UKPID MONOGRAPH
ALUMINIUM SULPHATE
SM Bradberry BSc MB MRCP
ST Beer BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service
(Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
ALUMINIUM SULPHATE
Toxbase summary
Type of product
Used in the paper industry, in water purification, for tanning
leather, fireproofing and water proofing cloth and in antiperspirants.
Toxicity
Most cases occur in renal dialysis patients exposed to intravenous or
intraperitoneal aluminium-containing dialysates.
Mild gastrointestinal symptoms were reported in Camelford in 1988
after residents drank water to which aluminium sulphate had
inadvertently been added in substantial amount, but there were no
confirmed on-going adverse sequelae.
Features
Topical
- Irritant to the skin and eyes.
Ingestion
Minor ingestions (dilute solutions):
- Burning in the mouth and throat, mild gastrointestinal
upset.
Substantial ingestions:
- Nausea, vomiting, diarrhoea, abdominal pain, rarely
haemorrhagic gastritis, circulatory collapse and multi-organ
failure.
- Increased aluminium absorption and retention in bone is
reported following acute ingestion without apparent adverse
sequelae.
- Chronic exposure to aluminium sulphate in drinking water may
be involved in the pathogenesis of Alzheimer's disease
though this remains a highly contentious issue.
Inhalation
- Potential pulmonary irritant
Injection
- Aluminium sulphate used in water purification is a source of
aluminium toxicity in haemodialysis patients and may cause
"dialysis dementia". Aluminium toxicity in these
circumstances may contribute also to renal osteodystrophy
and a microcytic anaemia.
Management
Topical
- Irrigate with copious volumes of lukewarm water.
Ingestion
Minor ingestions (dilute solutions; mildly acidic or neutral):
1. Gastrointestinal decontamination is unnecessary.
2. Symptomatic and supportive measures only.
Substantial ingestions (concentrated acid solutions):
1. Do not attempt gastric decontamination.
2. Secure cardiorespiratory stability.
3. Replace fluids and electrolytes if necessary.
4. Upper gastrointestinal endoscopy may be required.
5. Measure serum aluminium concentration in patients with clinical
features.
6. Parenteral desferrioxamine may be considered if there is evidence
of an increased aluminium body burden. Seek specialist advice
from the NPIS.
Injection
- There is clinical evidence that desferrioxamine therapy can
improve aluminium-induced encephalopathy, bone disease and
anaemia in dialysis patients but seek specialist advice from
the NPIS.
References
Day JP, Ackrill P.
The chemistry of desferrioxamine chelation for aluminum overload in
renal dialysis patients.
Ther Drug Monit 1993; 15: 598-601.
Eastwood JB, Levin GE, Pazianas M, Taylor AP, Denton J, Freemont AJ.
Aluminium deposition in bone after contamination of drinking water
supply.
Lancet 1990; 336: 462-64.
Lowermoor Incident Health Advisory Group; Department of Health.
Water pollution at Lowermoor, North Cornwall. 2nd report.
London: HMSO, 1991; 1-51.
McLaughlin RS.
Chemical burns of the human cornea.
Am J Ophthalmol 1946; 29: 1355-62.
Substance name
Aluminium sulphate
Origin of substance
Naturally occurring, as the mineral alunogenite.
(DOSE, 1992)
Synonyms
Alum
Cake alum
Aluminium sesquisulphate
Dialuminium trisulphate (CSDS, 1989)
Chemical group
Compound of aluminium, a group III metal
(CSDS, 1989)
Reference numbers
CAS 10043-01-3 (CSDS, 1989)
RTECS BD1700000 (RTECS, 1995)
UN NIF
HAZCHEM CODE NIF
Physicochemical properties
Chemical structure
Aluminium sulphate, Al2 (SO4)3
(DOSE, 1992)
Molecular weight
342.15 (DOSE, 1992)
Physical state at room temperature
Solid (powder) (CSDS, 1989)
Colour
White (CSDS,1989)
Odour
Odourless (HSDB, 1995)
Viscosity
NA
pH
Aluminium sulphate has a natural pH of 2.
(Anonymous, 1989)
Solubility
Soluble in water: 313 g/L at 0°C, 891 g/L at 100°C.
(DOSE, 1992)
Autoignition temperature
NIF
Chemical interactions
Sulphuric acid is formed on hydrolysis of aluminium sulphate. On
heating, toxic sulphur oxide and aluminium oxide fumes are
released. (CSDS, 1989)
Major products of combustion
NIF
Explosive limits
NA
Flammability
May burn, but will not ignite. (HSDB, 1995)
Boiling point
The solid decomposes at 770°C. (HAZARDTEXT, 1995)
Density
1.61 at 25°C (CSDS, 1989)
Vapour pressure
Essentially zero (HSDB, 1995)
Relative vapour density
NA
Flash point
NA
Reactivity
NIF
Uses
Aluminium sulphate is used in the paper industry, for tanning
leather and as a mordant in dyeing.
