of deferoxamine of 15.5 µmol/L (8.7 µg/mL) were measured 30 minutes after an intramuscular injection of 10 mg/kg (Allain et al., 1987). One hour after injection the peak concentration of ferrioxamine was 3.7 µmol/L (2.3 µg/mL).
Deferoxamine has a volume of distribution of 0.8-1.35 L/kg (Keberle 1964; Lee et al., 1993-4).
Less than 10% of deferoxamine is bound to serum proteins in vitro (Ciba-Geigy, 1994).
Normally, deferoxamine and ferrioxamine are excreted primarily by the kidneys after a wide range of dosages (Keberle, 1964). Biliary excretion of the chelate ferrioxamine only occurs when iron is chelated in the hepatocyte or when renal clearance is exceeded (Keberle, 1964; Octave et al., 1983). Deferoxamine distributes throughout total body water and is excreted by glomerular filtration and saturable tubular secretion. Ferrioxamine is excluded from the intracellular space and plasma concentrations are excreted entirely by the kidneys in patients without compromised renal function. In the nephrectomised human, injected labelled ferrioxamine appears in the faeces (Wolfe and Fosburg, personal communication 1989).
Both deferoxamine and ferrioxamine have a biphasic elimination pattern in healthy volunteers; for deferoxamine the half life is 1 hour, and for ferrioxamine 2.4 hours, in the first rapid phase (Allain et al., 1987). In the second slow phase the half-life is 6 hours for both. Within six hours of injection, 22% of the dose appears in the urine as deferoxamine and 1% as ferrioxamine.
In three healthy volunteers given 1 g of deferoxamine intravenously over one hour, the elimination was very rapid with a total plasma clearance of deferoxamine of 790-1090 mL/minute; no half-life could be calculated. The urinary excretion of ferrioxamine is very low (less than 1% of the dose). Deferoxamine excretion in urine in the first 24 hours was between 11 and 19%, with most of the drug excreted within the first 3 hours (Ciba-Geigy, 1987).
Deferoxamine is mainly metabolised in the plasma and hepatic metabolism is minimal. A number of metabolites have been isolated but not characterised (Lehmann & Heinrich, 1989; Kruck et al., 1993; Kraemer & Breithaupt, 1998). Animal studies have shown that some metabolites also chelate iron (Peters et al., 1966).
9.5 Effect of deferoxamine on oral iron absorption
Seven volunteers were given 5 mg/kg elemental iron in a control phase and again in an experimental phase followed by a single equimolar dose of oral buffered deferoxamine solution (Jackson et al., 1995). No influence on iron absorption was demonstrated. In another controlled study, a premixed 1:3 (weight/weight) deferoxamine/activated charcoal slurry significantly reduced the gastrointestinal absorption of ferrous sulphate in adult volunteers (Gomez et al., 1997).
- CLINICAL STUDIES
In reviewing the English language literature on deferoxamine the lack of controlled trials is striking. However, given the ample non-human literature regarding acute iron intoxication and the inherent difficulties in constructing comparative trials of an infrequent intoxication, this is not surprising. Although discussed in this section, the papers identified are primarily descriptive in nature and are not clinical trials in the real meaning of the term.
10.1 Use in acute iron poisoning
Whitten et al. (1965) reported a prospective open trial of deferoxamine in a group of 12 children aged 13-30 months. Serum iron as measured spectrophotometrically ranged from 53 to 141 µmol/L (300 to 792 µg/dL). Time after ingestion to assessment varied from 1.5 to 20 hours. Patients received intravenous and oral deferoxamine in a controlled manner. Three children received 800-1500 mg of deferoxamine over 15 minutes i.v. and two of these experienced severe hypotension including a 15 minute loss of blood pressure. The excretion of iron complex in the urine in these children was small with 25 mg/24 hours being the maximal rate in a child with an initial serum iron of 141 µmol/L (792 µg/dL). The only patient in this series with significant presenting symptoms (coma) remained comatose after treatment and had a poor neurological outcome. The authors concluded that the good outcome of their patients could not be related to deferoxamine as the iron excretion was limited compared to the amount ingested. It could, however, be argued that the assessment of deferoxamine efficacy by measuring renal excretion of iron may be difficult since the amount of iron absorbed, even in acute overdose, may not be more than the 10% observed following therapeutic ingestion. Furthermore, the process of chelation per se may be difficult to assess by the renal excretion of iron, especially in patients with hypotension and impaired renal function. This manuscript is important because of the observation regarding severe hypotension with rapid administration of deferoxamine in two patients.
McEnery & Greengard (1966) reported a prospective series of 20 children treated with deferoxamine over a two year period. Serum iron concentration on admission ranged from 11 to 296 µmol/L (64 to 1653 µg/dL). Deferoxamine therapy was started with oral doses in 16 patients and combinations of intravenous and intramuscular therapy in 17 of the 20. Nine patients received rapid infusions of i.v. deferoxamine without apparent sequelae. All patients survived and no morbidity was ascribed to the treatment. The lack of a control group and the relatively low serum iron concentrations in many patients makes it difficult to interpret this study particularly with respect to the efficacy of oral deferoxamine therapy.
Leikin et al. (1967) reported a randomised prospective clinical trial of oral, oral + intravenous and no chelation therapy in a group of 22 children aged from 1 to 6 years of age. Children with a history of ingestion and supranormal serum iron determinations on presentation were included in the trial. Serum irons were determined by colorimetric assay and ranged from 44 to 143 µmol/L (250 to 800 µg/dL). Assessment included estimation of quantity ingested, symptoms, time to treatment, initial serum iron, total urinary iron excretion and length of hospital stay. There were no fatalities in this series and the only serious morbidity was shock in a patient who inadvertently received 1000 mg of deferoxamine over 10 minutes. In the opinion of the authors the randomly assigned groups were comparable. The only appreciable benefit of therapy was an increase in urinary excretion which increased from 7.5 µg/h to 68.9 µg/h for oral therapy alone to 260.4 µg/h for oral + intravenous treatment. Once again there was no demonstrable benefit and one serious adverse event leading the authors to conclude that chelation was not predictably beneficial in a mild iron intoxication.
Barr & Fraser (1968) reported an open trial of 16 children with iron poisoning who were treated with deferoxamine (n=14) and DTPA (n=2). Serum iron concentrations at admission ranged from 69 to 404 µmol/L (390 to 2,260 µg/dL) in the deferoxamine treated group. The clinical symptoms varied widely but apparently correlated closely with serum iron concentration. A concentration greater than 179 µmol/L (1000 µg/dL) was associated with cardiovascular collapse, severe gastroenteritis, coma and death. This case series had no comparative group. The deferoxamine dose varied from 0 to 5 g orally and from 0.4 to 4 g parenterally with no consistent pattern. The authors concluded that deferoxamine was safe and biochemically effective but offered no comparative data, particularly to support the value of oral therapy.
Fischer et al (1971) reviewed 27 children treated for iron ingestion over a 10 year period. Serum iron ranged from 8 to 126 µmol/L (50 to 705 µg/dL). Nine patients received i.v. deferoxamine in doses ranging from 840 mg to 2000 mg over 12 hours. Three of the 27 patients received oral deferoxamine (7.5 to 8 g) in addition to their i.v therapy. No mortality was observed and the only morbidity was ascribed to the combination of 500 mg i.m. and 100 mg/h infusion of deferoxamine which produced hypotension. The authors correctly concluded that deferoxamine should be reserved for those patients in whom iron toxicity is likely, because of the risk of adverse effects from deferoxamine therapy.
