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ALUMINA TRIHYDRATE 99 6 Alumina Trihydrate THERE are limited toxicokinetic and toxicity data available on alumina trihydrate. Therefore, this chapter reviews the physical and chemical properties, toxicokinetics, toxicological, epidemiological and exposure data on alumina trihydrate and a number of chemically related aluminum compounds. The bioavailability of aluminum is dependent upon its form, however, the underlying mechanism of toxicity appears to be similar among the different forms (with the exception of aluminum phosphide for which the toxicity is associated with phosphine gas). The effect of bioavailability of the various forms of aluminum on toxicity is discussed in the Quantitative Risk Assessment and the Exposure Assessment and Risk Characterization sections. The subcommittee used that information to characterize the health risk from exposure to alumina trihydrate. The subcommittee also identified data gaps and recommended research relevant for determining the health risk from exposure to alumina trihydrate. PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of alumina trihydrate are summarized in Table 6â1.
ALUMINA TRIHYDRATE 100 TABLE 6â1 Physical and Chemical Properties for Alumina Trihydrate Characteristic Value Reference Chemical formula Al(OH)3 Lide 1991â1992 CAS registry # 21645â51â2 Lide 1991â1992 Synonyms aluminum hydroxide, aluminum hydrate, hydrated alumina Budavari et al. 1989 Molecular weight 77.99 Lide 1991â1992 Physical state White powder Budavari et al. 1989 Solubility Insoluble in hot or cold water; soluble in acid and alkali; insoluble in alcohol Lide 1991â1992 Melting point 300Â°C Lide 1991â1992 Density 2.42 at 25Â°C Lide 1991â1992 OCCURRENCE AND USE Alumina trihydrate is used as a flame retardant both within and outside the U.S. in the interiors of automobiles, commercial upholstered furniture, draperies, wall coverings and carpets (R.C.Kidder, Flame Retardant Chemical Association, unpublished material, April 21, 1998). It is also used in detergents, antiperspirants, and cosmetics, and used therapeutically as an antacid (e.g., Maalox) and to control phosphate levels. TOXICOKINETICS Absorption Dermal Exposure No data were found on the dermal absorption of alumina trihydrate. However, two reports were found on the dermal absorption of aluminum chloride. Dermal application of aqueous aluminum chloride (0.025â0.1 Âµg/ cm2) to shaved Swiss mice increased urine, serum, and whole brain aluminum concentrations (Anane et al. 1995). Dermal application (0.4 Âµg/d; 20 d of gestation) of aluminum chloride to pregnant Swiss mice resulted in elevated aluminum concentrations in the serum and organs of the dams and fetuses, and in the amniotic fluid (Anane et al. 1997).
ALUMINA TRIHYDRATE 101 Inhalation Exposure Workers exposed to aluminum dust or fumes had higher urinary aluminum concentrations at the end of a work shift than a control group (Mussi et al. 1984). Plasma aluminum concentrations, however, were not increased. Serum and urinary aluminum concentrations increased in three individuals not previously exposed to aluminum-containing welding fumes following an 8-hr exposure to those fumes (average exposure of 2.4 mg aluminum/m3) (SjÃ¶gren et al. 1985). SjÃ¶gren et al. (1988) reported that workers exposed to aluminum from welding fumes had elevated aluminum concentrations in their urine, and that a 16 to 37-d break from exposure resulted in decreased urinary aluminum concentrations (median levels decreased from 54 Âµg/g creatinine to 29 Âµg/g creatinine). Serum and urinary aluminum concentrations were higher in workers exposed to aluminum (25 Âµg/m3 respirable particles; 100 Âµg/m3 total particles) compared with pre-shift concentrations and concentrations in unexposed controls (Gitelman et al. 1995). The percentage of aluminum absorbed was not determined in those studies. No relevant animal data were identified on absorption of aluminum following inhalation exposure. Oral Exposure The bioavailability of orally administered aluminum is related to the form in which it is ingested and the presence of dietary constituents with which the metal can complex. Ligands in food can have a marked effect on absorption of aluminum; they can either enhance uptake by forming absorbable (usually water-soluble) complexes (e.g., with carboxylic acids such as citric acid or lactic acid), or reduce absorption by forming insoluble compounds (e.g., with phosphate or dissolved silicate). In humans, evidence suggests that the most important compound that aluminum complexes with that increases aluminum uptake is citric acid (or its conjugate base citrate). Citric acid is a constituent of many foods and beverages, and can be present in the gut at high concentrations (Reiber et al. 1995). Concomitant exposure to aluminum-containing antacids and orange juice caused a 10-fold increase in absorption of aluminum as compared to exposure to antacids alone (Fairweather-Tait et al. 1994). Milk had no effect on aluminum absorption in that study. Volunteers (n=7â10) who ingested antacids containing 976 mg of alumina trihydrate (approximately 14 mg/kg) absorbed 0.004%, 0.03%, or 0.2% of the aluminum when the antacids were suspended in tap water (pH 9.2), orange juice (pH 4.2), or citric acid (pH 2.4), respectively (Weberg
ALUMINA TRIHYDRATE 102 and Berstad 1986). Priest et al. (1996, as cited in ATSDR 1999) measured aluminum absorption in two male volunteers following administration of a single dose of Al-labeled aluminum citrate (aqueous solution) or alumina trihydrate (colloidal suspension in water) directly into the stomach; 0.5% of the aluminum in aluminum citrate and 0.01% of the aluminum in alumina trihydrate were absorbed. In that same study (Priest et al. 1996, as cited in ATSDR 1999), 0.14% of the aluminum was absorbed after concomitant exposure to alumina trihydrate and trisodium citrate; that exposure scenario is similar to ingestion of aluminum in orange juice. Urinary and plasma aluminum concentrations were significantly higher in women treated with calcium citrate than when they were not treated with calcium citrate, indicating that dietary factors can affect the uptake of aluminum from normal diets (Nolan et al. 1994, as cited in ATSDR 1999). Infants are able to absorb orally administered aluminum. Plasma aluminum concentrations increased (from 0.64 Âµmol/L prior to treatment to 3.48 Âµmol/L after treatment) in 7 infants treated with aluminum-containing antacids (400â800 Âµmol aluminum for 2 d) (Chedid et al. 1991). Individuals with young senile dementia of the Alzheimer's type (Taylor et al. 1992) and individuals with Down's Syndrome (Moore et al. 1997) appear to have increased absorption of aluminum. Evidence in animals indicates that absorption of aluminum is low following oral exposure, and that the form of aluminum ingested and dietary factors can affect aluminum absorption. Only 0.97% of the dose was absorbed in rats gavaged with AlCl3 (n=3/group) (Zafar et al. 1997). Following a single gavage dose of alumina trihydrate, aluminum citrate, aluminum citrate with sodium citrate added, or aluminum maltolate, 0.1%, 0.7%, 5.1%, and 0.1% of the aluminum was absorbed, respectively (Schonholzer et al. 1997). Jouhanneau et al. (1997) measured skeletal retention and urinary excretion of aluminum, as an indication of absorption, in 2-mo-old Wistar rats fed aluminum in the diet. In the absence of citrate, 0.05% of the aluminum dose was found in the urine and in the skeleton. The presence of citrate in the diet increased excretion by two- to five-fold (Jouhanneau et al. 1997). Plasma, bone, kidney, cerebral cortical, and cerebellar aluminum concentrations were not increased (compared to untreated controls) in rats fed alumina trihydrate alone, but were increased in rats fed an equivalent concentration of aluminum complexed with citrate, lactate, malate, or tartrate (Testolin et al. 1996). Domingo et al. (1993) investigated the effect of dietary constituents on the absorption of aluminum from the normal diet. The addition of lactic, tartaric, gluconic, malic, succinic, ascorbic, citric, or oxalic acid to drinking water increased the concentration of aluminum in the bone; all except succinic and ascorbic acid increased aluminum concentrations in the brain. Prolonged fasting increased the absorption of aluminum in Wistar rats (Drueke et al. 1997).