Other uses include water purification and sewage treatment,
fireproofing and waterproofing cloth, and as an ingredient of
antiperspirants. (CSDS, 1989; DOSE, 1992)
Hazard/risk classification
NIF
INTRODUCTION
Aluminium sulphate is relatively non toxic. In 1988, contamination of
drinking water with aluminium sulphate led to a variety of acute
symptoms (Lowermoor Incident Health Advisory Group, 1991) but there
are no case reports of substantial ingestions in the last 30 years.
Uraemic patients on long-term haemodialysis may have an increased
aluminium load via intravenous exposure to high concentrations of
aluminium sulphate in dialysis (usually tap) water (Ward et al, 1978;
Alfrey, 1980), although this should now be avoidable by deionization
or reverse osmosis of the water prior to use.
MECHANISM OF TOXICITY
There is experimental evidence that aluminium inhibits bone
mineralization partly by the deposition of aluminium at the
osteoid/calcified-bone boundary thereby directly inhibiting calcium
influx, and partly by aluminium accumulation in the parathyroid glands
with suppression of parathyroid hormone secretion (Visser and Van de
Vyver, 1985; Berland et al, 1988; Firling et al, 1994).
Proposed mechanisms of aluminium-induced neurotoxicity include
free-radical damage via enhanced lipid peroxidation, impaired glucose
metabolism, effects on signal transduction and protein modification
and alterations in the axunal transport and phosphorylation state of
neurofilaments (Birchall and Chappell, 1988; Exley and Birchall, 1992;
Erasmus et al, 1993; Winship 1993; Haug et al, 1994; Joshi et al,
1994; Strong, 1994).
TOXICOKINETICS
Absorption
In a healthy adult only approximately 15 µg of the average daily
dietary aluminium intake of 3-5 mg is absorbed (Winship, 1992). The
intestinal absorption of aluminium is enhanced by citrate which is
found frequently in effervescent drug formulations.
Main and Ward (1992) reported a reversible increase in the serum
aluminium concentration from 67.5 to 499.5 µg/L in a patient on
haemodialysis taking oral aluminium hydroxide when she was also given
an effervescent analgesic containing sodium citrate. Conversely the
bioavailability of aluminium in aqueous solution is greatly reduced by
silica, such that the toxicity of aluminium-containing phosphate
binders may be reduced significantly by the co-administration of
dissolved silica (Birchall, 1993).
In dialysis patients with aluminium overload, endogenous silicon may
serve a protective role in limiting tissue aluminium uptake (Fahal et
al, 1994). There may also be implications for domestic water supplies
if a high silicic acid concentration evades any hazards posed by
aluminium sulphate in water (Birchall, 1993).
Distribution
More than 90 per cent of absorbed aluminium is bound to transferrin
which does not cross the blood-brain barrier readily. The remaining
ten per cent is associated with low molecular weight complexes, such
as citrate, which can accumulate in brain tissue. In the body
aluminium is stored mainly in bone and liver.
Excretion
Aluminium is excreted predominantly via the kidneys and therefore will
accumulate in patients with renal failure (Alfrey, 1980). Preterm
infants also have a limited ability to excrete aluminium and there are
reports of accumulation in infants on long-term parenteral nutrition
(Sedman et al, 1985). Tsou et al (1991) demonstrated significantly
higher plasma aluminium concentrations (mean 37.2 µg/L) in normal
infants receiving oral aluminium-containing antacids for a prolonged
period compared to controls but this was not associated with adverse
clinical effects.
CLINICAL FEATURES: ACUTE EXPOSURE
Dermal exposure
Topical aluminium sulphate is irritant to the skin (Royal Society of
Chemistry, 1989; Meditext, 1995). Tohani et al (1991) reported a
macular, pruritic rash in association with the accidental addition of
aluminium sulphate to a water supply. The skin reaction may have been
due to the leaching of other metals (especially nickel) from the
domestic plumbing system due to the acidic pH of the water caused by
the high aluminium sulphate concentration.
Ocular exposure
Ocular exposure to aluminium sulphate may cause corneal burns
(McLaughlin, 1946).
Ingestion
Acute aluminium sulphate ingestion causes primarily gastrointestinal
upset though neuropsychological and musculoskeletal sequelae were also
reported in those who drank water to which 20 tonnes of eight per cent
aluminium sulphate had accidentally been added in Camelford, Cornwall
in 1988 (see below). However, a group reviewing this incident
concluded that although "early symptoms, such as gastrointestinal
disturbances, rashes and mouth ulcers, could probably be attributed to
the toxic effects of the incident....The research reported to us does
not provide convincing evidence that harmful accumulation of aluminium
has occurred, nor that there is greater prevalence of ill-health due
to toxic effects of the water in the exposed population" (Lowermoor
Incident Health Advisory Group, 1991).
Gastrointestinal toxicity
Following the Camelford incident a variety of acute symptoms were
reported (Eastwood et al, 1990; Lowermoor Incident Health Advisory
Group, 1991), mainly mild gastrointestinal disturbance and mouth
ulcers (McMillan et al, 1993b). Water aluminium concentrations
recorded at the time ranged from 30 to 620 mg/L (WHO recommended
maximum aluminium concentration in drinking water is 200 µg/L)
(Eastwood et al, 1990; WHO, 1993). The low pH of the water also led to
leaching of other metals, such as copper, from the distribution pipes
so that those washing in the water developed green-discoloration of
their hair.
