Aluminium in drinking-water
Background document for development of WHO Guidelines for Drinking-water Quality
Effects on experimental animals and in vitro test systems
The oral LD50 of aluminium nitrate, chloride, and sulfate in mice and rats ranges from 200 to 1000 mg of aluminium per kg of body weight (WHO, 1997).
Groups of 25 male Sprague-Dawley rats were fed diets containing basic sodium aluminium phosphate or aluminium hydroxide at 0, 5, 67, 141, or 288/302 mg of aluminium per kg of body weight per day for 28 days. No treatment-related effects on organ and body weights, haematology, clinical chemistry parameters, and histopathology were observed, and there was no evidence of deposition of aluminium in bones. The NOELs were 288 and 302 mg of aluminium per kg of body weight per day for sodium aluminium phosphate and aluminium hydroxide, respectively (Hicks et al., 1987).
In a study in which a wide range of end-points was examined, groups of 10 female Sprague-Dawley rats received drinking-water containing aluminium nitrate for 28 days at 0, 1, 26, 52, or 104 mg of aluminium per kg of body weight per day. The only effects noted were mild histopathological changes in the spleen and liver of the high-dose group. Although tissue aluminium concentrations were generally higher in treated animals, the increases were significant only for spleen, heart, and gastrointestinal tract of the high-dose group. The NOAEL was 52 mg of aluminium per kg of body weight per day (Gomez et al., 1986).
Groups of 10 female Sprague-Dawley rats received aluminium nitrate in their drinking-water at doses of 0, 26, 52, or 260 mg of aluminium per kg of body weight per day for 100 days. Organ and body weights, histopathology of the brain, heart, lungs, kidney, liver, and spleen, haematology, and plasma chemistry were examined. The only effect observed was a significant decrease in body-weight gain associated with a decrease in food consumption at 260 mg of aluminium per kg of body weight per day. Aluminium did not accumulate in a dose-dependent manner in the organs and tissues examined. The NOAEL in this study was 52 mg of aluminium per kg of body weight per day (Domingo et al., 1987a).
Sodium aluminium phosphate, a leavening acid, was administered to groups of six male and six female beagle dogs at dietary concentrations of 0, 0.3, 1.0, or 3.0% for 6 months. Statistically significant decreases in food consumption occurred sporadically in all treated groups of female dogs, but there was no associated decrease in body weight. No significant absolute or relative organ-weight differences were found between any of the treated groups and controls. Haematological, blood chemistry, and urinalysis data showed no toxicologically significant trend. The NOAEL was the highest dose tested, approximately 70 mg of aluminium per kg of body weight per day (Katz et al., 1984).
Beagle dogs (four per sex per dose) were fed diets containing basic sodium aluminium phosphate at 0, 10, 22–27, or 75–80 mg of aluminium per kg of body weight per day for 26 weeks. The only treatment-related effect was a sharp, transient decrease in food consumption and concomitant decrease in body weight in high-dose males. The LOAEL was 75–80 mg/kg of body weight per day (Pettersen et al., 1990)
No adverse effects on body weight or longevity were observed in Charles River mice (54 males and 54 females per group) receiving 0 or 5 mg of aluminium (as potassium aluminium sulfate) per kg of diet during their lifetime (Schroeder & Mitchener, 1975a; FAO/WHO, 1989).
Two groups of Long-Evans rats (52 of each sex) received 0 or 5 mg of aluminium (as potassium aluminium sulfate) per litre of drinking-water during their lifetime. No effects were found on body weight; average heart weight; glucose, cholesterol, and uric acid levels in serum; and protein and glucose content and pH of urine. The life span was not affected (Schroeder & Mitchener, 1975b; FAO/WHO, 1989).