ALUMINA TRIHYDRATE 103 Based on the data discussed above, it was concluded that alumina trihydrate is more poorly absorbed than other aluminum compounds. Some data indicate a direct linear relationship between the dose of soluble aluminum and the plasma aluminum level (Partridge et al. 1992, as cited in ATSDR 1999). However, the data on both solubility and bioavailability are inadequate to reliably extrapolate quantitatively from solubility in water to bioavailability, especially with the effects of dietary constituents. Distribution and Metabolism Dermal Exposure Following dermal absorption, aluminum chloride distributes to the brain in Swiss mice (Anane et al. 1995) and to the fetus in pregnant Swiss mice (Anane et al. 1997). Inhalation Exposure Autopsy results of men chronically exposed to aluminum via inhalation indicated that aluminum distributes to the lungs, liver, and spleen (Teraoka 1981). Rabbits exposed to low concentrations of aluminum dust (Al2O3; 1/20th of the threshold limit value) had 2.5-times higher concentrations of aluminum in the brain compared to controls. Serum concentrations were only slightly increased and concentrations in other tissues were not elevated (Rollin et al. 1991). Rats exposed via inhalation to aluminum acetylacetonate also demonstrated an accumulation of aluminum in the brain (Zatta et al. 1993). Oral Exposure Following gavage in rats, the highest accumulation of aluminum is in the bone, followed by the spleen, kidneys and liver, and brain (Zafar et al. 1997). Testolin et al. (1996) also demonstrated that aluminum distributes to the bone, kidneys, cerebral cortex, and cerebellum. Other Routes of Exposure Yokel and McNamara (1989) investigated the distribution and half-life of aluminum in rabbits after a 6-hr intravenous infusion. Aluminum concentra
ALUMINA TRIHYDRATE 104 tions were increased in the bile, kidneys, liver, lungs, serum, and spleen after 4 hr, but not in the brain. The half- life was tissue-dependent, ranging from 12 hr in the bile to 113 d in the spleen. After intravenous injection of aluminum lactate or aluminum citrate in rats and rabbits, aluminum appeared to freely diffuse into liver, but was lower in the brain than the blood, indicating that there is a partial barrier to aluminum entry into the brain (Yokel et al. 1991). Further research, however, indicates that an active process pumps aluminum out of the brain following administration of aluminum citrate (Yokel et al. 1994; Allen et al. 1995; Ackley and Yokel 1997). Regardless of the route of exposure, once absorbed and distributed in the body, aluminum can exist in different forms. Low concentrations of aluminum exist as free ions. Aluminum can also complex with organic acids, amino acids, nucleotides, phosphates, and carbohydrates. Aluminum can form reversible and practically irreversible complexes with proteins, polynucleotides, and glycosaminoglycans (Ganrot 1986). Excretion Dermal Exposure Aluminum was detected in the urine of Swiss mice following dermal exposure to aluminum chloride (Anane et al. 1995). Inhalation Exposure Following inhalation exposure, absorbed aluminum is primarily excreted via the urine. Excretion half-lives of 7.5 and 8 hr have been reported in workers exposed to aluminum from welding fumes (SjÃ¶gren et al. 1985; Pierre et al. 1995). The urinary excretion half-life appears to rise with increasing exposure duration (SjÃ¶gren et al. 1985). Urinary aluminum concentrations in workers exposed to aluminum were more than 10 times higher than those of individuals not exposed to aluminum in the workplace, and remained elevated many years after the occupational exposure ceased (Elinder et al. 1991). Oral Exposure The majority of ingested aluminum is excreted in the feces without being absorbed systemically (Gorsky et al. 1979; Jouhanneau et al. 1997). Absorbed
ALUMINA TRIHYDRATE 105 aluminum is primarily excreted in the urine (Kaehny et al. 1977; Recker et al. 1977; Gorsky et al. 1979; Greger and Baier 1983). HAZARD IDENTIFICATION1 Dermal Exposure Irritation Skin rashes in sensitive individuals are the only adverse effects observed in humans dermally exposed to aluminum compounds (ATSDR 1999). Damage to the skin was observed in mice, rabbits, and pigs following exposure to 10% aluminum chloride and aluminum nitrate for 5 d. No dermal effects were observed in animals exposed to 10% alumina trihydrate, aluminum sulfate, aluminum acetate, or aluminum chlorohydrate (Lansdown 1973, as cited in ATSDR 1999). Systemic Effects No studies were identified that report immunological, neurological, reproductive, developmental, carcinogenic, or other systemic effects of aluminum following dermal exposure. Inhalation Exposure Systemic Effects No studies were identified that investigated the effects of alumina trihydrate via inhalation exposure. Pulmonary fibrosis is the most common respiratory effect in workers exposed to finely ground aluminum dust (pyropowder) (Ueda et al. 1958; Edling 1961; Mitchell et al. 1961; McLaughlin et al. 1962). However, that effect appears to be associated with a specific type of oil coating on the aluminum dust (Crombie et al. 1944; Meiklejohn and Posner 1957; Posner and Kennedy 1967). Case reports indicate that inhalation exposure to various 1In this section, the subcommittee reviewed the toxicity data of alumina trihydrate, including the toxicity assessment prepared by the U.S. Consumer Product Safety Commission (Ferrante 1999).