Substantial ingestion of aluminium sulphate causes burning in the
mouth and throat, gingival necrosis, nausea, vomiting, diarrhoea,
abdominal pain and, in severe cases, haemorrhagic gastritis with
circulatory collapse (Gosselin et al, 1984; Royal Society of
Chemistry, 1989; Meditext, 1995).
Spira (1933) reported dry mouth and throat, anorexia, nausea and
vomiting, glossitis, stomatitis, gingivitis and hiccup (in addition to
cutaneous and neurological symptoms) suspected to be caused by the
ingestion of elemental aluminium plus "aluminized" tap water. There
are, however, no case reports of substantial aluminium sulphate
ingestion in the literature over at least the last 30 years.
Dermal toxicity
Spira (1933) believed that skin conditions including urticaria,
telangiectasia, alopecia and palmar keratosis were caused by ingestion
of elemental aluminium plus "aluminized" tap water but this was not
confirmed.
Neuropsychological toxicity
McMillan et al (1993b) reported "possible impairment of memory" in
those who drank aluminium sulphate-contaminated water in Camelford.
Serial neuropsychological assessments of 10 individuals between eight
and 26 months after the incident showed mild cognitive impairment but
a causal link with aluminium exposure could not be verified and in no
patient was there evidence of residual aluminium in bone or plasma
McMillan et al, 1993b).
Retrospective psychological testing on 39 children from schools in the
contaminated area showed no significant differences compared to
unexposed children (McMillan et al, 1993a). Muscle twitching, limb
paraesthesiae, arthralgia, neuralgia, giddiness, depression and
lassitude have been attributed to the ingestion of elemental aluminium
and aluminium contaminated tap water (Spira, 1933) but this was
speculative.
Musculoskeletal toxicity
Some individuals who drank the aluminium sulphate-contaminated water
in Camelford later complained of joint and muscle pains and fatigue
(Anonymous, 1991; McMillan et al, 1993b).
Bone toxicity
Bone biopsies some six months after the Camelford incident from two
individuals who drank the contaminated water showed increased
aluminium staining in bone formed at a time compatible with exposure
but normal bone aluminium concentrations overall, suggesting increased
aluminium absorption and retention following acute ingestion without
apparent adverse sequelae (Eastwood et al, 1990).
Injection
Cumming et al (1982) reported four dialysis patients who developed
anorexia, nausea, vomiting, abdominal pain, weight loss and malaise
within three days of using a contaminated peritoneal dialysis fluid
containing 620-1460 µg/L aluminium.
CLINICAL FEATURES: CHRONIC EXPOSURE
Inhalation
Pulmonary toxicity
No evidence of respiratory disease was found in 25 workers engaged in
the manufacture of aluminium sulphate from aluminium hydroxide where
the aluminium concentration in factory air was kept below the
permissible limit of 3 mg/m3 (Elo and Uksila, 1977).
Ingestion
Neuropsychological toxicity
Aluminium sulphate is widely used in water purification. This source
has in the past contributed to aluminium toxicity in haemodialysis
patients (see below) and may be involved in the pathogenesis of
Alzheimer's disease via accumulation of aluminium in the brain but
this remains a highly contentious issue (Ebrahim, 1989; Petit, 1989;
Murray et al, 1991; Crapper McLachlan, 1994; Munoz, 1994).
Martyn et al (1989) and Neri and Hewitt (1991) reported a geographical
relationship between Alzheimer's disease and the concentration of
aluminium in drinking water but Wood et al (1988) found no significant
difference in mental test score between hip fracture patients living
in high versus low water aluminium areas.
Animal studies have demonstrated the ability of aluminium to induce
the formation of neurofibrillary tangles (Klatzo et al, 1965), impair
the learning ability of rats, and increase brain acetylcholinesterase
activity in a similar way to that seen in Alzheimer's disease
(Bilkei-Gorzó, 1993).
Other workers have shown elevated aluminium concentrations in brain
tissue from patients with Alzheimer's disease (Crapper et al, 1973)
and laser microprobe studies have demonstrated aluminium accumulation
in the neurofibrillary tangles of these patients (Good et al, 1992).
Harrington et al (1994) described Alzheimer's-disease-like
pathological changes in the brains of renal dialysis patients in
association with aluminium accumulation without clinical evidence of
dialysis encephalopathy (see below).
Injection
Neuropsychological toxicity
'Dialysis dementia' involves the accumulation of aluminium, mainly in
the brain, in patients on haemodialysis where the dialysis water
contains significant amounts of aluminium sulphate (McDermott et al,
1978). This should now be avoidable by reverse osmosis or deionization
of dialysis water prior to use.
Peritoneal dialysis solutions and haemofiltration and plasma exchange
substitution fluids also may contain excessive aluminium although the
incidence of toxicity from these preparations is small (Mion, 1985;
Mousson et al, 1989).
Elliott et al (1978a) reported a significant correlation between serum
aluminium concentrations and the concentrations of aluminium in the
water supply in eight patients on home dialysis with cases of dialysis
dementia confined to regions with high water aluminium concentrations
(>350 µg/L).
