Reaction mass of aluminium and aluminium oxide and calcium oxide and magnesium oxide

Endpoint summary

Additional information

ABSORPTION, DISTRIBUTION, METABOLISM, ELIMINATION (ADME)

Considering the target substances, several studies have investigated the oral bioavailability of aluminium hydroxide, the most recent being the oral gavage study of Priest (2010) in female Sprague-Dawley rats. The whole body fractional uptake calculated for aluminium hydroxide was 0.025% (±0.041%, sd). Priest (2010) is the only study identified that investigated the bioavailability of aluminium metal or aluminium oxide, the other poorly soluble aluminium substances that are the focus of this review. The results that were reported for aluminium oxide and pot electrolyte were similar to aluminium hydroxide (0.018±0.038% and 0.042±0.0036%, respectively). Aluminium uptake from aluminium metal powder was below the detection limit of the method and, following a repeat of the experiment, was reported as <0.015%. Priest (2010) also studied a suite of other aluminium substances, including the more soluble salts aluminium chloride and aluminium sulphate and the organic complex aluminium citrate. These substances showed fractional uptakes of 0.054% (0.015%, sd), 0.21% (0.079%, sd) and 0.079% (0.0057%, sd), respectively. Due to the use of the same experimental methods for the different substances, the results can be quantitatively compared. The tests substances were administered without co-exposures to ligands that may influence the bioavailability. The results of Priest (2010) contribute to the evidence (as described in Krewski et al., 2007 and ATSDR, 2008) supporting a lack of dependence of aluminium whole body fractional uptake on animal species and also the low bioavailability of the target substances.

The concentrations of organic and inorganic ligands in the stomach when aluminium-containing substances, including the target substances, are consumed will influence speciation and the fraction of aluminium that remains more bioavailable on entry to the more alkaline conditions of the small intestine. Based on a review of the available data, Krewski et al. (2007) proposed values of 0.1 to 0.3% as representative of the bioavailability of aluminium substances entering the gastrointestinal tract from the diet and drinking water.

The amount and location of deposition in the respiratory tract depend on respiratory tract architecture, breathing pattern, hygroscopicity of the material and the particle size distribution. Models are available to estimate deposition in the alveolar region in rats and humans for relevant particle size distributions and ventilation patterns. 

Lung clearance and retention depend on the particle size and shape, animal species, thei n vivodissolution rate and any biochemical interaction between the dissolved moiety and lung proteins (Bailey et al., 1985 a, b). The only study identified that estimated rat lung retention half-times specifically for a poorly soluble alumina (high purity, calcined boehmites; AlO(OH)-40 [MMAD 0.6μm]; AlO(OH)-10 [MMAD 1.7μm]) was Pauluhn (2009a). For AlO(OH)-40 [MMAD 0.6μm], the deposited alveolar fractions were 0.105, 0.108 and 0.103 at external exposure levels of 0.4, 3 and 28 mg/m³, respectively. For AlO(OH)-10 [MMAD 1.7μm], the corresponding deposited fractions were 0.063, 0.067 and 0.065. The lung tissue elimination half-times (t_1/2) for the smaller agglomerated particulate were 56, 43 and 144 days at 0.4, 3 and 28 mg/m³. For the larger agglomerated particle size exposure, the elimination half-times were 42, 60 and 295 days. An overload effect on alveolar clearance was evident at 28 mg/m³.

Based on differences between estimated alveolar deposition and the Al excreted in urine over the 24 hour period during and following an 8 hour workshift, Riihimaki et al. (2008) estimated that 1.2% of the Al deposited in the alveolar region of the lungs of a MIG welder/grinder exposed predominantly to aluminium oxide and aluminium metal was transferred to the systemic circulation. This calculation assumes that the urinary excretion during that time period represents 100% of the systemic uptake which is not an unreasonable assumption. Although crude, this estimate is in good agreement with the radiotracer-based result of 1.9% of the initial deposited dose of²⁶Al₂O₃alumina (MMAD = 1.2μm) obtained by Priest (2004) and results from other studies in workers (Pierre et al., 1995; Sjögren et al., 1988). The results reported by Priest (2004), Priest et al. (1998) and McAughey et al. (1998) based on measurements in two human volunteers showed that 30 to 40% of deposited particles are removed by mucociliary clearance to the gastrointestinal tract, predominantly during an initial rapid removal phase.