ALUMINA TRIHYDRATE 106 forms of aluminum leads to pulmonary toxicity (Chen et al. 1978; Miller et al. 1984; Park et al. 1996, as cited in ATSDR 1999; Vandenplas et al. 1998). In a study of 17 occupationally exposed individuals, pulmonary fibrosis was associated with inhalation exposure to aluminum silicate dust (Musk et al. 1980). Avolio et al. (1989) reported interstitial fibrosis following inhalation exposure to aluminum. Those occupational studies are limited by concomitant exposures to other chemicals and cigarettes. However, in one study of nonsmoking individuals occupationally exposed to aluminum compounds (14 exposed; 28 controls) there were indications of increased alveolar capillary permeability and activation of alveolar macrophage in bronchoalveolar lavage, but no evidence of restrictive lung disease (Eklund et al. 1989). Granulomatous reactions (at concentrations of 2.5 and 25 mg/m3 aluminum chlorohydrate), decreases in body weight (at concentrations of 25 mg/m3), and increases in lung to body weight ratios (at concentrations of 25 mg/m3) were seen in rats and guinea pigs exposed to aluminum chlorohydrate for 6 mo (Steinhagen et al. 1978). Exposure of female Wistar rats to aluminum fibers for 86 wk resulted in minimal pulmonary reactions (Pigott et al. 1981). Neurological Effects Subclinical neurological effects have been observed in workers chronically exposed to aluminum dust, welding fumes, and McIntyre powder (finely ground aluminum and aluminum oxide) (Hosovski et al. 1990; Rifat et al. 1990; White et al. 1992; Bast-Pettersen et al. 1994; HÃ¤nninen et al. 1994; SjÃ¶gren et al. 1996; Dick et al. 1997; Sim et al. 1997). Those effects include changes in neurobehavioral test performance (e.g., eye-hand coordination, reaction time, cognitive tests) and increased incidences of subjective symptoms (e.g., incoordination, depression, fatigue). A role of aluminum has been hypothesized in the etiology of Alzheimer's disease (AD). However, in an unmatched case-control study (198 AD cases; 340 controls made up of 164 individuals with non-AD dementias and 176 individuals with no dementias), no significant association (odds ratio=0.98) between occupational aluminum exposure and AD was reported (Salib and Hillier 1996). Cancer There are a number of epidemiological studies on cancer incidence in workers in aluminum reduction plants (Gibbs and Horowitz 1979; Milham 1979;
ALUMINA TRIHYDRATE 107 Theriault et al. 1981; Rockette and Arena 1983; Gibbs 1985; Armstrong et al. 1986; Spinelli et al. 1991). In a review of many of those studies, Ronneberg and Langmark (1992) concluded that some data were suggestive of an increased risks for specific cancers for workers in aluminum reduction plants. However, those conclusions were limited by inadequate information on smoking and exposure to other carcinogenic compounds, including asbestos and polycylic aromatic hydrocarbons. In a retrospective cohort study that was initiated because of a cluster of pituitary adenoma cases (four cases over 5 yr), there was no indication of an increased risk for pituitary adenoma at an aluminum production factory (Cullen et al. 1996). There was no overall excess risk for cancer and no excess risk for bladder or liver cancer among men or women workers in aluminum foundries and scrap aluminum smelters in Sweden (n=6,454) (Selden et al. 1997). However, risk estimates for lung cancer in males (standardized incidence ratio [SIR] =1.49), anorectal cancer (SIR=2.13), and sinonasal cancer (SIR=4.70) were increased. Socioeconomic status appeared to underlie the increased risk of lung cancer, except for individuals employed in the sand casting of aluminum for 10 yr or more. Epidemiological studies of workers in aluminum smelters report an increased mortality from malignant lung neoplasm, however, many of the workers had evidence of co-exposure to asbestos, silicates, and metal-rich nonfibrous particles, such as chromium and cobalt (Dufresne et al. 1996), or polycyclic aromatic hydrocarbons (Armstrong et al. 1994). In the only animal study investigating the carcinogenic potential of inhaled aluminum compounds, there was no evidence of an increased incidence of tumors in the lungs of male or female Wistar rats exposed to aluminum fibers (2.18â2.45 mg aluminum/m3; 96% aluminum oxide) for 86 wk (Pigott et al. 1981). Other Systemic Effects No studies were identified on the immunological, reproductive, or developmental effects following inhalation of aluminum. Oral Exposure Systemic Effects Aluminum compounds have low acute toxicity because of their low solubility. The maximum tolerated daily dose for alumina trihydrate in a healthy, 70-
ALUMINA TRIHYDRATE 108 kg adult is 50 to 128 mg/kg (17.5â45 mg aluminum/kg) (Poisindex 1998). Constipation, diarrhea, distension, and/ or obstruction with perforation have been reported in individuals on chronic antacid therapy. However, the role of aluminum in that effect is not known (HSDB 1990). Individuals with chronic renal failure who ingest large amounts of aluminum trihydrate to treat hyperphosphatemia can accumulate aluminum in the body, resulting in hypercalcemia, microcytic anemia, proximal myopathy, osteomalacia, and progressive dialysis encephalopathy (Sideman and Manor 1982; HSDB 1990; Ellenhorn 1997). Osteomalacia has also been observed in healthy children treated with aluminum-containing antacids for colic (Pivnick et al. 1995). Preterm infants are at risk for aluminum toxicity from ingestion of some infant formulas that contain aluminum compounds, and from aluminum-containing parenteral nutrition solutions (Sedman et al. 1985; Koo et al. 1992; Golub and Domingo 1996). There is an extensive oral toxicity database in animals, but many of the studies are limited by a lack of information on background concentrations of aluminum compounds in the diet. Commercial grain-based feeds for laboratory animals contain high concentrations of aluminum compounds which can contribute substantially to total aluminum exposure. The background aluminum concentrations in feed, therefore, should be considered when assessing the toxicity of aluminum compounds. A summary of