A larger study (Registration Committee of the European Dialysis and
Transplant Association, 1980) of patients treated in 65 dialysis
centres in Europe in 1976 and 1977 identified 150 cases of dialysis
dementia with a clear association between the occurrence of dementia
and dialysis with water which was not treated by deionization or
reverse osmosis. Only 23 of 150 patients were still alive in 1978.
Similar findings were reported by Davison et al (1982).
Although the problem of aluminium contamination of dialysates has
reduced in recent years, these patients may still accumulate aluminium
via oral aluminium hydroxide given as a phosphate binder (Salusky et
al, 1991). The contribution this makes to dialysis dementia is likely
to be small (McDermott et al, 1978; Registration Committee of the
European Dialysis and Transplant Association, 1980).
It has been suggested (Hodge et al, 1981) that to ensure no aluminium
uptake by dialysis patients, the dialysate aluminium concentration
should not exceed 14 µg/L. This corresponds to a maximum aluminium
concentration in the water supply of 5 µg/L since aluminium is present
in significant quantity in the dialysate concentrate (Hodge et al,
1981). The WHO recommended maximum aluminium concentration in drinking
water is 200 µg/L (WHO, 1993).
Dialysis dementia is progressive and often fatal (Alfrey et al, 1976;
Burks et al, 1976). In a review of 412 dialysis patients admitted to
one renal unit since 1972, Garret et al (1988) described 38 cases. The
mean time between onset of regular dialysis and development of
symptoms was 40 months with speech difficulties, seizures and
myoclonus the most common presenting features. Dyspraxia, involuntary
movements, poor concentration, loss of short-term memory, confusion,
depression and anxiety were also described and only nine patients were
still alive at the conclusion of the study (Garret et al, 1988).
The neurological consequences of aluminium intoxication may be
exacerbated in patients with aluminium bone disease who sustain
fractures, probably via increased bone aluminium mobilization
(Davenport and Ahmad, 1988).
There are reports of impaired cerebral function in haemodialysis
patients who have an increased body burden of aluminium but no
evidence of "dialysis dementia" (Altmann et al, 1989; Bolla et al,
1992). Altmann et al (1989) found significant abnormalities of
psychomotor function in 27 long-term haemodialysis patients who had
only mildly raised serum aluminium concentrations (mean 59 ± (SEM) 9
µg/L, normal < 10 µg/L).
In another study, 23 haemodialysis patients accidentally exposed to
aluminium for up to six months following failure of a reverse osmosis
system had a mean serum aluminium concentration of 147.3 ± (SEM) 11.7
µg/L without apparent neuropsychiatric sequelae (Caramelo et al,
1995).
Bone toxicity
In patients with renal failure aluminium toxicity may contribute to
renal osteodystrophy (Goyer et al, 1994). In a survey conducted by the
European Dialysis and Transplant Association, 102 of 150 patients with
dialysis dementia also had evidence of bone disease (Registration
Committee of the European Dialysis and Transplant Association, 1980).
Parkinson et al (1979) demonstrated a significant correlation
(p = 0.01) between the mean aluminium content of the water supply and
the incidence of fracturing dialysis osteodystrophy in 1293 patients
undergoing intermittent haemodialysis and Ward et al (1978) reported
significantly fewer cases of osteomalacia in patients maintained on
regular haemodialysis in Newcastle when the dialysate water was
deionised. Another study (Chan et al, 1990) found that the incidence
of osteomalacic fractures in dialysis patients could not be explained
by the aluminium concentration in dialysate alone and a significant
contribution by oral aluminium hydroxide was suggested.
Aluminium associated osteomalacic osteodystrophy is progressive and
characterized by bone pain, a proximal myopathy and spontaneous
fractures. In a review of skeletal surveys of 67 patients with
end-stage renal failure Garrett et al (1986) found that moderate or
severe fracturing osteodystrophy with greater than five fractures had
a diagnostic specificity for aluminium intoxication of 100 per cent,
provided trauma could be excluded.
Investigations typically show normal or only slightly increased
alkaline phosphatase activity, normal serum calcium and normal or
slightly high serum phosphate concentrations with reduced circulating
parathyroid hormone and increased bone and serum aluminium
concentrations (Winship, 1992). It is resistant to treatment with
vitamin D but improvement may follow desferrioxamine therapy as
discussed below.
Cardiovascular toxicity
Elliott et al (1978b) proposed aluminium induced cardiotoxity (via
inhibition of magnesium and ATP-dependent enzymes) as a contributing
factor in the sudden death of five dialysis patients, four with
dialysis encephalopathy and one non-encephalopathic patient whose
serum aluminium concentration was 600 µg/L.
Haemotoxicity
Aluminium intoxication may exacerbate the microcytic hypochromic
anaemia of chronic renal failure via impaired iron utilization
(Caramelo et al, 1995). This effect is at least partly reversible with
desferrioxamine therapy as discussed below.
Dermal toxicity
Brown et al (1992) suggested aluminium overload as the cause of a
widespread pruritic nodular rash (prurigo nodularis) in three patients
on maintenance haemodialysis. The serum aluminium concentration,
measured in two patients, was normal but complete resolution occurred
in all cases following weekly treatment for some three months with one
gram intravenous desferrioxamine.