The available information shows low rates of transfer of aluminium to the systemic circulation following inhalation exposure to aluminium oxide. McAughey et al. (1998) calculated a half-time for pulmonary clearance by dissolution processes i.e. transfer to the systemic circulation from the lungs, on the order of 3000 days (8.25 years). Increases in the levels of Al in the urine of workers (Riihimaki et al., 2008; Schaller et al., 2007; Pierre et al., 1995; Mussi et al., 1984), however, show that exposure by inhalation does lead to transfer to the systemic circulation most likely with a significant contribution from uptake in the gastrointestinal tract following mucociliary clearance.

No data were available concerning the deposition and transfer of aluminium metal dust/powder or aluminium hydroxide powder to the systemic circulation specifically. Detailed data are lacking on theirin-vivobioavailability and biochemical reactivity in the lungs. However, as the water solubilities and mean fractional uptakes in the gastrointestinal tract of aluminium metal and aluminium hydroxide powder are similar to or less than that of aluminium oxide (Priest, 2010), the results from McAughey et al. (1998) are sufficiently representative of the rate at which these substances are transferred to the systemic circulation following inhalation exposure of similarly sized-particulates.

Considering local effects, dermal penetration and subsequent binding of aluminium with skin proteins can occur on dermal exposure to ionic aluminium complexes in solution. The exposure situations of interest involve dermal exposure to particulate forms of the target compounds. The target compounds are sparingly soluble and are unlikely to be available for adsorption and penetration when in this physical form. If dissolved in, for example sweat, and in the form of an ionic Al complex, the target compounds will exhibit only shallow penetration due to binding in the upper layers of the stratum corneum.HERAG (2007)proposed default dermal absorption factors of 0.1% for metal cations from dry dust exposures.

Systemic Distribution & Metabolism

Aluminium Speciation in Blood & Aluminium Kinetics in Blood After Exposure

After a bolus oral gavage dose, maximum serum concentrations occur during the first hour post-dosing. After intake, aluminium blood concentrations fall rapidly but renal excretion is maintained during this period. The evidence suggests that a large fraction of available aluminium is initially bound to low molecular weight species that can move out into tissue fluids. Aluminium in this form can move easily between tissue fluids and blood and remains available for excretion allowing maintenance of the early excretion levels. In contrast, in blood itself most aluminium is bound to transferrin which is retained in blood vessels. With time the tissue fluid pool is depleted and renal clearance rates decrease as it becomes more difficult first to excrete aluminium that is bound to higher molecular weight proteins and then aluminium that is bound to red blood cells.

Aluminium Levels and Accumulation in the Brain

In summary, a small fraction (on the order of 10^-7– 10^-8) of orally administered Al was found in the rat brain byFink et al.(1994)andJouhanneau et al. (1997). After intravenous infusion,Yokel et al.(2001b)found that the Al concentration in the brain of rats reached its peak (~0.005% of the administered dose per gram of brain tissue) on day 1, regardless of the form of the Al compound (Al transferrin or Al citrate).Yokel et al. (2001b)also showed that Al was retained in the brain for longer than 256 days after administration and that the Al chelator, desferrioxamine, modestly enhanced Al elimination from the brain. The terminal brain half-times were 150 days and 55 days, respectively, for rats that did not receive and received DFO.