the studies is presented in Table 6â2. Most aluminum compounds have LD50s in the range of 1â4 g aluminum/kg (Poisindex 1998). No significant effects on mortality or body weight were observed in Sprague-Dawley rats fed 989 or 1,070 Âµg aluminum/g of food (as alumina trihydrate; calculated to be equivalent to approximately 158 mg aluminum/kg-d) for 16 d (background concentrations, 9â26 Âµg aluminum/g food) (Greger and Donnaubauer 1986). Hicks et al. (1987) reported no significant alterations in hematology, clinical chemistry, histopathology, or organ weights in Sprague-Dawley rats fed 302 mg aluminum/kg-d as alumina trihydrate in the diet for 28 d (background concentration, 66 ppm; reported as 5 mg aluminum/kg-d). In general, subchronic and chronic studies in mice and rats examining a number of systemic end points do not demonstrate adverse effects following dietary or drinking water exposure to aluminum. Oteiza et al. (1993) fed Swiss-Webster mice 1,000 Âµg aluminum/g in food (background levels; 3 mg aluminum/g food) as aluminum chloride for 5 or 7 wk. No systemic effects were seen. Oneda et al. (1994) fed male and female B6C3F1 mice 1%, 2.5%, 5%, or 10% aluminum potassium sulfate for 20 mo and reported a decrease in liver weight (5â10%), and an increase in kidney weight (2.5%) and heart weight (5%). Relative organ weight and blood parameters were not affected in
ALUMINA TRIHYDRATE 109 TABLE 6â2 Selected Toxicity Studies of Orally Administered Alumina Compoundsa Animal Species Dose (mg Al/ Effects NOAEL (mg LOAEL (mg Reference and Strain/ kg-d) Al/kg-d) Al/kg-d) Aluminum Compound/ Duration of Exposure Systemic toxicity Female Sprague- 25 (control), None 284 ND Domingo et al. Dawley rats; 51, 77, 284 1987a aluminum nitrate (drinking water); 100 d Sprague-Dawley 5 (control), 302 None 302 ND Hicks et al. 1987 rats; aluminum trihydrate (diet); 28 d Female Sprague- 25 (control), Hyperemia in the 79 133 Gomez et al. 1986 Dawley rats; 52, 79, 133 liver, periportal aluminum nitrate monocytic infiltrate (drinking water) 1 in liver mo Sprague-Dawley 158 None 158 ND Greger and rats; aluminum Donnaubauer 1986 trihydrate (diet); 16 d Neurotoxicity Female Swiss- 3 (control), 62, Decreased motor 62 130 Golub et al. 1989 Webster mice; 130 activity aluminum lactate (diet); 6 wk Female Swiss- 4.9 (control), Decreased motor ND 195 Golub et al. 1992a Webster mice; 195 activity, hindlimb aluminum lactate grip strength and (diet); 90 d startle responsiveness Female Swiss- 0.6 (control), Decreased forelimb ND 195 Oteiza et al. 1993 Webster mice; 195 and hindlimb grip aluminum strength chloride and 3.5% sodium citrate (diet) 5â7 wk
ALUMINA TRIHYDRATE 110 Animal Species and Strain/ Dose (mg Al/ Effects NOAEL (mg LOAEL (mg Reference Aluminum Compound/ kg-d) Al/kg-d) Al/kg-d) Duration of Exposure Neurodevelopmental toxicity Pregnant Swiss-Webster 7.5 (control), Decreased ND 155 Donald et al. mice; aluminum lactate 155, 310 forelimb and 1989 (diet); gestational d 0 hindlimb grip through weaning strength and increased foot splaying in weanlings Pregnant Swiss-Webster 7.5 (control), Decreased ND 155 Golub et al. 1995 mice; aluminum lactate 155, 310 forelimb and (diet); gestational d 0 hindlimb grip through weaning strength Pregnant Swiss-Webster 7.5 (control), Decreased ND 155 Golub et al. 1995 mice; aluminum lactate 155, 310 forelimb and (diet); gestational d 0 hindlimb grip through weaning; strength and offspring exposed for decreased air another 150 d puff startle response Pregnant Swiss-Webster 1 (control), 250 Decreased ND 250 Golub et al. mice; aluminum lactate forelimb grip 1992b (diet); gestational d 1â21 strength Pregnant Swiss-Webster 1 (control), 250 Increased ND 250 Golub et al. mice; aluminum lactate hindlimb grip 1992b (diet); gestational d 1â21 strength and tail and lactational d 1â21 withdrawal times Pregnant Swiss-Webster 1 (control), 250 Increased ND 250 Golub et al. mice; aluminum lactate negative geotaxis 1992b (diet); lactational d 1â21 latency
ALUMINA TRIHYDRATE 111 Pregnant Swiss-Webster 1.2 (control), 200 Reduced auditory startle ND 200 Golub et al. 1994 mice; aluminum lactate responsiveness (diet); gestational d 1â 21 and lactational d 1â21 Pregnant Swiss-Webster 0.7 (control), 200 Reduced auditory startle ND 200 Golub et al. 1994 mice; aluminum lactate responsiveness (diet); gestational d 1 through postnatal d 52 Swiss-Webster mice; 4.1 (control), 17.5, 28.3 Treated animals lagged ND 17.5 Golub et al. 1987 aluminum lactate (diet); behind controls on the gestational d 0 to Wahlsten neurobehavioral postnatal d 21 test battery Developmental toxicity Pregnant Sprague- 25 (control), 158 Increase in number of fetuses ND 158 Gomez et al. 1991 Dawley rats; aluminum with absent xiphioides citrate (gavage); gestational d 6â15 Pregnant Sprague- 25 (control), 158 None (developmental end 158 ND Gomez et al. 1991 Dawley rats; aluminum points examined included hydroxide (gavage); number of implantation sites, gestational d 6â15 resorptions, dead and live fetuses, and external malformations) Pregnant Sprague- 25 (control), 38, 51, 77 Decreased fetal weight, ND 38 Paternain et al. 1988 Dawley rats; aluminum decreased tail length, nitrate (gavage); increased rib, skull, and gestational d 6â14 sternebral malformations Reproductive toxicity Female Sprague- 13 (control), 38, 52 No effects on fertility were 52 ND Domingo et al. 1987b Dawley rats; aluminum observed nitrate (gavage); 14 d prior to mating and throughout gestation and lactation
ALUMINA TRIHYDRATE 112 Animal Species Dose (mg Al/ Effects NOAEL (mg LOAEL (mg Reference and Strain/ kg-d) Al/kg-d) Al/kg-d) Aluminum Compound/ Duration of Exposure Reproductive toxicity Pregnant Sprague- 25 (control), 158 None (reproductive 158 ND Gomez et al. Dawley rats; end points examined 1991 aluminum included numbers of hydroxide litters, corpora lutea (gavage); per dam, implantation, gestational d 6â15 preimplantation loss, viable implants, nonviable implants, postimplantation loss, and sex ratio) ND, not determined aSrudies that did not provide information on the concentration of aluminum in the base diet were not included in the table.