Westlin (1971) reviewed the American clinical trials of deferoxamine undertaken by the manufacturer. Data on 474 patients were collected from multiple centres. One important contribution of this study was the finding that a serum iron less than 89 µmol/L (<500 µg/dL) had 6% incidence of serious signs and symptoms whereas an iron of greater than 179 µmol/L (1000 µg/dL) was associated with a 62% incidence of shock and coma. The deferoxamine dosage regimen was not controlled and included both oral, i.m. and i.v. administration at a variety of doses. There were 5 deaths in this series, attributable to very high iron concentrations and/or co-ingested toxins. Thirteen patients developed hypotension attributed to rapid administration of deferoxamine. Eight others had histaminergic symptoms also related to deferoxamine. The author correctly concluded that deferoxamine is an ‘adjunct to, and not a substitute for' supportive care. The incidence of hypotension was notable enough to prompt caution on the rate of i.v. administration.
McEnery (1971) presented a three year review of 55 patients treated with nasogastric deferoxamine (5 g) and i.v. deferoxamine (15 mg/kg/h). No adverse events related to deferoxamine were recorded in this series. Seventeen the patients excreted more than 5 mg of iron in the urine giving it a vin rose appearance and this correlated with the serum iron generally being greater than 89 µmol/L (500 µg/dL). The author inappropriately concluded that this series with 100% survival supported the approach of combined oral and parenteral deferoxamine although no comparative data of any type was presented.
Shnaps & Tirosh (1981) reported the survival of five patients with acute iron overdose managed with a combination of oral and i.v. deferoxamine, but included no control or detailed case reports. No conclusion can be drawn from this report.
10.2 Use in aluminium toxicity
Yaqoob et al. (1993) reported on the efficacy of deferoxamine to reverse resistance to recombinant human erythropoietin, due to aluminium overload, present in 9 of their 17 patients receiving erythropoietin for uraemic anaemia (haemoglobin <7 g/dL). Aluminium toxicity was diagnosed by a positive deferoxamine test and bone biopsy. Seven out of the 8 patients without aluminium toxicity responded to erythropoietin therapy. In the group with aluminium toxicity, only the 4 patients pretreated with deferoxamine responded, whereas the 5 patients not given deferoxamine were non-responders. All subjects in the latter group became responders when pretreated with deferoxamine. Resistance to erythropoietin therapy due to aluminium toxicity may therefore be reversed by low dose deferoxamine therapy in transfusion-dependent haemodialysis patients.
- CLINICAL STUDIES - CASE REPORTS
11.1 Evidence of efficacy in iron poisoning
Isolated case reports on the use of deferoxamine have appeared in the literature and do not always contribute to our understanding of the actions or safety of this compound. Some reports however are worthy of note. The first two case reports are reviewed for historical reasons as the earliest demonstrations of deferoxamine use.
Henderson et al. (1963) reported of the use of deferoxamine in a 14 month old child following an ingestion of ferrous gluconate. The initial serum iron concentration at least 4.5 hours after ingestion was 456 µmol/L (2,550 µg/dL) and the child was tachycardic and acidotic. Both oral and intravenous deferoxamine were administered with the i.v. dose given as 800 mg in 20 mL of water. Urinary excretion was reported at 25 mg of iron over 3 days. At 24 hours after admission the child suffered 5 generalised seizures and had a residual hemiparesis that resolved over a period of months. The authors attributed the prompt improvement in the child's clinical status to deferoxamine administration, although other supportive therapies were instituted simultaneously.
Santos & Pisciotta (1964) reported the treatment of a 14 month old child with deferoxamine for acute iron poisoning. The initial serum iron concentration approximately 1 hour after ingestion was 102 µmol/L (575 µg/dL) and the child was treated with oral, intravenous and intramuscular deferoxamine. Urinary excretion of iron was 4.6 mg over 6 days. The authors suggest that the good outcome in this case was due in part to deferoxamine.
Peck et al. (1982) reported continuous deferoxamine administration in a 19 year old using an infusion of 15 mg/kg/h up to a total of 37.1 g over a 52 hour period. The patient continued to excrete a vin rose urine over this time period but recovered without sequelae from either toxin or treatment. This exceeds the generally recommended 6 g/24 hour dosage regimen for deferoxamine.
More recently, Sipahi et al. (2002) reported using deferoxamine to treat two cases of symptomatic iron poisoning in children aged 60 and 14 months with serum iron concentrations of 332 µg/dL (60 µmol/L) and 302 µg/dL (54 µmol/L), respectively. Both did well despite ingesting 88 mg/kg and 100 mg/kg of elemental iron respectively, although the need for antidotal therapy in such cases could be questioned.
In a retrospective study of 32 patients with moderately severe iron poisoning (serum iron concentrations of 300-500 µg/dL; 53-92 µmol/L), conservative management without deferoxamine therapy was sufficient (Bosse, 1995). However, both early intravenous deferoxamine therapy (at a rate of 15 mg/kg/hour) and gastrotomy did not prevent the death of a 17 month old child who presented with haemorrhagic emesis, coagulopathy, shock, acidosis, respiratory failure, and an initial blood iron concentration of 18,570 µg/dL (3,305 µmol/L) (Perrone et al., 2000).
11.2 Assessment of severity of iron poisoning
Various indicators have been used to assess iron toxicity, but they are generally unreliable. In the past, a serum iron concentration in excess of the total iron-binding capacity (TIBC) has been considered as an indication for deferoxamine therapy in acute iron poisoning. Traditionally the presence of radiopacities on abdominal X-rays, leucocytosis, hyperglycaemia, metabolic acidosis and diarrhoea were thought to be associated with severe poisoning and high serum iron concentrations, but this is not the case (Palatnick & Tenenbein, 1996). Provocative chelation with deferoxamine has also been espoused as a measure of severity of iron poisoning.
Chyka & Butler (1993) in their review of 128 cases of acute iron poisoning in children found that 65 patients had a serum iron and a TIBC taken simultaneously allowing the authors to test the predictive value of these and other parameters, in the assessment of the severity of poisoning. They were unable to confirm that vomiting, diarrhoea, leucocytosis, hyperglycaemia and radiopacities were associated with a serum iron concentration in excess of 300 µg/dL (54 µmol/L); only one observation, coma, was associated (p <0.02) with a serum iron concentration greater than 500 µg/dL (90 µmol/dL). Coma, radiopacities, leucocytosis, and an elevated anion gap were concurrently present (predictive value positive = 100%) when the serum iron concentration was greater than 500 µg/dL; moreover, they were absent collectively (predictive value negative = 95%) when the serum iron concentration was below 500 µg/dL. Individually, these features had a low positive predictive value, but the absence of any one of these variables was likely to be associated with serum concentrations less than 500 µg/dL (predictive value negative >93%). The ratio of serum iron concentration to the TIBC was not associated with symptoms of systemic iron toxicity or the presence of vin rose urine after parenteral deferoxamine administration.
The fact that a serum iron concentration in excess of TIBC may not identify patients with serious iron poisoning (Chyka & Butler, 1993; Siff et al., 1999), may be partly related to the unsatisfactory low precision found for this analysis (variation coefficient 16%) and the observation that the in vitro addition of iron to test serum samples produced a relative increase in the TIBC (Tenenbein & Yatscoff, 1991). Toxicity is seen in patients in whom it has been determined that the TIBC is greater than the serum iron concentration (Schauben et al., 1990; Tenenbein & Yatscoff, 1991). The presence of deferoxamine itself makes the measurement of TIBC inaccurate (Siff et al., 1991). As such, the TIBC should not be used in the decision for the initiation of deferoxamine therapy in acute iron poisoning, and high TIBC values occasionally seen in such patients should not be considered as providing a protective effect.