Potential mechanisms of transport of Al [administered as the citrate] across the BBB have been examined in severalin-vitroandi n-vivostudies; these have shown that Al transport cannot be explained solely by diffusion and that the process is carrier-mediated( Allen et al., 1995; Ackley and Yokel, 1997; Yokel et al., 2002; Nagasawa et al., 2005). A monocarboxylate transporter(Ackley and Yokel, 1997; Yokel et al., 2002)and system Xc-(Nagasawa et al., 2005)have been suggested as a potential carrier of Al across the BBB. Al uptake by brain cells is likely to occur through a transferrin - transferrin receptor system(Roskams and Connor, 1990).

Based on the results of their experiments with intranasal administration of Al salts to New Zealand rabbits ,Perl and Good (1987)suggested that Al may enter the central nervous system directly via nasal-olfactory pathways.The available evidence does not suggest that this is an important route of exposure for aluminium, however (Krewski et al., 2007; Perl and Good, 1987).

Aluminium Levels in Different Regions of the Brain

Healthy humans

Markesbery et al. (1984)analyzed trace element concentrations in various brain regions in 28 neurologically normal adults aged up to 85 years and also in seven infants. The measurements were conducted by instrumental neutron activation analysis. Brain Al concentrations increased with increasing age. The mean Al concentration was 0.467±0.033 µg/g wet weight in adults and 0.298±0.05 in infants. Based on information presented on the graph, mean Al concentrations in the brain were ~0.35 µg/g in the age group 20-39 years, around 0.43-0.47 µg/g in the age groups 40-59 and 60-79 years, and ~0.70 µg/g in those older than 80 years. Mean concentrations were highest in the globus pallidus (0.893 µg/g), putamen (0.663 µg/g) and middle temporal lobe (0.654 µg/g), and lowest in the superior parietal lobule (0.282 µg/g). Based on the review of available literature(Priest, 2004), normal human brain Al levels are within the range <1 to ~5 µg/g, with most results being closer to the lower end of this range.

Dialysis encephalopathy

Elevated concentrations of Al were observed in the frontal cortex of 21 uraemic patients(McDermott et al., 1978). The concentrations were significantly higher in the 7 patients with dialysis encephalopathy (mean 15.9 ±10.5 µg/g dry weight) than in the 12 patients on dialysis but without encephalopathy (4.4±2.7 µg/g), and than in the 2 uraemic patients who were not dialyzed (2.7±1.4 µg/g). In patients with dialysis encephalopathy, the mean Al concentration in the grey matter was about 3 times higher than that in the white matter (20.6±16.4 µg/g and 6.9±5.3 µg/g, respectively). This difference was small in the other two groups of patients.

Alfrey et al. (1980)determined tissue Al concentrations (by atomic absorption spectrometry) in 38 dialyzed uraemic patients dying of dialysis encephalopathy, 57 dialyzed uraemic patients dying of other causes, 30 non-dialyzed uraemic patients and 36 control subjects who had had no known illness and died of external causes. Tissue Al levels were increased in all uraemic patients. Al levels in brain grey matter were 24.5±9.9 mg/kg dry tissue in patients who died of dialysis encephalopathy (significantly higher than in all the other groups), 8.5±3.5 mg/kg in dialyzed uraemic patients who died of other causes, 4.1±1.7 mg/kg in non-dialyzed uraemic patients and 2.4±1.3 mg/kg in the control subjects. There was no correlation between brain Al and duration of dialysis in patients with encephalopathy. For any duration of dialysis, patients dying of encephalopathy had higher brain Al levels than patients dying of other causes.

Aluminium Accumulation in Organs and Tissues from the Systemic Circulation

 

Priest (2004)reviewed data collected by the International Commission on Radiological Protection on aluminium content in organs and tissues (ICRP publication 23). Excluding the lung and lymph nodes (which can contain un-dissolved Al that is not part of the systemic Al body burden); only theliver, connective tissues, skin and skeletonconcentrate more Al than the body average. Data for the skin might not be valid because of the likelihood of external contamination. Other data on Al tissue distribution in workers occupationally exposed to Al and members of the public (also summarized by Priest, 2004) are generally consistent with those reported by the ICRP.The skeletal system is the primary site of accumulation in humans.As discussed in the section on inhalation, aluminium also accumulates in the lungs due to inefficient transfer to the systemic circulation.