Reproductive and developmental toxicity
Aluminium nitrate was administered by gavage to groups of pregnant Sprague-Dawley rats on day 14 of gestation through day 21 of lactation at doses of 0, 13, 26, or 52 mg of aluminium per kg of body weight per day. These doses did not produce overt fetotoxicity, but growth of offspring was significantly delayed (body weight, body length, and tail length) from birth to weaning in aluminium-treated groups (Domingo et al., 1987b).
Aluminium nitrate was administered by intubation to male Sprague-Dawley rats at 0, 13, 26, or 52 mg of aluminium per kg of body weight per day for 60 days prior to mating and to virgin females for 14 days prior to mating, with treatment continuing throughout mating, gestation, parturition, and weaning of the litters. No reproductive effects on fertility (number of litters produced), litter size, or intrauterine or postnatal offspring mortality were reported. There was a decrease in the numbers of corpus lutea in the highest dose group. However, a dose-dependent delay in the growth of the pups was observed in all treatment groups; female offspring were affected at 13 mg of aluminium per kg of body weight per day and males at 26 and 52 mg of aluminium per kg of body weight per day. Because of the design of this study, it is not clear whether the postnatal growth effects in offspring represented general toxicity to male or female parents or specific effects on reproduction or development. However, the reported LOAEL in females in this study was 13 mg of aluminium per kg of body weight per day (Domingo et al., 1987c). The developmental toxicity of aluminium by the oral route is highly dependent on the form of aluminium and the presence of organic chelators that influence bioavailability. Aluminium hydroxide did not produce either maternal or developmental toxicity when it was administered by gavage during embryogenesis to mice at doses up to 92 mg of aluminium per kg of body weight per day (Domingo et al., 1989) or to rats at doses up to 265 mg of aluminium per kg of body weight per day (Gomez et al., 1990). When aluminium hydroxide at a dose of 104 mg of aluminium per kg of body weight per day was administered with ascorbic acid to mice, no maternal or developmental toxicity was seen, in spite of elevated maternal placenta and kidney concentrations of aluminium (Colomina et al., 1994); on the other hand, aluminium hydroxide at a dose of 133 mg of aluminium per kg of body weight per day administered with citric acid produced maternal and fetal toxicity in rats (Gomez et al., 1991). Aluminium hydroxide (57 mg of aluminium per kg of body weight) given with lactic acid (570 mg/kg of body weight) to mice by gavage was not toxic, but aluminium lactate (57 mg of aluminium per kg of body weight) produced developmental toxicity, including poor ossification, skeletal variations, and cleft palate (Colomina et al., 1992).
Mutagenicity and related end-points
Aluminium can form complexes with DNA and cross-link chromosomal proteins and DNA, but it has not been shown to be mutagenic in bacteria or induce mutation or transformation in mammalian cells in vitro. Chromosomal aberrations have been observed in bone marrow cells of exposed mice and rats (WHO, 1997). Carcinogenicity
There is no indication that aluminium is carcinogenic. JECFA evaluated the limited studies of Schroeder and Mitchener (1975a,b; section 5.3) and concluded that there was no evidence of an increase in tumour incidence related to the administration of potassium aluminium sulfate in mice or rats (FAO/WHO, 1989).
Behavioural impairment has been reported in laboratory animals exposed to soluble aluminium salts (e.g. lactate, chloride) in the diet or drinking-water in the absence of overt encephalopathy or neurohistopathology. Both rats (Commissaris et al., 1982; Thorne et al., 1987; Connor et al., 1988) and mice (Yen-Koo, 1992) have demonstrated such impairments at doses exceeding 200 mg of aluminium per kg of body weight per day. Although significant alterations in acquisition and retention of learned behaviour were documented, the possible role of organ damage (kidney, liver, immunological) due to aluminium was incompletely evaluated in these studies (WHO, 1997).
In studies on brain development in mice and rats, grip strength was impaired in offspring of dams fed 100 mg of aluminium (as aluminium lactate) per kg of body weight per day in the diet, in the absence of maternal toxicity (WHO, 1997).