Provocative chelation with deferoxamine has not proven clinically useful in the diagnosis of iron poisoning. Administration of a single dose of deferoxamine does indicate free unbound iron in the plasma if the urine subsequently turns pinkish in colour (vin rose urine). However it has been previously demonstrated that the urine can contain considerable ferrioxamine without any detectable colour change (Eisen et al., 1988), therefore provocative chelation as a diagnostic strategy has limited precision and usefulness.
A serum iron concentration taken at 4 hours post-ingestion is generally the best guide to severity and indicator of the need to treat with deferoxamine. Westlin (1971) reviewed 474 patients with iron poisoning and patients with a serum iron concentration less than 89 µmol/L (<500 µg/dL) had 6% incidence of serious toxicity whereas those with a serum iron greater than 179 µmol/L (1000 µg/dL) had a 62% incidence of shock and coma. Based on this and other clinical data, normal practice is to treat all patients with a serum iron concentration greater than 90 µmol/L(500 µg/dL) at 4 hours with deferoxamine. While a serum iron concentration obtained 4 hours post-exposure may be preferred, serum iron concentrations obtained anywhere between 3 to 6 hours after exposure are serviceable in predicting the clinical severity to be anticipated from iron poisoning.
The criteria for stopping deferoxamine therapy in the acutely iron poisoned patient are not precise, recommendations being to stop chelation when the vin rose colour of the urine disappears or 24 hours later (Robotham & Leitman, 1980). A urinary iron assay has been developed for this assessment and may be useful, especially in centres which regularly treat these patients, however further work is required to validate this assay and assess its clinical applicability (Yatscoff et al., 1991).
11.3 Use in pregnancy
The problem of iron intoxication in pregnancy has been the subject of several reviews (McElhatton et al., 1991; Lacoste et al., 1992; Tran et al., 2000) and case reports (Rayburn et al., 1983; Blanc et al., 1984; Schauben et al., 1990; Turk et al., 1993).
In a review of iron overdose in 49 pregnant women the dose ingested was known in 48 patients and in 28 (60%) exceeded 20 mg/kg of elemental iron. The serum iron concentration was measured in 36 women, and 20 patients had a concentration greater than 60 µmol/L (338 µg/dL). Of the 49 pregnancies 43 resulted in live babies; there were 2 spontaneous abortions and 4 elective terminations. Three babies were premature and 3 had malformations. A total of 25 women (51%) were treated with deferoxamine, 2 of these had babies with malformations. However, all babies with malformations were born to mothers who had taken the overdose after the first trimester, so the abnormalities cannot be directly associated with the overdose or the treatment. The authors recommended that pregnancy should not be considered a contraindication to deferoxamine therapy in iron poisoning (McElhatton et al., 1991).
Rayburn et al. (1983) reported an iron overdose during the third trimester of pregnancy showing that iron is not specifically sequestered in the fetus. The peak serum iron concentration in the mother was 247 µmol/L (1,380 µg/dL). Fourteen hours later a viable preterm infant was born with a serum iron of 21 µmol/L (121 µg/dL). Deferoxamine was administered to the mother prior to the delivery. Of note is that the follow up iron concentrations in the infant showed the rapid onset of iron deficiency, which was treated with oral iron. Both mother and infant did well.
In the fifteenth week of gestation a 15 year old ingested 50 x 300 mg ferrous sulphate tablets (approximately 30 to 50 mg/kg elemental iron). The patient was treated with i.m. deferoxamine (total 3 g) without difficulty. The serum iron concentration between 4 and 5 hours post-ingestion (but not available until 24 hours later) was 324 µg/dL (58 µmol/L). The patient recovered without sequelae and later delivered a healthy term infant (Blanc et al., 1984).
Schauben et al (1990) report an 18 year old in week 25 of gestation who was treated with 2 g i.m. deferoxamine after ingesting 45 mg/kg elemental iron. Abdominal X rays showed an iron bezoar distal to the pylorus and whole bowel irrigation was performed using a polyethylene glycol solution. Serum iron concentrations were 289, 415 and 384 µg/dL (51, 74 and 68 µmol/L) at 2, 3 and 4 hours post-ingestion, respectively. She made a complete recovery and delivered a healthy infant at 39 weeks term.
Turk et al. (1993) reported ingestion of a large dose of iron (3.9 g of elemental iron; 36 mg/kg or 64 mg/kg calculated on lean body weight) in an adult patient in week 26 of gestation. The serum iron concentration about 2 hours after ingestion was 91 µmol/L (507 µg/dL). She was treated with 10.2 g of deferoxamine i.v. over 14 hours and whole bowel irrigation for 12 hours. The patient survived without sequelae and no adverse effects were reported in the fetus.
11.4 Evidence of acute toxicity
Severe hypotension was associated with rapid infusion of deferoxamine in two children given 80-150 mg/kg over 15 minutes (Whitten et al., 1965). Hypotension from rapid infusion of deferoxamine has also been demonstrated in other patients (Leikin et al., 1967; Fisher et al., 1971; Westlin, 1971; Dickerhoff, 1987). Nephrotoxicity may also occur and can develop without hypotension (Koren et al., 1989).
Tenenbein et al. (1992) reported fatal lung injury in four patients, aged 19-26 years, who received deferoxamine infusions of 15 mg/kg/hour for 65-92 hours. Respiratory distress developed after 32-72 hours. Their suggestion that the ARDS seen in these patients was a consequence of free-radical generation was supported by their later study in mice (Adamson et al., 1993). Severe ARDS developed in a 3.5 year old girl who was treated for iron poisoning with deferoxamine at 15 mg/kg/hour for 20 hours and then 5 mg/kg/hour for 14 hours (Ioannides & Panisello, 2000). Respiratory distress may, however, occur in severe iron poisoning (Shannon, 1992). It is generally recommended that a deferoxamine infusion should not be given for more than 24 hours, although prolonged infusions have been tolerated by several patients (Peck et al., 1982; Shannon, 1992).
11.5 Evidence of chronic toxicity
While not generally occurring in the setting of acute iron intoxication, it is nevertheless important to review the accumulated knowledge concerning the toxic effects of chronic deferoxamine therapy.
11.5.1 Infectious complications
Infectious complications of iron overdose and of treatment with deferoxamine are areas of controversy.
Melby et al. (1982) and Mofenson et al. (1987), reported children with ingestion of iron and subsequent deferoxamine therapy who developed septicaemia with Yersinia enterocolitica. It is unclear whether these cases represent compromise of the gastrointestinal tract from iron-induced enteritis, promotion of growth by the propensity for Yersinia enterocolitica to use iron when present in high concentrations or deferoxamine acting as a specific siderophore promoting the growth of this organism (Brock et al. 1988).
Seifert et al. (1987) found a general correlation between iron overload states and bacterial infections in patients receiving regular haemodialysis. Deferoxamine seemed to have no influence on the incidence of bacteraemia in the 39 study patients compared to a control group of 193 patients on haemodialysis, but not receiving deferoxamine. Fungal infections have also been reported in association with chronic iron overload treated with deferoxamine. Boelaert et al. (1988) and Rex et al. (1988) reported cases of fungal infections in a total of four patients. Similarly, Koren et al. (1988) reported a similar saprophytic infection, Pneumocystis carinii, in a patient, without evidence of HIV infection, with transfusional iron overload receiving deferoxamine.