ALUMINA TRIHYDRATE 113 Sprague-Dawley rats (10/group) exposed to aluminum nitrate (0, 375, 750, and 1,500 mg/kg-d) for 1 mo (Gomez et al. 1986). Mild histopathological changes occurred in the two highest dose groups. Domingo et al. (1987a) exposed female Sprague-Dawley rats to aluminum nitrate (0, 360, 720, and 3,600 mg/kg-d) for 100 d and no effects were seen on organ weights or histology. An increase in serum glutamic pyruvic transaminase was seen in the 3,600 mg/kg-d group and an increase in blood urea in the 720 mg/kg-d group. Neurological Effects A role of aluminum in the etiology of AD has been suggested, but remains controversial (see reviews Savory et al. 1996; Exley 1998; Forbes and Hill 1998; Munoz 1998; Smith andPerry 1998). Because of the conflicting data and the lack of quantitative data for a risk assessment, the literature pertaining to the role of aluminum in AD is not reviewed in this report. Neurotoxicity and neurobehavioral studies in animals provide strong evidence that the nervous system is the most sensitive target organ for aluminum toxicity. Neurobehavioral effects have been observed in animals exposed as adults, weanlings, during gestation and lactation, and during gestation through adulthood. Although studies lacking information on background aluminum concentrations in the diet provide valuable hazard identification information, NOAELs and LOAELs from these studies cannot be derived with confidence because they are not suitable for dose-response assessment. Therefore, the following discussion of oral toxicity studies focuses on those reports that provide information on the concentrations of aluminum in the control diet. Some studies that used alumina trihydrate but did not report control diet aluminum concentrations are also discussed. A diminished learning ability was observed in Long-Evans rats exposed to 30 or 100 mg/kg aluminum chloride (6 or 20 mg aluminum/kg-d), 300 mg/kg aluminum trihydrate (104 mg aluminum/kg-d), or 100 mg/kg aluminum trihydrate plus citric acid (35 mg aluminum/kg-d) (Bilkei-Gorzo 1993). Although aluminum content was not measured in the control diet, the aluminum levels were measured in the brains of all animals in that study. Thorne et al. (1987) did not observe neurological effects in rats following oral exposure to aluminum trihydrate (NOAEL=14 mg aluminum/kg-d) for 60 d during the weaning period. Background aluminum intake was not measured. Comprehensive neurobehavioral testing of N: NIH Swiss-Webster mice exposed to 195 mg aluminum/kg-d as dietary aluminum lactate for 90 d found reduced motor activity, decreased hindlimb grip strength, decreased startle response, and increased tissue concentrations of aluminum (in brain and liver,
ALUMINA TRIHYDRATE 114 but not bone), but no overt clinical signs of neurotoxicity (Golub et al. 1992a). Oteiza et al. (1993) fed adult N: NIH Swiss-Webster mice 195 mg aluminum/kg-d as aluminum chloride in a diet that also contained 3.5% sodium citrate. Neurobehavioral effects similar to those observed by Golub et al. (1992a) were seen, except grip strength was reduced in forelimbs as well as hindlimbs. Aluminum concentrations were elevated in the bone, brain, and liver. The more pronounced effects are most likely due to increased absorption of aluminum in the presence of citrate. Golub et al. (1987) fed pregnant Swiss-Webster mice diets containing aluminum lactate (100 [control], 500, and 1,000 ppm elemental aluminum; approximately equivalent to 4.1, 17.5, and 28.3 mg/kg-d based on average food intake during gestation and lactation) on gestational d 0 to postnatal d 21. There were no consistent adverse effects on organ weight that were not seen in the pair-fed control group. Performance in the Wahlsten neurobehavioral test battery was affected in the 500 and 1,000 ppm groups on postnatal d 14 and 16 (but not postnatal d 11â13, 15, and 17â18). Golub et al. (1989) fed female Swiss-Webster mice (n=16) diets containing 500 or 1,000 ppm aluminum as aluminum lactate (doses estimated as 3 (control), 62, and 150 mg aluminum/kg-d) for 6 wk. During the 5th wk of exposure, motor activity in a 24-hr period was measured using an automated method. No overt signs of neurotoxicity were observed. Total activity was significantly decreased (20%) in the 130-mg aluminum/kg-d group as compared with controls, with vertical movement affected more than horizontal movement. Those animals were less active than controls during the diurnal period of peak activity and had shorter periods of activity (130 versus 200 min), but there were no shifts in the diurnal activity cycle or any prolonged periods of inactivity. Motor activity was not significantly affected in the 62-mg aluminum/kg-d group. A LOAEL of 130 mg aluminum/kg-d and a NOAEL of 62 mg aluminum/kg-d were identified. Golub et al. (1995) fed pregnant Swiss-Webster mice (group size inadequately reported) diets containing 500 or 1,000 ppm aluminum as aluminum lactate throughout gestation and lactation (control diet contained 25 ppm aluminum). Daily doses of 7.5 (control), 155, and 310 mg aluminum/kg-d were estimated by averaging reported estimated doses at the beginning of pregnancy and during lactation. At weaning, each litter was assigned to continue with a diet similar to the dam or transferred to a control diet, therefore there were subgroups of offspring that received pre- and post-weaning exposure (continuous exposure group) or only pre-weaning exposure (developmental exposure group). A neurobehavioral test battery that assessed strength, responsiveness, and coordination was administered on d 150â170. Additionally, one male and one female from each litter were tested in either a discrimi
ALUMINA TRIHYDRATE 115 nation reversal test or a delayed spatial alternation testing paradigm. In the developmentally exposed animals, there was a significant decrease in forelimb and hindlimb grip strength in the 155- and 310-mg/kg-d exposure groups and air puff startle response was decreased in the 155-mg/kg-d group. In the continuously exposed animals, significant decreases in forelimb and hindlimb grip strength and air puff startle responses were observed in the 155- and 310-mg/kg-d groups. No differences in grip strength or startle responses were observed between the developmental exposure group and the continuous exposure group. No significant alterations in auditory startle response, temperature sensitivity, or negative geotaxis were observed in any of the aluminum-exposed offspring. Mice in the developmental exposure group required fewer operant training sessions to reach criterion than controls. The continuous exposure group reached the criterion in fewer sessions than the developmental exposure group. Aluminum exposure (developmental or continuous) did not markedly affect learning of the spatial alternation task, or performance of the delayed spatial alternation task or the discrimination reversal task. A LOAEL of 155 mg aluminum/kg-d was identified. No NOAEL was identified. Donald et al. (1989) fed 16 pregnant Swiss-Webster mice diets containing 500 or 1,000 ppm aluminum as aluminum lactate throughout gestation and lactation (control diet contained 25 ppm aluminum). Approximate doses at the beginning of gestation and maximal intake during lactation were averaged to estimate doses of 7.5 (control), 155, and 310 mg aluminum/kg-d. On postnatal d 8â18, neurobehavioral tests were conducted on one male and one female from each litter. The offspring were also tested on postnatal d 25 and 39 using a neurobehavioral test battery. Composite scores on the neurobehavioral maturation tests did not differ significantly between groups, although results on specific days and tests did differ between groups. On postnatal d 9 and 16, pups in the 310-mg/kg-d group had lower test scores than controls, and only 72% of the pups in the 310-mg/kg-d group reached the criterion by postnatal d 18 (as compared to 100% in the control and 155-mg/kg-d groups). On postnatal d 25, significant increases in forelimb grip strength (310 mg aluminum/kg-d) and hindlimb grip strength (155 and 310 mg aluminum/kg-d) were observed. On postnatal d 39, forelimb grip strength in the 155-mg/kg-d group was significantly lower than in control animals, and hindlimb grip strength in both treated groups was similar to controls. Higher latencies for the temperature aversion test were seen in the 310-mg/kg-d group offspring at postnatal d 25 and 39. An increase in foot splay distance was observed in the 155- and 310-mg/ kg-d group offspring on postnatal d 21 and in the 155-mg/kg-d group on postnatal d 35. Startle response and negative geotaxis were not consistently affected by aluminum exposure. A LOAEL of 155 mg aluminum/kg-d was identified. A NOAEL was not identified.