MANAGEMENT
Dermal exposure
Remove all soiled clothing, wash the exposed area thoroughly with
copious amounts of water and treat symptomatically.
Ocular exposure
The affected eye should be irrigated with lukewarm water for not less
than 15-30 minutes and any visible particles removed. Installation of
local anaesthetic is usually necessary to enable adequate
decontamination. An ophthalmic opinion should be obtained.
Ingestion
The likelihood of adverse effects following aluminium sulphate
ingestion depends on the pH of the solution. Although pure aluminium
sulphate has a pH of 2 most cases will involve ingestion of dilute
solutions causing no, or only mild, gastrointestinal upset.
Ingestion of dilute solutions
These cases will require only symptomatic and supportive measures.
Gastrointestinal decontamination is unnecessary as gastrointestinal
aluminium absorption is poor. Measurement of the serum aluminium
concentration or the administration of desferrioxamine are not
necessary.
Ingestion of concentrated solutions
Theoretically, ingestion of a concentrated aluminium sulphate solution
will cause severe gastrointestinal corrosion and, if this is
clinically suspected, gastric aspiration or lavage should not be
attempted. Activated charcoal does not adsorb aluminium and the
administration of ipecac is not advocated under any circumstances.
Measures to secure cardiorespiratory stability are mandatory and
clinical suspicion of oesophageal or gastric corrosion may require
endoscopic examination. Corticosteriods are not indicated and their
administration may mask signs of abdominal perforation.
The serum aluminium concentration should be measured in patients with
clinical features and parenteral desferrioxamine therapy should be
considered if there is evidence of an increased aluminium body burden;
such as increase is only likely to occur after chronic aluminium
ingestion.
Inhalation
The patient should be removed from exposure, and those with evidence
of respiratory distress should receive high flow oxygen by face-mask.
Corticosteriods may be employed if laryngeal or pulmonary oedema are
present and, theoretically endotracheal intubation or tracheostomy may
be required although there are no such case reports in the literature.
Injection
Most cases of aluminium intoxication following aluminium sulphate
exposure occur in renal dialysis patients exposed to either
intravenous or intraperitoneal aluminium-containing dialysates. The
oral administration of aluminium containing phosphate binders may
exacerbate aluminium accumulation in these circumstances.
Prevention
The prevention of aluminium intoxication in renal dialysis patients
requires:
1. Monitoring of the water aluminium concentration in the supply
used to prepare the dialysate. The maximum EC admissible
aluminium concentration in domestic water is 0.2 mg/L (Eastwood
et al, 1990) but Hodge et al (1981) suggested a maximum water
aluminium concentration of 5 µg/L as the 'safe' limit for use in
haemodialysis.
2. Judicious use of aluminium-containing phosphate binding agents
with the use of alternative preparations, such as calcium
carbonate, where possible.
3. Monitoring the total body aluminium load. There is some
disagreement regarding the role of plasma aluminium
concentrations in the estimation of total body aluminium burden
(Gilli et al, 1983; Seyfert et al, 1987; D'Haese et al, 1990) but
it is likely to be a useful measurement provided it is undertaken
by a qualified laboratory.
4. The definitive investigation for aluminium osteodystrophy is a
bone biopsy (Seyfert et al, 1987). The desferrioxamine infusion
test is a less invasive method of assessing body aluminium
although its interpretation requires clarification (see 'Medical
Surveillance').
Antidotes
There is some evidence that parenteral desferrioxamine therapy slows
the rate of cognitive deterioration in patients with Alzheimer's
disease (Crapper McLachlan et al, 1991; Crapper McLachlan et al, 1993)
but further studies are required.
Desferrioxamine (deferoxamine)
Desferrioxamine forms a stable complex with aluminium and in animal
studies it mobilises aluminium primarily from bone with subsequent
urinary elimination of the chelate (Gómez et al, 1994; Yokel 1994). It
is absorbed poorly from the gastrointestinal tract and parenteral
therapy is necessary. Theoretically 100 mg desferrioxamine can bind
4.1mg aluminium (Winship, 1993).
The desferrioxamine chelate is dialyzable and all published clinical
studies of aluminium chelation using desferrioxamine involve patients
with renal failure undergoing haemodialysis or, less commonly,
peritoneal dialysis (O'Brien et al, 1987) or haemofiltration (Sulkova
et al, 1991).
Following intravenous desferrioxamine administration the
concentrations of protein (mainly transferrin)-bound and erythrocyte
aluminium remain relatively constant as chelatable aluminium is
mobilized from bone (Day and Ackrill, 1993). The
aluminium-desferrioxamine chelate concentration reaches a maximum
12-24 hours post infusion (Day and Ackrill, 1993) producing a rise in
the total plasma aluminium concentration which persists until the next
dialysis. The administration of desferrioxamine shortly before
dialysis will reduce this effect (Douthat et al, 1994). In the longer
term, a fall in the erythrocyte aluminium concentration is observed as
red cells are formed from bone marrow with a lower aluminium load (Day
and Ackrill, 1993).