11.5.2 Ocular and auditory toxicity
Both visual toxicity (decreased acuity, night blindness, cataract formation, retinal degeneration) and ototoxicity attributable to deferoxamine have been described in patients with thalassaemia receiving repeated infusions of the drug (Davies et al., 1983; Olivieri et al., 1986; Bentur et al., 1991; Howland, 1996).
Reports of neurotoxicity began to emerge after approximately 20 years of deferoxamine use for iron chelation in patients receiving repeated blood transfusions (Freedman et al., 1988). Davies et al. (1983) and Lakhanpal et al. (1984) reported on patients receiving high dose therapy for chronic iron overload. These patients were found to have retrobulbar optic neuropathy with central scotomas and colour vision abnormalities. Most patients improved following discontinuation of therapy. Orton et al. (1985) reported ocular and auditory toxicity from chronic deferoxamine therapy. While the visual changes were partially reversible, both of the patients reported had permanent sensorineural hearing loss.
Blake et al. (1985) and Pall et al. (1986) suggested the possibility that these acute neurotoxic effects of deferoxamine may be related to chelation of copper. To further add to the confusion, Dickerhoff (1987) reported hypotension, transient blindness and aphasia in a patient who received a sudden bolus of deferoxamine. After restoration of intravascular volume, the symptoms and signs reversed and were attributed to a vasoregulatory phenomenon. Of particular concern to toxicologists is a report by Pengloan et al. (1987) describing two patients who received 10 mg/kg/h infusions of deferoxamine for four hours for the diagnosis of aluminium overload during chronic dialysis. These patients both had an acute reversible deterioration of vision. A similar case was reported by Bene (1989) in a patient receiving 1.8 g of deferoxamine over a two hour period to evaluate aluminium accumulation.
Although now considered a rare idiopathic effect, cataract formation has been reported in patients receiving deferoxamine (Bloomfield et al., 1978). More recently, as a result of higher infusion doses (75-235 mg/kg/day), note has been made of a retinopathy resembling tapetoretinal dystrophy (Davies et al., 1983; Olivieri et al., 1986; Hershko & Weatherall, 1988).
11.5.3 Local reactions
The most frequent adverse effects of deferoxamine are local reactions at the site of infusion or injection, such as pain, swelling, induration, erythema, burning, pruritus, wheals and rash, occasionally accompanied by fever, chills and malaise (Ciba-Geigy, 1994).
11.5.4 Other side effects
Hypotension is the most frequently reported adverse effect of deferoxamine. It appears to be due to a direct effect on mast cells resulting in histamine release, and is most frequent with rapid administration. True IgE mediated anaphylaxis has been reported (Athanasion et al., 1977), but this appears to be infrequent. An isolated case report of thrombocytopenia associated with intravenous deferoxamine is unclear as to aetiology (Walker et al., 1985). Another study of chronic toxicity by De Virgiliis et al. (1988) has demonstrated that excessive deferoxamine therapy in children resulted in poor longitudinal growth. Batey et al. (1979) reported a single case of acute renal failure associated with chronic deferoxamine therapy in a 14 year old treated for chronic iron overload following treatment for thalassaemia. The patient died from hyperkalaemia with renal pathology consistent with a proliferative glomerulonephritis.
Renal toxicity has been reported in a few cases of high-dose deferoxamine therapy (180 mg/kg/day); this may have significance for high-dose deferoxamine treatment in acute iron poisoning. The patient reported by Freedman et al. (1989) had mildly elevated creatinine concentrations, which returned to normal when therapy was discontinued. Koren et al. (1989) reported three patients with acute impairment of renal function from deferoxamine, one of whom was treated for acute iron poisoning.
11.6 Use in renal failure
The effectiveness of deferoxamine treatment in iron poisoning is dependent on an adequate urine output in order to ensure that the iron-deferoxamine complex (ferrioxamine) is excreted. If oliguria or anuria develops, peritoneal dialysis, haemodialysis, or haemofiltration may be necessary (Ciba-Geigy, 1994). The extent to which the dose of deferoxamine should be reduced in renal failure has not been studied.
11.7 Use in pregnancy
Iron poisoning in pregnant women can result in spontaneous abortion, preterm delivery, or, in rare instances, maternal and/or perinatal death. Deferoxamine has been given to pregnant women without adverse effect, although its efficacy in pregnancy has not been studied in controlled clinical trials.
An 18 year old pregnant woman ingested 45mg/kg of elemental iron at 25 weeks gestation and was treated with whole bowel irrigation and i.m. deferoxamine (2 g), with subsequent complete recovery and delivery of an apparently normal male infant at term (Schauben et al., 1990). A 27 year old woman ingested 24 mg/kg of elemental iron in a suicide attempt at 27 weeks gestation (Tran et al., 1998). Deferoxamine treatment was performed without any complications. Tran and associates (2000) performed a meta-analysis of 61 published cases of intentional iron poisoning in pregnancy, including 29 cases in which deferoxamine was given. The authors observe that deferoxamine was withheld from 47% of eligible symptomatic patients despite the lack of evidence of adverse fetal effects of the drug. They recommend the use of deferoxamine in pregnant women with serious acute iron poisoning.
- SUMMARY OF EVALUATION
Experimental studies have shown that deferoxamine may counteract the toxic effects of free iron. It is thought to act by provision of excess iron binding capacity (chelation), and its effects are not necessarily dependent on the subsequent excretion of iron. Studies in animals give evidence of reduced serum iron concentration associated with deferoxamine administration, although conflicting data exists. No clinical studies have demonstrated any beneficial effect of deferoxamine on morbidity or mortality in subjects with acute iron poisoning. However, in some case reports the use of deferoxamine has been associated with a favourable outcome. As such, supportive care is the cornerstone of treatment for the most severe cases of iron poisoning with deferoxamine as an important adjunct.
In chronic aluminium toxicity (that is, patients on haemodialysis) there are still too few reports to evaluate a possible role of deferoxamine therapy.
Deferoxamine is indicated for the management of acute iron intoxication as an important adjunct to supportive care.
In considering triage of iron intoxications, it is important to remember that a 300 mg ferrous sulphate tablet contains 60 mg of elemental iron. Other preparations such as paediatric multivitamins usually contain only 4 to 20 mg of elemental iron per tablet. It is generally recommended that ingestions in excess of 60 mg/kg of elemental iron be considered for intensive gut decontamination and monitoring of the serum iron concentration. Ingestions of elemental iron in the 30-60 mg/kg range may still warrant decontamination, but are less likely to need further intervention. Obviously, in some cases the history may be unavailable or misleading and adjunctive support such as abdominal radiographs and examination of vomitus or gastric contents may be helpful in determining appropriate management. The final arbiter of any decision to discharge a patient should be the clinical condition of the patient, in conjunction with the serum iron concentration at 4-6 hours post-ingestion.
There is little controversy that serum iron concentrations above 89 µmol/L (>500 µg/dL) and/or patients with serious clinical manifestations of iron toxicity (e.g. coma, gastrointestinal haemorrhage) warrant treatment. Similarly patients with serum concentrations less than 53 µmol/L (300 µg/dL) generally do not show significant urinary excretion of iron during chelation (i.e. they do not display vin rose urine). Controversy exists over the patient with a serum iron between 53 µmol/L (300 µg/dL) and 90 µmol/L (500 µg/dL). In these patients, and if serum concentrations are not available, a history of a large ingestion and clinical signs of severity should dictate therapy (see section 13.1).
The serum iron concentration is unreliable in deferoxamine-treated patients and declines in both chelated and non-chelated patients due to redistribution. The decision to terminate chelation therapy is a clinical judgement made on the basis of the patient's condition and clearing of the vin rose colouration of urine (if present).