ALUMINA TRIHYDRATE 116 Findings in other mouse studies using similar or higher estimated doses of aluminum lactate corroborate the neuromotor alterations summarized above (Golub et al. 1992b). The findings include increased grip strength, increased tail withdrawal time from hot water, and increased negative geotaxis latency in weanling mice following gestation and/or lactation exposure to 250 mg aluminum/kg-d (Golub et al. 1992b). Reduced auditory startle responsiveness was also seen in pups exposed during gestation and lactation, or from gestation continuing into the post-weaning period and tested at 52 d of age (maternal dose was 200 mg aluminum/kg-d) (Golub et al. 1994). Reproductive and Developmental Effects Neurodevelopmental effects are discussed in the section on Neurological Effects. No marked maternal or developmental effects were seen in Swiss mice treated orally with aluminum trihydrate during organogenesis (0, 66.5, 133, or 266 mg/kg-d; gestational d 6â15) (Domingo et al. 1989). Colomina et al. (1992) fed pregnant Swiss albino mice 57.5 mg aluminum/kg as alumina trihydrate, aluminum lactate, or alumina trihydrate concurrently with lactic acid. Alumina trihydrate alone had no marked effect on maternal body weight or organ weights (uterine, liver, and kidney), or on reproductive end points or skeletal development. Sporadic effects on maternal body weight and relative liver weight were seen with the other treatments. Aluminum lactate decreased fetal body weight per litter and increased the occurrence of cleft palate, dorsal hyperkiphosis, and delayed parietal ossification. Lactic acid alone increased delayed parietal ossification (Colomina et al. 1992). Colomina et al. (1994) gavaged pregnant Swiss mice with 103.8 mg aluminum/kg as alumina trihydrate in the presence or absence of ascorbic acid on gestational d 6â15. Dams were killed on gestational d 18. No marked effects of aluminum were seen on the number of resorptions per litter, number of dead and live fetuses per litter, percentage of postimplantation loss, sex ratio, or fetal body weight per litter. There were also no apparent malformations or developmental variations based on gross external, visceral, and skeletal parameters (Colomina et al. 1994). Gomez et al. (1991) gavaged pregnant Sprague-Dawley rats on gestational d 6 to 15 with aluminum (133 mg/kg-d) as alumina trihydrate, aluminum citrate, or alumina trihydrate concurrently with citric acid. Gestational body weight, food consumption, body, and organ (liver, kidney, and brain) weights were measured at the end of the study, and reproductive and developmental endpoints were examined. Neither alumina trihydrate alone nor aluminum
ALUMINA TRIHYDRATE 117 citrate had any marked effects on the end points studied. In the presence of citric acid, alumina trihydrate significantly decreased gestational body weight gain during the treatment period (gestational d 6â15), but significantly increased it during the post-treatment period (gestational d 16â20). Combined treatment with alumina trihydrate and citric acid also significantly decreased fetal body weight per litter, increased the incidence of delayed occipital and sternebrae ossification, and increased the absence of xiphoides (Gomez et al. 1991). Domingo et al. (1987b) gavaged male and female Sprague-Dawley rats with aluminum nitrate at doses of 0, 180, 360, or 720 mg/kg-d for 60 d (males) or 14 d (females) prior to mating, and throughout the mating period, gestation, delivery, and lactation. A decrease in the number of corpora lutea on gestational d 13 in the high-dose group was the only effect seen on fertility measures. Survival of the treated offspring was affected, with significant decreases in the number of living offspring and increases in the number of dead offspring at the two highest doses. Body weight was also decreased in the offspring at all three dose levels. The baseline aluminum concentration was not reported in the study (Domingo et al. 1987b), but were provided at a later date (25 mg aluminum/kg-d) (Domingo et al. 1993; Colomina et al. 1998). Cranmer et al. (1986) observed an increased incidence of resorptions in mice exposed during gestation to aluminum chloride (100, 150, 200, 300 mg AlCl3/kg-d) via gavage. A decrease in sperm count was observed in rats exposed to aluminum chloride for 6â12-mo, but this study did not assess reproductive function (Krasovskii et al. 1979). Misawa and Shigeta (1993) found that administration of a single dose of aluminum chloride (0, 900, or 1,800 mg/kg, by gavage) on d 15 of gestation resulted in a decrease in body weight and affected the timing of pinna detachment and eye opening in the offspring. Other Systemic Effects No studies were identified that investigated the immunological or carcinogenic effects of alumina trihydrate following oral exposure. Genotoxicity An increase in chromatid-type aberrations occurred in mice injected intraperitoneally with aluminum chloride (0.01, 0.05, or 0.1 M aluminum chloride), but no apparent dose-response relationship was identified (Manna and Das 1972).
ALUMINA TRIHYDRATE 118 Aluminum chloride caused cross-linking of proteins to DNA in intact Novikoff ascites hepatoma cells, with optimal cross-linking occurring at 0.5 mM (Wedrychowski et al. 1986). Aluminum compounds were negative in Syrian hamster cell transformation experiments (DiPaolo and Casto 1979), in recombination repair assays with Bacillus subtilis (Kanematsu et al. 1980), and in the Ames assay with Salmonella typhimurium (Marzin and Phi 1985). QUANTITATIVE TOXICITY ASSESSMENT Noncancer Dermal Assessment There are inadequate dermal toxicity data on aluminum compounds to derive a dermal RfD. Inhalation RfC There are inadequate inhalation toxicity data on aluminum compounds to derive an RfC. Oral RfD There is an extensive database on the oral toxicity of aluminum in animals. Collectively, the results of the animal studies provide strong evidence that the nervous system is the most sensitive target organ for aluminum toxicity. Golub et al. (1989) identified a NOAEL of 62 mg aluminum/kg-d and a LOAEL of 130 mg aluminum/ kg-d based on neurobehavioral effects in adults. That study was not selected as the critical study for the derivation of the RfD because it was only of six weeks duration. Golub et al. (1995) identified a LOAEL of 155 mg aluminum/kg-d based on neurodevelopmental effects following exposure to aluminum lactate throughout pregnancy and lactation, and into adulthood in mice. No NOAEL was identified. The subcommittee selected that study as the critical study for derivation of the oral RfD because exposure occurred from conception until adulthood. The results of the study by Golub et al. (1995) are supported by Donald et al. (1989) who also identified 155 mg aluminum/kg-d as the LOAEL for neurobehavioral effects.