In chronic renal failure patients treated with 1 gram intravenous
desferrioxamine, Sulkova et al (1991) observed a mean 41 per cent
decrease in the serum aluminium concentration during 28 five hour
haemodialyses (aluminium clearance 28 mL/min during each dialysis)
compared to a mean 66 per cent reduction in the serum aluminium
concentration during 36 sessions of haemofiltration (volume exchange
60 per cent of body weight and calculated aluminium clearance 42
mmol/L in the 60th minute of each filtration). The authors concluded
haemofiltration is superior to haemodialysis in enhancing aluminium
elimination using desferrioxamine.
In another study O'Brien et al (1987) calculated aluminium clearance
rates in a 32 year-old male with aluminium osteomalacia following a
change from haemodialysis to chronic ambulatory peritoneal dialysis
(CAPD). CAPD plus intravenous desferrioxamine (six grams once a week)
gave an aluminium clearance of 4.2 mL/min compared to a clearance of
3.1 mL/min when the same cumulative dose of desferrioxamine was given
into the peritoneal cavity and an aluminium clearance of 2.5 mL/min
with CAPD alone.
Indications for desferrioxamine therapy
There is clinical evidence that desferrioxamine therapy can improve
aluminium-induced encephalopathy, bone disease and anaemia in dialysis
patients (Day and Ackrill, 1993). Its use should be considered,
therefore, in these patients in the following circumstances:
1. When features are present compatible with dialysis encephalopathy
in the absence of an alternative neurological diagnosis.
2. Where a desferrioxamine infusion test indicates an increased body
aluminium load. As discussed below (see Medical Surveillance)
there are some problems with the interpretation of this test.
Milliner et al (1984) found that a 200 µg/L increase above
baseline in the plasma aluminium concentration following 40 mg/kg
intravenous desferrioxamine provided 50 per cent specificity for
a diagnosis of aluminium osteodystrophy with the diagnostic
specificity improving to 71 per cent with an increase above
baseline in the plasma aluminium concentration of 300 µg/L.
3. Where there is clinical evidence of aluminium-related bone
disease. This is usually associated with a 'positive'
desferrioxamine infusion test.
4. Possibly in the presence of severe, transfusion-dependant anaemia
even in the absence of characteristic clinical or analytical
features of aluminium overload (Praga et al, 1987).
5. In the presence of an increased "baseline" serum aluminium
concentration. D'Haese et al (1990) suggested that a serum
aluminium concentration in excess of 60 µg/L reliably indicated
aluminium overload.
Desferrioxamine and dialysis encephalopathy
McCarthy et al (1990) treated 28 dialysis patients suffering from
aluminium toxicity with long-term (mean 11.0 months) intravenous
desferrioxamine, initially at a mean dose of 41.7 mg/kg body weight
once weekly, increasing to a maximum dose of 60 mg/kg as tolerated.
After five to seven months of treatment serum aluminium concentrations
decreased from a mean of 401 µg/L to 245 µg/L. Four patients, who had
advanced dementia before treatment, died during the study period. With
desferrioxamine treatment seven of 28 patients showed neurological
improvement and 25 patients showed improved or stable muscle strength
and overall functional capacity. The authors concluded that whilst
long-term desferrioxamine therapy can be important in the treatment of
patients with significant aluminium exposure it should be employed
only when symptoms demand treatment and when patients can be monitored
regularly for desferrioxamine toxicity (McCarthy et al, 1990).
A 44 year-old man treated with home dialysis (with deionized water)
for four years and oral aluminium hydroxide 2850 mg daily for four
months, developed severe short-term memory loss and myoclonic jerks
(Arze et al, 1981). The serum aluminium concentration was 84 µg/L.
Symptomatic improvement followed the additional use of a reverse
osmosis unit with reduction in the dialysate aluminium concentration
from 6-109 µg/L to 1-12 µg/L but no aluminium was eliminated during
dialysis. Two to six grams intravenous desferrioxamine once weekly for
six months removed 259mg aluminium with considerable improvement on
psychometric testing and no myoclonus at the end of this time.
In another report (Payton et al, 1984) a patient with aluminium
encephalopathy on CAPD improved substantially following two months
treatment with intraperitoneal desferrioxamine (500-750 mg added to
each two litre bag of dialysate). There was a significant (p<0.001)
increase in the post-dialysis dialysate aluminium concentration during
desferrioxamine treatment with an initial increase (from 189 µg/L to
224 µg/L) then progressive decrease (to 27 µg/L) in the serum
aluminium concentration.
Desferrioxamine and aluminium bone disease
In 32 patients desferrioxamine therapy controlled progression of
dialysis-associated aluminium osteodystrophy with bone scans in 21
cases reverting to normal or showing a pattern typical of
hyperparathyroidism (Botella et al, 1984). Charhon et al (1986)
reported similar findings with intravenous desferrioxamine (3-6 grams
once a week for 5-11 months) leading to dramatic clinical improvement
in the bone disease of three haemodialysed patients.
Desferrioxamine and dialysis-associated anaemia
A three month course of desferrioxamine (30 mg/kg iv three times a
week) significantly improved the microcytic anaemia of 15
haemodialysis patients who had only modestly raised serum aluminium
concentrations (5-125 µg/L) and no neurological symptoms of aluminium
toxicity (Altmann et al, 1988).