12.2 Advised routes and dose
At the current time an intravenous infusion of 15 mg/kg/h of deferoxamine is recommended for acute iron intoxication. Since bolus deferoxamine may release histamine, a controlled infusion rate is critical to avoid adverse effects. A small degree of histamine release in a hypovolaemic patient may compromise the circulation and so maintenance of intravascular volume is recommended prior to administration of deferoxamine. This may also prevent deferoxamine-induced nephrotoxicity which can occur without hypotension. This dose of deferoxamine is empirical and has not been validated, however it is widely recommended by many authors.
The total intravenous dose of deferoxamine should generally not exceed 80 mg/kg/24 hours. There have, however, been reports of administration of much higher doses with no adverse effects, for example 425 mg/kg over 24 hours in one report of patients with thalassaemia (Propper et al., 1976).
The intramuscular route is discouraged and should be avoided in shock states. However, this route may be recommended in certain transport situations or where accurate delivery by infusion pump cannot be guaranteed. Doses ranging from 20 to 100 mg/kg every 4 to 8 hours i.m. have been recommended with an upper limit of 6 g/24 hours.
The subcutaneous dosing for chronic iron and aluminium overload (usually at 20-40 mg/kg/day) is not evaluated in this monograph.
12.3 Other consequential or supportive therapy
Supportive care remains the mainstay of treatment for iron intoxication. Initial management should focus upon support of the airway, respiration and cardiac function.
Fluid resuscitation needs may be tremendous (up to 100 ml/kg) and it is clear that intravascular monitoring such as central venous pressure or Swan-Ganz catheterisation is an important adjunct to the management of critically ill patients with iron intoxication. Evidence of negative inotropic and chronotropic effects of iron in overdose supports the use of catecholamines in hypotension or low perfusion states unresponsive to fluid therapy (Vernon et al., 1989). Iron intoxication results in acidosis directly from liberation of an unbuffered hydrogen ion when ferrous iron is converted to ferric iron and indirectly from the effects of hypoperfusion; it should be corrected.
Gut decontamination may be undertaken considering the following points. Ipecacuanha syrup and gastric lavage may be appropriate choices, if given early, because iron poisoning may involve large tablets in various states of decomposition. The use of various alkalinising agents in attempts to maintain the iron in an insoluble state has been suggested and studied in vitro and in vivo (Czajka et al., 1981). Dilute sodium bicarbonate solution may be a reasonable approach, as may the use of antacids or H2 antagonists to achieve the same effect. Phosphate used for the same purpose has been demonstrated to produce severe systemic toxicity and is no longer recommended. Given the direct damage to the gastric mucosa by iron, protection of the stomach by decreasing gastric acid secretion with H2 antagonists and antacids seems prudent. However, there are no compelling data to support the efficacy of any of these agents at controlling tablet dissolution and absorption rate in a clinical setting.
Tenenbein (1987) has reported a series of patients treated with whole bowel irrigation and this may be useful in selected patients. In several anecdotal cases (Peterson and Fifield, 1980), gastrotomy for removal of tablets has been suggested, if a large number of tablets are visible in one location on abdominal radiograph.
Activated charcoal has low maximal binding for iron and therefore has limited value for the large amounts that may be present in the gastrointestinal tract. While deferoxamine has a relatively good absorptive quality for charcoal, the relative amounts of iron that can be bound to deferoxamine make the combination of charcoal and deferoxamine a relatively ineffective approach to binding iron in the gastrointestinal tract. Unless other agents have also been ingested, there is probably no role for charcoal in iron intoxication.
In a number of the more serious cases of iron intoxication, necrosis of the gastrointestinal tract (involving areas from the stomach to the ileocecal junction) has been reported. Ferrioxamine may promote the growth of organisms such as Yersinia enterocolitica and this may contribute to bacterial sepsis. These complications should be considered in any patient who deteriorates suddenly.
12.4 Controversial issues and areas of use where there is insufficient information to make recommendations
Some sources continue to recommend the administration of oral deferoxamine to form ferrioxamine in the stomach, although efficacy remains unproven. Controversial evidence is available that ferrioxamine is absorbed and is toxic although less toxic than the iron absorbed uncomplexed. The recommended dose of 2-10 grams is very expensive, and this use may decrease the availability of deferoxamine for parenteral use in areas where supplies are limited. At present the oral use of deferoxamine cannot be recommended.
Infusion rates of deferoxamine above the currently recommended 15 mg/kg/h may be tolerated in most patients. There are no large series or carefully acquired animal data regarding the risk of higher infusion rates in patients with acute iron poisoning.
The use of oral ascorbate (200 mg/day in divided doses) has been studied in patients with chronic iron excess being treated with deferoxamine; these studies have shown an increase in urinary iron excretion with the addition of ascorbate (Hussain et al., 1977; Pippard et al., 1982). There have been no studies that have assessed the potential role for ascorbate in acute iron poisoning.
Newer iron-chelating agents, such as the oral drug deferiprone (Berkovitch et al., 2000) and NaHBED ligand (Bergeron, 2002), may be promising alternatives to deferoxamine. However, they require further experimental studies before they can be recommended. N,N'-Bis(2-hydroxybenzylethylenediamine-N,N'-diacetic acid (HBED), a synthetic hexadentate ligand, forms a high-affinity, selective bond to iron and can be administered intravenously as a monosodium salt. Unlike deferoxamine it does not produce hypotension and in monkeys induced iron clearance 2-3 times greater than that produced by an equimolar dose of deferoxamine (Bergeron, 1998; Bergeron, 1999).
Chemical modification of deferoxamine, by conjugating the drug to polysaccharides such as dextran and hydroxylethyl starch, has been investigated as a means of improving its efficacy. This creates a high molecular weight drug that retains the chelant efficacy of deferoxamine while being retained in the vascular compartment for a prolonged period of time. Consequently larger doses and higher blood concentrations of the drug can be achieved, with greater chelating capacitance and a lower risk of such adverse effects as hypotension (Dragsten et al., 2000).
12.5 Proposals for further study
A detailed animal study to evaluate the efficacy and safety of oral deferoxamine in acute iron poisoning is critical because of the continued use of this approach. The risk that this may worsen outcome, for example by increasing absorption or altering bowel flora, mandate clarification of this issue.
Animal data followed by collaborative studies in iron intoxicated patients may help to define the range of safe doses of infused deferoxamine in patients with dramatically elevated serum iron concentrations. Animal data may demonstrate the benefit of pretreatment with antihistamine drugs in avoiding the cardiovascular effects of deferoxamine. Further animal and human studies of the safety and efficacy of high molecular weight deferoxamine chelants in the context of acute iron poisoning are also warranted.
Some recent work has demonstrated that the use of adjunctive techniques such as charcoal haemoperfusion and dialysis (Chang and Barre, 1983; Molitoris et al., 1988; Weiss et al., 1989), in some cases with deferoxamine bound to polymers outside the dialysis cartridge (Ambrus et al., 1987), may be methods of removing the iron complex from the circulation in patients with chronic iron and aluminium overload. The potential usefulness of this approach in acute iron intoxication has been supported in an animal model (Banner et al., 1989).
The criteria for cessation of deferoxamine therapy are not well defined, however a preliminary study has shown that urine free iron:creatinine ratio could be used as a guide (Yatscoff et al., 1991). Further work is required to validate the assay that was used in this study and to assess the iron:creatinine cut off at which deferoxamine can be stopped.
12.6 Adverse effects
The relatively extensive use of deferoxamine over several years for acute iron poisoning has revealed few severe side effects, if used as recommended by the manufacturer.