ALUMINA TRIHYDRATE 119 To derive the RfD, the LOAEL of 155 mg aluminum/kg-d was divided by a composite uncertainty factor of 300 (10 for interspecies extrapolations, 10 for intraspecies variability; and 3 for use of a LOAEL rather than a NOAEL; see Table 6â3 for summary) to yield an RfD of 0.5 mg aluminum/kg-d. An UF of 3 for the use of a LOAEL rather than a NOAEL was used rather than the default factor of 10 because the observed effects appear to be marginal in severity. The RfD of 0.5 mg aluminum/kg-d is equivalent to an RfD of 1.5 mg alumina trihydrate/kg-d. Current estimated dietary intakes of aluminum are 0.10 to 0.12 mg aluminum/kg-d (Pennington and Schoen 1995), which are below the RfD that the subcommittee is recommending. It should be noted that because of the lack of data available for alumina trihydrate, a critical study (Golub et al. 1995) was selected in which exposure was to aluminum lactate. The form of aluminum can affect the bioavailability of aluminum, but data suggest that alumina trihydrate is less bioavailable, and consequently less toxic, than other aluminum compounds. Therefore, the use of data on aluminum lactate should yield a conservative RfD for alumina trihydrate. The subcommittee's confidence in this RfD is medium. That confidence rating is based on medium-to-high confidence in the principal studies and medium confidence in the database. The study by Golub et al. (1995) was well conducted. Confidence in the study is low to moderate because of inadequate reporting of the number of offspring tested. The medium confidence in the database is reflective of the number of studies which have assessed the systemic toxicity of aluminum in several species, developmental toxicity studies in two species, and a large number of studies assessing neurotoxicity and neurodevel TABLE 6â3 Derivation of Oral Reference Dose for Alumina Trihydrate Critical effect Species Effect level (mg Uncertainty factors RfD Reference Al/kg-d) Neurodevelopmental effects Mouse LOAEL: 155 UFA: 10 0.5 mg Al/kg-d Golub et al. 1995 UFH: 10 (equivalent to 1.5 UFL: 3 mg Al(OH)3/kg-d) Total: 300 LOAEL, lowest-observed-adverse-effect level; RfD, reference dose; UFA, uncertainty factor for extrapolation from animals to humans; UFH, uncertainty factor for intraspecies variability; UFL, uncertainty factor for the use of a LOAEL rather than a no- observed-adverse-effect level (NOAEL).
ALUMINA TRIHYDRATE 120 opmental toxicity. Although a multigeneration reproductive study was not identified, the available single- generation studies suggest that reproductive toxicity is not a sensitive end point. The database lacks studies that identify a NOAEL for neurodevelopmental effects and a study that adequately assesses potential differences in the toxicity of various aluminum compounds. Cancer The potential carcinogenicity of alumina trihydrate cannot be determined based on inadequate data for an assessment of carcinogenicity via the dermal, inhalation, and oral routes. EXPOSURE ASSESSMENT AND RISK CHARACTERIZATION Noncancer Dermal Exposure The assessment of noncancer risk by the dermal route of exposure is based on the scenario described in Chapter 3. This exposure scenario assumes that an adult spends 1/4th of his or her time sitting on furniture upholstery treated with alumina trihydrate, that 1/4th of the upper torso is in contact with the upholstery, and that clothing presents no barrier. Alumina trihydrate is considered to be ionic, and is essentially not absorbed through the skin. However, to be conservative, the subcommittee assumed that ionized alumina trihydrate permeates the skin at the same rate as water, with a permeability rate of 10â3 cm/hr (EPA 1992). Using that permeability rate, the highest expected application rate for alumina trihydrate (7.5 mg/cm2), and Equation 1 in Chapter 3, the subcommittee calculated a dermal exposure level of 5.9Ã10â2 mg/kg-d. The oral RfD for alumina trihydrate (1.5 mg/kg-d; see Oral RfD in Quantitative Toxicity section) was used as the best estimate of the internal dose for dermal exposure. Dividing the exposure level by the oral RfD yields a hazard index of 3.9Ã10â2. Thus it was concluded that alumina trihydrate used as a flame retardant in upholstery fabric is not likely to pose a noncancer risk by the dermal route. Inhalation Exposure Particles The assessment of the noncancer risk by the inhalation route of exposure is
ALUMINA TRIHYDRATE 121 based on the scenario described Chapter 3. This scenario corresponds to a person spending 1/4th of his or her life in a room with a low air-change rate (0.25/hr) and with a relatively large amount of fabric upholstery treated with alumina trihydrate (30 m2 in a 30-m3 room), with this treatment gradually being worn away over 25% of its surface to 50% of its initial quantity over the 15-yr lifetime of the fabric. A small fraction, 1%, of the worn-off alumina trihydrate is released into the indoor air as inhalable particles and may be breathed by the occupant. Equations 4 through 6 in Chapter 3 were used to estimate the average concentration of alumina trihydrate present in the air. The highest expected application rate for alumina trihydrate is about 7.5 mg/cm2. The estimated release rate for alumina trihydrate is 2.3Ã10â7/d. Using those values, the estimated time-averaged exposure concentration for alumina trihydrate is 0.71 Âµg/m3. Although lack of sufficient data precludes deriving an inhalation RfC for alumina trihydrate, the oral RfD (1.5 mg alumina trihydrate/kg-d; see Oral RfD in Quantitative Toxicity Assessment section), which represents a very conservative estimate (see Chapter 4 for the rationale), was used to estimate an RfC of 5.25 mg/m3. Division of the exposure concentration (0.71 Âµg/m3) by the estimated RfC (5.25 mg/m3) results in a hazard index of 1.4Ã10â4, indicating that under the worst-case exposure scenario, exposure to alumina trihydrate, used as an upholstery fabric flame retardant, is not likely to pose a noncancer risk from exposure to alumina trihydrate particles. Vapors In addition to the possibility of release of alumina trihydrate in particles worn from upholstery fabric, the subcommittee considered the possibility of its release by evaporation. However, because of alumina trihydrate's negligible vapor pressure at ambient temperatures, the subcommittee concluded that exposure to alumina trihydrate vapors from its use as an upholstery fabric flame retardant is not likely to pose a noncancer risk. Oral Exposure The assessment of the noncancer risk by the oral exposure route is based on the scenario described in Chapter 3. That exposure assumes a child is exposed to alumina trihydrate through sucking on 50 cm2 of fabric backcoated with alumina trihydrate daily for two yr, one hr/d. The highest expected application rate for alumina trihydrate is about 7.5 mg/cm2. A fractional rate (per unit
ALUMINA TRIHYDRATE 122 time) of alumina trihydrate extraction by saliva is estimated as 0.001/d, based on leaching of antimony from polyvinyl chloride cot mattresses (Jenkins et al. 1998). Using those assumptions and Equation 15 in Chapter 3, the average oral dose rate was estimated to be 0.0016 mg/kg-d. Division of that exposure estimate (0.0016 mg/ kg-d) by the oral RfD (1.5 mg/kg-d; see Oral RfD in Quantitative Toxicity Assessment Section) results in a hazard index of 1.0Ã10â3. Therefore, under the worst-case exposure assumptions, alumina trihydrate, used as a flame retardant in upholstery fabric, is not likely to pose a noncancer risk by the oral exposure route. Cancer There are inadequate data to characterize the carcinogenic risk from exposure to alumina trihydrate from any route of exposure. RECOMMENDATIONS FROM OTHER ORGANIZATIONS The Agency for Toxic Substances and Disease Registry (ATSDR 1999) has established an intermediate- duration oral minimal risk level (MRL) for aluminum of 2.0 mg aluminum/kg-d. The Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) for aluminum dust is 15 mg/m3 (for total dust) and 5 mg/m3 (for respirable dust) (OSHA 1974). The American Conference of Governmental Industrial Hygienists (ACGIH 1999) has set a Threshold Limit Value (TLV) for alumina trihydrate of 10 mg/m3. DATA GAPS AND RESEARCH NEEDS Although there are toxicity data on other aluminum compounds, data on aluminum trihydrate are lacking. In addition, chronic carcinogenic studies following dermal, inhalation, and oral exposure, and reproductive and developmental studies following dermal and inhalation exposure are lacking for any relevant aluminum compound. However, alumina trihydrate is used extensively in antacids (e.g., âMaaloxâ) and cosmetics, and the hazard indices are less than 1 for all routes of exposure using the subcommittee's conservative assumptions. Therefore, the subcommittee concludes that further research is not needed to assess the health risks from alumina trihydrate when used as a flame-retardant chemical in furniture upholstery fabric.