Praga et al (1987) reported significant reduction in the transfusion
requirement of seven anaemic haemodialysis patients following
desferrioxamine therapy (two grams intravenously after each
haemodialysis session for six months) even though none had either
clinical or analytical characteristic features of aluminium
intoxication.
Treatment protocol for desferrioxamine
In patients with an indication for desferrioxamine therapy 40-80 mg/kg
should be administered, usually intravenously, once a week. The dose
can be reduced to 20-60 mg/kg (as indicated by response and adverse
effects) if treatment is to be continued for several months (Domingo
1989) . Canavese et al (1989) have suggested the therapeutic
effectiveness of desferrioxamine may be exhausted after some two years
therapy even if aluminium bone deposits persist after this time.
Adverse effects of desferrioxamine
Side-effects of long-term treatment with desferrioxamine include
hypotension, gastrointestinal upset, porphyria cutanea tarda-like
lesions, transient visual disturbances (McCarthy et al, 1990),
posterior cataracts, ototoxicity (Domingo, 1989) and an increased
potential for septicaema, especially Yersinia sepsis (Boyce et al,
1985). Some dialysis patients with aluminium encephalopathy develop
worsening of neurological symptoms within hours of desferrioxamine
treatment which may be due to desferrioxamine alone or in combination
with a rising plasma aluminium concentration (McCauley and Sorkin,
1989).
There are several reports of desferrioxamine-associated systemic
fungal infection (mucormycosis) in dialysis patients (Goodill and
Abuelo, 1987; Windus et al, 1987) and an international registry of
this potentially fatal complication has been established (Boelaert et
al, 1991) although a causal link between desferrioxamine and fungal
infection in these patients has not been confirmed (Vlasveld and van
Asbeck, 1991).
Desferrioxamine and charcoal haemoperfusion
Chang and Barre (1983) compared aluminium clearance by desferrioxamine
plus charcoal haemoperfusion with desferrioxamine plus haemodialysis
in 17 patients with chronic renal failure who were stable on standard
haemodialysis. Neither method enhanced aluminium clearance without
desferrioxamine but forty-eight hours after intravenous
desferrioxamine charcoal haemoperfusion produced more effective
aluminium clearance (mean 65.3 ± (SD) 11.2 mL/min; n=6) than
haemodialysis (mean 44.6 ± (SD) 13.7 mL/min; n=4). The authors
proposed haemoperfusion plus desferrioxamine as a effective method of
rapid aluminium elimination in intoxicated patients to be used in
series with haemodialysis in patients with renal failure.
Other chelating agents
The practical problems of desferrioxamine administration and its side
effects have prompted a search for an alternative aluminium chelator.
Uncontrolled clinical studies with d-penicillamine and dimercaprol in
dialysis encephalopathy were unsuccessful (Yokel, 1994) and although
in animal studies parenteral citric acid is effective (Domingo et al,
1988), evidence in man that oral citrate enhances gastrointestinal
aluminium absorption means the problems of parenteral administration
persist.
Although as yet there is no confirmed alternative to desferrioxamine
(Domingo, 1989; Main and Ward, 1992; Yokel, 1994), in a recent
clinical trial Kontoghiorghes et al (1994) demonstrated that the
administration of oral 1,2-dimethyl-3-hydroxypyrid-4-one in a dose of
40-60 mg/kg to six haemodialysis patients resulted in rapid aluminium
mobilization. The plasma aluminium concentration peaked at one hour
post chelation therapy and returned to baseline in most cases within
seven hours. The aluminium chelate was readily dialysable during both
haemodialysis and continuous ambulatory peritoneal dialysis.
Haemoperfusion, haemodialysis and haemofiltration
Chang and Barre (1983) demonstrated that haemoperfusion and
haemodialysis only enhance aluminium elimination in the presence of
desferrioxamine and that under these circumstances haemoperfusion is
more effective than haemodialysis (see above). Protein-bound aluminium
is not dialyzable (Day and Ackrill, 1993). Sulkova et al (1991) also
observed no aluminium elimination during four sessions of
haemodialysis in patients with known aluminium accumulation who were
not pre-treated with intravenous desferrioxamine. The same authors
reported a 15 per cent fall in the mean serum aluminium concentration
during four haemofiltrations without desferrioxamine therapy.
AT-RISK-GROUPS
Chronic renal failure patients
As discussed above, patients with chronic renal failure are at
increased risk of aluminium toxicity from "tapwater" dialysate and
possibly also oral aluminium-containing phosphate binders.
Infants
Sedman et al (1985) found significantly increased plasma (p<0.0001),
urine (p<0.01) and bone (p<0.0001) aluminium concentrations in 18-23
premature infants receiving parenteral nutrition. Aluminium
accumulation in these circumstances reflects a combination of
aluminium contamination of the intravenous fluid and impaired renal
aluminium excretion.
Ten infants with normal renal function who had received oral aluminium
containing antacids for at least one week had significantly higher
plasma aluminium concentrations (mean 37.2 ± (SEM) 7.13 µg/L compared
to controls (4.13 ± 0.66 µg/L) (p<0.005) without signs of toxicity
(Tsou et al, 1991).