In patients with acute iron poisoning hypotension may develop if deferoxamine is infused rapidly (>15 mg/kg/h); renal failure may also occur. Use of deferoxamine for more than 24 hours may be associated with severe pulmonary complications (ARDS) as shown in some iron-poisoned patients and supported by one experimental study in mice. Infectious complications, especially septicaemia with Yersinia enterocolitica, has been seen in some patients but may not be related to use of deferoxamine.
Chronic deferoxamine therapy in iron-overloaded patients has been associated with ocular and auditory toxicity and renal impairment.
12.7 Restrictions of use
None, except for previous anaphylaxis to deferoxamine, which has been reported but appears to be very uncommon.
In renal failure the dose must be reduced accordingly. Haemodialysis may be necessary to remove the ferrioxamine.
- MODEL INFORMATION SHEET
Deferoxamine is indicated for the management of acute iron intoxication where the total body burden is great, symptoms and signs severe, or the serum iron concentration is greater than 90 µmol/L (500 µg/dL) at 4-6 hours after ingestion. The indications for the use of deferoxamine following an acute ingestion include:
A serum iron concentration >90 µmol/L (>500 µg/dL).
Ingestion of greater than 100 mg/kg of elemental iron by history, in the context of a sick patient, where access to a serum iron concentration is delayed.
Signs of circulatory compromise.
A plasma bicarbonate concentration <15 mmol/L (mEq/L).
13.2 Dosage and route
Deferoxamine may be given by subcutaneous, intramuscular or, preferably, by intravenous routes of administration.
Intravenous administration represents the most consistent mode of drug delivery but must be carefully controlled to deliver no more than 15 mg/kg/h as a continuous infusion, in order to avoid hypotension. This dose should be reduced as soon as the clinical situation permits, usually after 4 to 6 hours so that the total dose does not exceed 80 mg/kg in any 24 hour period. A 10% Desferal® solution (5 mL of sterile water into 500 mg of deferoxamine, then shake well) can be further diluted with isotonic saline, glucose or Ringer's lactate.
Intramuscular therapy may be indicated in doses of 20-100 mg/kg for treatment where intravenous therapy may be difficult to control adequately, such as during patient transport. No more than 80 mg/kg per 24 hour period should be given as for the intravenous route. The manufacturer recommends the following intramuscular dose to normotensive patients: A single dose of 2 g for an adult and 1 g for a child. The subcutaneous route is not recommended in acutely poisoned patients.
The decision to terminate deferoxamine treatment is essentially based on the clinical condition of the patient, supported by the disappearance of the vin rose colour of urine which is often, but not always, seen. The fact that severe pulmonary toxicity may develop after more than 24 hours of therapy must also be taken into account.
There are no specific contraindications to the use of deferoxamine in acute iron intoxication except for a history of prior hypersensitivity. Control of the infusion rate to avoid rapid administration is required to prevent hypotension. An adequate output of urine is essential to ensure that the iron-deferoxamine complex (ferrioxamine) is excreted. In the presence of acute renal failure, dialysis or haemofiltration will be required to remove this complex.
13.4 Adverse effects
Hypotension is well documented as an adverse effect of rapid infusion of deferoxamine. However, it has never been seen when the drug is given at a rate less than 1 mg/kg/minute - a rate that rarely needs be exceeded.
The possibility that renal function may deteriorate during therapy should be considered and monitored. Pulmonary toxicity can occur with prolonged infusions.
Formation of the iron-deferoxamine complex changes the spectral characteristics of deferoxamine and forms an orange-red colour that when present in urine has been described as vin rose. This colouration of urine indicates excretion of chelated iron and is not an adverse event.
Local reactions at site of infusion or injection are common ranging from pain and erythema to wheals and rash, occasionally accompanied by fever, chills and malaise.
In chronic iron intoxication, auditory and ocular function should be monitored periodically to avoid toxicity, which is usually reversible.
13.5 Use in pregnancy and lactation
The US Food and Drug Administration has categorised this drug as a Category C product (that is, risk cannot be ruled out). Skeletal abnormalities have occurred in the offspring of exposed mice and rabbits, but not rats. However, single case reports of treatment for acute iron intoxication in pregnant humans have not demonstrated any adverse effects.
Vials of powder should be stored in a cool place (below 15°C). This drug is manufactured as a lyophilised powder. After reconstitution it is stable at room temperature in the dark for up to one day.
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Medical Director, The Children's Hospital at Saint Francis, Tulsa, USA
Children's Hospital, Harvard Medical School, Boston, USA
Consultant Physician, Medical Toxicology Unit, London, UK
Medical Director, New South Wales Poisons Centre & WA Poisons Information Centre, Australia.
Clinical Toxicologist, Department of Clinical Toxicology, Jagiellonian University Medical College, Kraków, Poland
The following information has been extracted from our CHEMINFO database, which also contains hazard control and regulatory information. [More about...] [Sample Record]
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SECTION 1. CHEMICAL IDENTIFICATION
CHEMINFO Record Number: 156
CCOHS Chemical Name: Aluminum hydroxide
Chemical Name French: Hydroxyde d'aluminium
Chemical Name Spanish: Hidroxido de aluminio
CAS Registry Number: 21645-51-2
RTECS Number(s): BD0940000
EU EINECS/ELINCS Number: 244-492-7
Chemical Family: Aluminum and compounds / inorganic aluminum compound / hydroxide
Molecular Formula: Al-H3-O3
Structural Formula: Al(OH)3
SECTION 2. DESCRIPTION
Appearance and Odour:
Odourless, white crystals, powder or granules.(17,23)
NONE - odourless and essentially non-irritating.
Aluminum hydroxide can exist and is commercially available in crystalline and gelatinous forms. Several crystalline forms are known including trihydroxides, gibbsite, bayerite and nordstrandite. The crystalline form is available as granules and powder in different particle sizes including coarse to ground to extra-fine precipitated grades. Common impurities include soda (sodium oxide), ferric oxide, silica and small amounts of titanium dioxide.(23,24) Aluminum hydroxide gels contain considerable amounts of water.(23)
Uses and Occurrences:
Used in the manufacture of iron-free aluminum, activated alumina, calcined alumina and aluminum salts, glass, fire clay, pottery and printing inks, waterproofing fabrics; antiperspirants, dentifrices, detergents, lubricants and packaging materials; as a filler for paper, plastics, rubber and cosmetics; in the preparation of alumina ceramics, refractories, polishing products, catalysts and catalyst supports; as an adsorbent, dessicant, flame retardant, and ion-exchanger; in chromatography; as an emulsifier, mordant in dyeing, and filtering medium; and as a soft abrasive for brass and plastics. Used as the gel or dried gel in pharmaceutical preparations, for example, as an antacid and antihyperphosphatemic.(17,23)
SECTION 3. HAZARDS IDENTIFICATION
Odourless, white crystals, powder or granules. Will not burn. Essentially non-toxic following short-term exposure.
POTENTIAL HEALTH EFFECTS
Effects of Short-Term (Acute) Exposure
Dusts are probably not irritating at low airborne concentrations. In general, high concentrations of dust may cause coughing and mild, temporary irritation.
Aluminum hydroxide dust is probably not irritating to the skin, based on limited animal information. There is no human information available.
It has been assumed that aluminum is very poorly absorbed through the skin, however, one recent report indicates that aluminum can be absorbed through the skin of mice following application of a water solution of one salt (aluminum chloride hexahydrate).(1,2)
Aluminum hydroxide dust is probably not irritating to the eye, except as a "foreign object". Some tearing, blinking and mild temporary pain may occur as the solid material is rinsed from the eye by tears. There is no human or animal information available.