 

The injection studies by Guo et al. (2005 a, b) and Llobet et al. (1995) show that systemic aluminium can be transferred to the testes when administered at high doses. The study by Ondreicka et al. (1966) shows that Al levels may increase in the testes on chronic oral exposure. Older rats may show increased accumulation relative to adult and young rats (Gomez et al., 1997). Further information on the toxicokinetics of aluminium in the testes is not currently available.

Urinary excretion is the main route by which systemic aluminium is eliminated from the body (Priest, 2004; Talbot et al., 1993, 1995). The filtration of aluminium from the blood into urine occurs in the kidney glomerulus and its efficiency shows a dependency on the chemical species to which the Al is complexed in the blood (Shirley and Cote, 2005).

Elimination

Talbot et al. (1993, 1995) observed an average of 59 (sd, 10) % of²⁶Al excreted in urine during the first 24 hours after intravenous injection and 72 (sd, 7) % - by day 5 in a study with six healthy, male volunteers. A marked inter-individual variability in the pattern of early urinary excretion of²⁶Al was observed. The cumulative fraction of²⁶Al excreted by day 5 was in the range from 62% to 84%. The mean renal clearance rate was 16 litres of whole blood per day (sd, 10) and the range 5 to 33 suggesting a change in the binding of Al with increasing time in the blood. Based on the series of²⁶Al radiotracer experiments conducted in human volunteers at the Harwell Laboratory, UK, Priest (1997) reported that 85 to 90% of aluminium is excreted in urine during the first day after IV exposure.

 

Results from several studies support an enhancement of excretion when aluminium is introduced into the blood already complexed with citrate (Lote et al., 1992, 1995; Maitani et al., 1994). Studies in humans that have investigated whether co-administration of silicate with aluminium enhances the efficiency of excretion have produced conflicting results, however (Jugdaosingh et al. 2000, King et al., 1997; Bellia et al., 1994, 1996; Birchall et al., 1996).

 

A dose-dependence of efficiency of initial urinary excretion has been observed that may result from the formation of high molecular weight aggregates at high blood aluminium concentrations (Xu et al., 1991; Yokel and McNamara, 1988). Studies that have been conducted on the rate of elimination of aluminium in animals and humans have shown half-times that increase with the duration of follow-up indicating the presence of several compartments.The longer elimination half-times, reflecting slower elimination from compartments other than blood, do not show evidence of dose-dependence.

 

Greger and Radzanowski (1995) observed differences in the accumulation and kinetics of aluminium administered by oral gavage to Sprague-Dawley rats of different ages in a 44 day experiment. The growing rats accumulated more aluminium in their tibias on day 1 of the experiment and also retained more aluminium over the 44-day experimental period. Half-times in the bone of the ageing rats were several times greater than in the growing and mature rats (173 days versus 38 and 58 days in the growing and mature rats, respectively). Iron status may also affect the distribution and retention of aluminium. Greger et al. (1994) observed more aluminium in the livers but less aluminium in the tibias and spleens of male anaemic rats compared with male normal rats but these differences were not significant at all time-points.

 

As filtration in the kidneys is the main route by which systemic aluminium is excreted, individuals with renal insufficiency will retain more aluminium. The immature renal systems of neonates, particularly those who are pre-term, put them at increased risk of accumulating higher levels of aluminium (Krewksi et al., 2007). 

 

EXISTING BIOKINETIC MODELS

At present, there is no PBPK model that incorporates aluminium inputs from both the inhalation and oral routes. Data available at the time of development of these models did not sufficiently characterise rates of transfer to, from and within the brain, transfer to the foetusin utero, or transfer to and distribution in the suckling infant. Uncertainties in the speciation of Al in the blood and its effect on transfer to different tissues and renal elimination currently limit the models.