The aluminium content of cow's milk and soy milk are considerably
higher (10-20 and 100 fold respectively) than human breast milk which
has an aluminium concentration of 5-20 µg/L and this may contribute to
aluminium intoxication in premature infants with renal failure (Bishop
et al, 1989). Freundlich et al (1985) reported two infants with
congenital uraemia and aluminium toxicity where the source of excess
aluminium was believed to be a powdered milk formulation.
MEDICAL SURVEILLANCE
Aluminium toxicity should be considered in those exposed
occupationally to aluminium dust who develop respiratory or
neuropsychiatric symptoms and in patients with renal failure who may
be at risk of aluminium retention. Useful indicators of exposure
include the 24 hour urine aluminium excretion (normal range < 15
µg/24 hours) and the blood aluminium concentration (normal range < 10
µg/L). Aluminium is evenly distributed between plasma and blood cells
so that plasma and whole blood aluminium concentrations have similar
value in assessing toxicity (van der Voet and de Wolff, 1985).
In 71 dialysis patients D'Haese et al (1990) demonstrated that a serum
aluminium concentration of 60 µg/L or greater identified
aluminium-related bone disease with 82 per cent sensitivity and 86 per
cent specificity. However, Gilli et al (1983) suggested serum
aluminium concentrations were unlikely to reflect total aluminium
accumulation in uraemic patients and Seyfert et al (1987) suggested
plasma aluminium concentrations were not reliable in the diagnosis of
aluminium-related bone disease. This author emphasised the importance
of bone biopsy as the definitive investigation for aluminium
osteomalacia and advocated the 'desferrioxamine test' as a useful
diagnostic tool.
Desferrioxamine infusion test
The desferrioxamine infusion test involves the intravenous
administration, to renal failure patients with suspected aluminium
toxicity, of a standard desferrioxamine dose (usually 20-40 mg/kg) and
comparison of the peak post-infusion plasma aluminium concentration
with the "baseline" concentration, as an indication of the total body
aluminium burden (Day and Ackrill, 1993).
Ackrill et al (1980) suggested that an increase in the serum aluminium
concentration of at least 200 µg/L was required following a
desferrioxamine test dose if a significant amount of aluminium was to
be removed by desferrioxamine during dialysis. The interpretation of
this test has not yet been standardized and its predictive value in
the assessment of aluminium bone disease requires clarification.
Furthermore, the investigation is not without risk.
Ravelli et al (1990) reported acute visual disturbances in 13 of 15
patients given a standard desferrioxamine test with persisting
symptoms in four patients some six months later. It recently has been
suggested that a lower test dose of desferrioxamine can reduce
toxicity without loss of diagnostic efficacy (Yaqoob et al, 1991).
Hair analysis (Wilhelm et al, 1989) and individual spot urine
concentrations (Gitelman et al, 1995) are poor indicators of aluminium
exposure. Furthermore, the kinetics of urine aluminium excretion
varies depending on the form of aluminium involved (Pierre et al,
1995). Estimation of the aluminium content of cerebrospinal fluid may
be important in the investigation of aluminium-related dementia
(Sjögren et al, 1994).
OCCUPATIONAL DATA
Occupational exposure standard
Aluminium salts, soluble: Long-term exposure limit (8 hour TWA
reference period 2 mg/m3 (Health and Safety Executive, 1995).
OTHER TOXICOLOGICAL DATA
Carcinogenicity
There is no evidence that aluminium salts are carcinogenic in man
(Leonard and Gerber, 1988).
Reprotoxicity
Pregnant rats given oral aluminium hydroxide 192-768 mg/kg/day on
gestational days 6-15 showed no maternal or foetal developmental
toxicity (Gomez et al, 1990). There was no evidence of adverse effects
in pregnancy following the accidental contamination of drinking water
with aluminium sulphate in Camelford, Cornwall in 1988 (Golding et al,
1991).
Genotoxicity
Bacillus subtilis H17 (rec+) M45 (rec-) negative DNA damage.
In vitro human lymphocyte cells (72 hr) 20 µg/mL induced chromosomal
aberrations in cells from male and female subjects, while the
frequency of translocations and dicentrics was low.
Oral rat (prolonged exposure) induced dose-dependent inhibition of
dividing cells and increased chromosomal aberrations, not influenced
by duration of exposure (DOSE, 1992).
Fish toxicity
LC50 goldfish (12-96 hr) 100 mg/L (DOSE, 1992).
EEC Directive on Drinking Water Quality 80/778/EEC
Aluminium: Guide level 0.05 mg/L, maximum admissible concentration 0.2
mg/L.
Sulphate: Guide level 25 mg/L, maximum admissible concentration 250
mg/L (DOSE, 1992).
AUTHORS
SM Bradberry BSc MB MRCP
ST Beer BSc
JA Vale MD FRCP FRCPE FRCPG FFOM
National Poisons Information Service (Birmingham Centre),
West Midlands Poisons Unit,
City Hospital NHS Trust,
Dudley Road,
Birmingham
B18 7QH
UK
This monograph was produced by the staff of the Birmingham Centre of
the National Poisons Information Service in the United Kingdom. The
work was commissioned and funded by the UK Departments of Health, and
was designed as a source of detailed information for use by poisons
information centres.
Date of last revision
16/7/96
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