Short-term oral toxicity is expected to be low.(3) Aluminum is a normal component of the human diet and the normal daily intake of various aluminum compounds is significant. In adults, daily aluminum intake has been estimated at about 9 to 14 mg (4) in one reference and 1 to 100 mg (mean 5 mg) (5) in another. It can be much higher (1000 mg or more (6)) in individuals taking antacids containing aluminum hydroxide. Animal toxicity values are not available since death occurs from intestinal blockage rather than systemic toxicity.(5) Ingestion is not a typical route of occupational exposure.
Effects of Long-Term (Chronic) Exposure
NEUROLOGICAL EFFECTS: A link between exposure to aluminum or aluminum compounds and Alzheimer's disease or other neurological diseases has been suggested. This link was suggested because of severe neurological effects which have been observed in patients receiving dialysis treatment (with dialysis fluids containing aluminum); effects seen in animals exposed to aluminum using non-occupational routes of exposure; case reports of neurological effects in individual workers; and findings of elevated aluminum levels in the brains of patients with neurological diseases. However, at present whether or not this association is a true effect is controversial and findings are inconsistent. Based on the available information, including studies of occupationally-exposed employees, recent reviewers have concluded that the evidence is inadequate to establish a link between occupational exposure to aluminum and specific effects on the nervous system or Alzheimer's disease, in normal, healthy workers.(1,4,5,7,8,9) One reviewer has concluded that there is a likely connection between long-term occupational exposure to aluminum and a specific effect, impaired co-ordination, but not other toxic effects on the nervous system or Alzheimer's disease.(10)
INGESTION: Ingestion of large amounts of aluminum salts over a prolonged period may cause phosphate deficiency, based on animal and human information.(11) This effect may eventually cause softening and bending of the bones (osteomalacia).(12) There are no reports of these effects from occupational exposures to aluminum salts.
Aluminum hydroxide was not carcinogenic in animal tests. There is no human information available.
The International Agency for Research on Cancer (IARC) has not evaluated the carcinogenicity of this chemical.
The American Conference of Governmental Industrial Hygienists (ACGIH) has no listing for this chemical.
The US National Toxicology Program (NTP) has not listed this chemical in its report on carcinogens.
Teratogenicity and Embryotoxicity:
Aluminum hydroxide has not produced harmful effects when administered orally to animals. However, when administered with common dietary constituents, such as citric acid, lactic acid and ascorbic acid, fetotoxicity was observed, in the presence of maternal toxicity. These studies indicate that aluminum absorption may be significantly enhanced by certain dietary constituents. There is no human information available.
There is no human or animal information available.
There is no specific information available. In general, aluminum compounds have been found to be non-mutagenic in in vitro tests with both mammalian and non-mammalian cells.(11,13,14)
Toxicologically Synergistic Materials:
There is no information available.
Potential for Accumulation:
Aluminum hydroxide is absorbed only to a limited degree from either the gastrointestinal tract or the lungs, and is rapidly excreted in the urine. A certain amount of tissue uptake does occur.(3) Ingestion of aluminum hydroxide has resulted in the accumulation of aluminum in the bones (femur and tibia) and brain (cerebral cortex) in rats and dogs.(28)
SECTION 4. FIRST AID MEASURES
If symptoms are experienced, remove source of contamination or move victim to fresh air. Obtain medical advice immediately.
No health effects expected. If irritation occurs, gently blot or brush away excess chemical quickly. Wash gently and thoroughly with water and non-abrasive soap. If irritation persists, obtain medical advice.
Do not allow victim to rub eye(s). Let the eye(s) water naturally for a few minutes. Have victim look right and left, and then up and down. If particle/dust does not dislodge, flush with lukewarm, gently flowing water for 5 minutes or until particle/dust is removed, while holding the eyelid(s) open. If irritation persists, obtain medical attention. DO NOT attempt to manually remove anything stuck to the eye(s).
If irritation or discomfort occur, obtain medical advice immediately.
First Aid Comments:
All first aid procedures should be periodically reviewed by a doctor familiar with the material and its condition of use in the workplace.
SECTION 5. FIRE FIGHTING MEASURES
Not applicable (non-combustible solid)
Lower Flammable (Explosive) Limit (LFL/LEL):
Upper Flammable (Explosive) Limit (UFL/UEL):
Autoignition (Ignition) Temperature:
Sensitivity to Mechanical Impact:
Not sensitive. Stable metal.
Sensitivity to Static Charge:
Not applicable. Not combustible.
Combustion and Thermal Decomposition Products:
Fire Hazard Summary:
Aluminum hydroxide does not burn or support combustion.
Does not burn. Use extinguishing media appropriate for the surrounding fire.
Fire Fighting Instructions:
Not a fire hazard. Does not burn or support combustion.
No special firefighting procedures required.
NATIONAL FIRE PROTECTION ASSOCIATION (NFPA) HAZARD IDENTIFICATION
NFPA - Comments:
NFPA has no listing for this chemical in Codes 49 or 325.
SECTION 9. PHYSICAL AND CHEMICAL PROPERTIES
Molecular Weight: 77.99
Physical State: Solid
Melting Point: Loses water at 300 deg C (572 deg F) (25,26)
Boiling Point: Loses water at 300 deg C (25,26)
Relative Density (Specific Gravity): 2.42 (water = 1) (23,25,26)
Solubility in Water: Virtually insoluble (0.01 g/100 mL at 18 deg C). Forms gels on prolonged contact with water.
Solubility in Other Liquids: Insoluble in ethanol; soluble in acidic and alkaline aqueous solutions.(25,26)
Coefficient of Oil/Water Distribution (Partition Coefficient): Not applicable
pH Value: Approximately 4-10.5.*(23)
Vapour Density: Not applicable
Vapour Pressure: Essentially zero at room temperature
Saturation Vapour Concentration: Not applicable
Evaporation Rate: Not applicable
Critical Temperature: Not available
Other Physical Properties:
*Aluminum hydroxide is amphoteric, that is, it has the capacity to act either as an acid or a base.(23)
SECTION 10. STABILITY AND REACTIVITY
Normally stable. Absorbs carbon dioxide from the air.(24) Loses water at 300 deg C.(25,26)
Does not occur.
Incompatibility - Materials to Avoid:
NOTE: Chemical reactions that could result in a hazardous situation (e.g. generation of flammable or toxic chemicals, fire or detonation) are listed here. Many of these reactions can be done safely if specific control measures (e.g. cooling of the reaction) are in place. Although not intended to be complete, an overview of important reactions involving common chemicals is provided to assist in the development of safe work practices.
STRONG ACIDS (e.g. sulfuric acid or hydrochloric acid) - vigorous or violent reaction.(24)
STRONG BASES (e.g. sodium hydroxide) - vigorous or violent reaction.
CHLORINATED RUBBER - react violently or explosively when heated, with or without hydrocarbon or chlorinated solvents.(24,27)
Hazardous Decomposition Products:
Corrosivity to Metals:
Stability and Reactivity Comments:
Aluminum hydroxide has catalytic activity. Violent reactions may occur when it is combined with some materials such as chlorinated rubber at elevated temperatures.(24,27)
SECTION 11. TOXICOLOGICAL INFORMATION
There are no standard animal toxicity values available.
No evidence of irritation was observed following application of a 10% suspension of aluminum hydroxide in a non-irritating solution (0.2% Tween-80) (pH 7.2) to mice, rabbits and guinea pigs for 5 days.(18)
Effects of Short-Term (Acute) Exposure:
No harmful effects and no significant accumulation of aluminum in the bone were observed in rats fed 14470 ppm aluminum hydroxide (873 mg/kg/day) for 28 days.(19)
Effects of Long-Term (Chronic) Exposure:
In general, no adverse effects have been observed in experimental animals following ingestion of 1-2% aluminum hydroxide in the diet (duration of studies unspecified). Decreased growth, disturbances of calcium and phosphorus metabolism, muscle weakness and death have been observed following ingestion of higher dietary concentrations (greater than 2%).(20) No significant effects were observed in rats fed 156 mg/kg/day (reported as 40.2 umol/g aluminum, as aluminum hydroxide) for 178 or 208 days. When approximately the same dose was administered with sodium citrate dihydrate, temporary kidney effects were observed. Thus, indicated that the citrate increased absorption of the aluminum.(21) Subtle effects on metabolism (decreased serum triglyceride and increased phosphorus in the blood) were observed in rats fed 289 mg/kg/day (2000 ppm aluminum, as aluminum sulphate) for 67 days.(22) These high doses are not relevant to occupational exposures. NEUROLOGICAL EFFECTS: Decreased body weight and increased aluminum accumulation in the brain, but no neurological impairment, were observed in rat pups fed 41 mg/kg/day (reported as 14 mg Al/kg/day) for 60 days.(1)
No carcinogenic effects attributable to aluminum hydroxide have been observed following administration to experimental animals by various routes of exposure.(13)
Teratogenicity, Embryotoxicity and/or Fetotoxicity:
Aluminum hydroxide produced no evidence of embryotoxicity or fetotoxicity when administered orally to rats and mice. However, when it was administered with common dietary constituents, such as citric acid, lactic acid and ascorbic acid, fetotoxicity was observed, in the presence of maternal toxicity. These studies indicate that aluminum absorption may be significantly enhanced by certain dietary constituents. Other reports have indicated that very high oral exposure of rats to soluble aluminum compounds during pregnancy or lactation have caused fetotoxicity, in the absence of maternal toxicity.(15) It is not known if similar effects would be expected from aluminum or its insoluble compounds.
SECTION 16. OTHER INFORMATION
(1) Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for aluminum. TP-91/01. US Department of Health and Human Services, July 1992
(2) Anane, R., et al. Bioaccumulation of water soluble aluminium chloride in the hippocampus after transdermal uptake in mice. Archives of Toxicology. Vol. 69, no. 8 (1995). p. 568-571
(3) Beliles, R.P. The metals. In: Patty's industrial hygiene and toxicology. Edited by G.D. Clayton, et al. 4th ed. Vol. II. Toxicology. Part C. John Wiley and Sons, Inc., 1994. p. 1880-1900
(4) Industrial Disease Standards Panel. Interim Report to the Workers' Compensation Board on Aluminum. IDSP report of findings No. 9. Toronto, Ontario, May 1992
(5) Bertholf, R.L., et al. Aluminum. In: Handbook on toxicity of inorganic compounds. Edited by H.G. Seiler. Marcel Dekker, 1988. p. 56-64
(6) Kilburn, K.H. Pulmonary and neurologic effects of aluminum. In: Environmental and occupational medicine. Edited by W.N. Rom. Little, Brown and Company, 1992. p. 465-473
(7) Wennberg, A. Neurotoxic effects of selected metals. Scandinavian Journal of Work, Environment and Health. Vol. 20, Special Issue (1994). p. 65-71
(8) Martyn, C.N. The epidemiology of Alzheimer's disease in relation to aluminium. In: Aluminium in biology and medicine. Ciba Foundation Symposium 169. John Wiley and Sons, 1992. p. 69-86
(9) Sjogren, B., et al. Aluminium. Arbete och Halsa. Criteria documents from the Nordic Expert Group 1992. Edited by B. Beije, et al. No. 1 (1993)
(10) Doll, R. Review: Alzheimer's disease and environmental aluminium. Age and Aging. Vol. 22, no. 2 (Mar. 1993). p. 138-153
(11) Krueger, G.L., et al. The health effects of aluminum compounds in mammals. Critical Reviews in Toxicology. Vol. 13, issue 1 (1984). p. 1-24
(12) Elinder, C.-G., et al. Aluminum. In: Handbook on the toxicology of metals. 2nd ed. Vol. II: Specific metals. Edited by L. Friberg, et al. Elsevier, 1986. p. 2-25
(13) Leonard, A., et al. Mutagenicity, carcinogenicity and teratogenicity of aluminium. Mutation Research. Vol. 196, no. 3 (Nov. 1988). p. 247-257
(14) Bhamra, R.K., et al. Trace elements aluminum, arsenic, cadmium, mercury and nickel. In: Environmental toxicants: human exposures and their health effects. Edited by M. Lippmann. Van Nostrand Reinhold Company, 1992. p. 575-632
(15) Domingo, J.L. Reproductive and developmental toxicity of aluminum: a review. Neurotoxicology and Teratology. Vol. 17, no. 4 (July 1995). p. 515- 521
(16) Yokel, R.A. Benefit vs. risk of oral aluminum forms: antacid and phosphate binding vs. absorption. Drug and Chemical Toxicology. Vol. 12, nos. 3 and 4 (1989). p. 277-286
(17) HSDB record for aluminum hydroxide. Last revision date: 96/06/06
(18) Lansdown, A.B.G. Production of epidermal damage in mammalian skins by some simple aluminium compounds. British Journal of Dermatology. Vol. 89 (1973). p. 67-76
(19) Hicks, J.S., et al. Toxicity and aluminium concentration in bone following dietary administration of two sodium aluminium phosphate formulations in rats. Food and Chemical Toxicology. Vol. 25, no.7 (1987). p. 533-538
(20) Sorenson, J.R.L., et al. Environmental Health Perspectives. Vol. 8 (Aug. 1974). p. 3-95
(21) Ecelbarger, C.A., et al. Tissue aluminum accumulation and toxic consequences in rats chronically fed aluminum with and without citrate. Journal of Agricultural and Food Chemistry. Vol. 42, no. 10 (Oct. 1994). p. 2220-2224
(22) Sugawara, C., et al. Decrease of serum triglyceride in normal rat fed with 2000 ppm aluminum diet for 67 days. II. Feeding young and adult rats a sucrose diet with addition of aluminum hydroxide and aluminum potassium sulfate. Fundamental and Applied Toxicology. Vol. 10, no. 4 (1988). p. 616- 623
(23) Misra, C. Aluminum oxide (hydrated). In: Kirk-Othmer encyclopedia of chemical technology. 4th ed. Vol. 2. John Wiley and Sons, 1992. p. 317-330
(24) The Sigma-Aldrich library of chemical safety data. Ed. II. Vol. 1. Sigma-Aldrich Corporation, 1988. p. 113C
(25) James, A.M., et al. Macmillan's chemical and physical data. The Macmillan Press Ltd, 1992. p. 285
(26) Weast, R.C., ed. Handbook of chemistry and physics. 66th ed. CRC Press, 1985-1986. p. B-68
(27) Urben, P.G., ed. Bretherick's handbook of reactive chemical hazards. 5th ed. Vol. 2. Butterworth-Heinemann Ltd., 1995. p. 67
(28) International Programme on Chemical Safety. Aluminum. Environmental Health Criteria 194. World Health Organization, 1997
Information on chemicals reviewed in the CHEMINFO database is drawn from a number of publicly available sources. A list of general references used to compile CHEMINFO records is available in the database Help.
Review/Preparation Date: 1997-10-29
Potential for accumulation 2005-01-18
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