ALUMINA TRIHYDRATE 123 REFERENCES ACGIH (American Conference of Government Industrial Hygienists). 1999. Threshold Limit Values and Biological Exposure Indices. Cincinnati, OH: American Conference of Government Industrial Hygienists, Inc. Ackley, D.C., and R.A.Yokel. 1997. Aluminum citrate is transported from brain into blood via the monocarboxylic acid transporter located at the blood-brain barrier. Toxicology 120(2):89â97. Allen, D.D., C.Orvig, and R.A.Yokel. 1995. Evidence for energy-dependent transport of aluminum out of brain extracellular fluid. Toxicology 98(1â3):31â39. Anane, R., M.Bonini, J.M.Grafeille, and E.E.Creppy. 1995. Bioaccumulation of water soluble aluminium chloride in the hippocampus after transdermal uptake in mice. Arch. Toxicol. 69(8):568â571. Anane, R., M.Bonini, and E.E.Creppy. 1997. Transplacental passage of aluminum from pregnant mice to fetus organs after maternal transcutaneous exposure. Hum. Exp. Toxicol. 16(9):501â504. Armstrong, B.G., C.G.Tremblay, D.Cyr, and G.P.Theriault. 1986. Estimating the relationship between exposure to tar volatiles and the incidence of bladder cancer in aluminum smelter workers. Scand. J. Work Environ. Health 12(5):486â493. Armstrong, B., C.Tremblay, D.Baris, and G.Theriault. 1994. Lung cancer mortality and polynuclear aromatic hydrocarbons: A case-cohort study of aluminum production workers in Arvida, Quebec, Canada. Am. J. Epidemiol. 139(3):250â262. ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile for Aluminum. U.S. Department of Health & Human Services, Public Health Service, Atlanta, GA. Avolio, G., F.Galietti, M.lorio, and A.Oliaro. 1989. Aluminum lung as an occupational disease. Case reports. [Article in Italian]. [Abstract in English]. Minerva Med. 80(4):411â414. Bast-Pettersen, R., P.A.Drablos, L.O.Goffeng, Y.Thomassen, and C.G.Torres. 1994. Neuropsychological deficit among elderly workers in aluminum production. Am. J. Ind. Med. 25(5):649â662. Bilkei-Gorzo, A. 1993. Neurotoxic effect of enteral aluminum. Food Chem. Toxicol. 31(5):357â361. Budavari, S., M.J.O'Neil, A.Smith, and P.E.Heckelman. 1989. The Merck Index, 11th Ed. Rahway,NJ: Merck and Co., Inc. Chedid, F., A.Fudge, J.Teubner, S.L.James, and K.Simmer. 1991. Aluminium absorption in infancy. J. Paediatr. Child Health 27(3): 164â166. Chen, W.J., R.J.Monnat, Jr., M.Chen, and N.K.Mottet. 1978. Aluminum induced pulmonary granulomatosis. Hum. Pathol. 9(6):705â711. Colomina, M.T., M.Gomez, J.L.Domingo, J.M.Llobet, and J.Corbella. 1992. Concurrent ingestion of lactate and aluminum can result in developmental toxicity in mice. Res. Commun. Chem. Pathol. Pharmacol. 77(1):95â106. Colomina, M.T., M.Gomez, J.L.Domingo, and J.Corbella. 1994. Lack of maternal and developmental toxicity in mice given high doses of aluminum hydroxide and
ALUMINA TRIHYDRATE 124 ascorbic acid during gestation. Pharmacol. Toxicol. 74(4â5):236â239. Colomina, M.T., J.L.Esparza, J.Corbella, and J.L.Domingo. 1998. The effect of maternal restraint on developmental toxicity of aluminum in mice. Neurotoxicol. Teratol. 20(6):651â656. Cranmer, J.M., J.D.Wilkins, D.J.Cannon, and L.Smith. 1986. Fetal-placental-maternal uptake of aluminum in mice following gestational exposure: Effect of dose and route of administration. Neurotoxicology 7(2): 601â608. Crombie, D.W., J.L.Blaisdell, and G.MacPherson. 1944. The treatment of silicosis by aluminum powder. Can. Med. Assoc. J. 50:318â328. Cullen, M.R., H.Checkoway, and B.H.Alexander. 1996. Investigation of a cluster of pituitary adenomas in workers in the aluminum industry. Occup. Environ. Med. 53(11):782â786. Dick, R.B., E.F.Krieg, Jr., M.A.Sim, B.P.Bernard, and B.T.Taylor. 1997. Evaluation of tremor in aluminum production workers. Neurotoxicol. Teratol. 19(6):447â453. DiPaolo, J.A., and B.C.Casto. 1979. Quantitative studies of in vitro morphological transformation of Syrian hamster cells by inorganic metal salts. Cancer Res. 39(3):1008â1013. Domingo, J.L., J.M.Llobet, M.Gomez, J.M.Tomas, and J.Corbella. 1987a. Nutritional and toxicological effects of short-term ingestion of aluminum by the rat. Res. Commun. Chem. Pathol. Pharmacol. 56(3):409â419. Domingo, J.L., J.L.Paternain, J.M.Llobet, and J.Corbella. 1987b. The effects of aluminum ingestion of reproduction and postnatal survival in rats. Life Sci. 41(9):1127â1131. Domingo, J.L., M.Gomez, M.A.Bosque, and J.Corbella. 1989. Lack of teratogenicity of aluminum hydroxide in mice. Life Sci. 45(3):243â 247. Domingo, J.L., M.Gomez, D.J.Sanchez, J.M.Llobet, and J.Corbella. 1993. Effect of various dietary constituents on gastrointestinal absorption of aluminum from drinking water and diet. Res. Commun. Chem. Pathol. Pharmacol. 79(3):377â380. Donald, J.M., M.S.Golub, M.E.Gershwin, and C.L.Keen. 1989. Neurobehavioral effects in offspring of mice given excess aluminum in diet during gestation and lactation. Neurotoxicol. Teratol. 11(4):345â351. Drueke, T.B., P.Jouhanneau, H.Banide, B.Lacour, F.Yiou, and G.Raisbeck. 1997. Effects of silicon, citrate and the fasting state on the intestinal absorption of aluminium in rats. Clin. Sci. 92(1):63â67. Dufresne, A., P.Loosereewanich, B.Armstrong, G.Theriault, and R.Begin. 1996. Inorganic particles in the lungs of five aluminum smelter workers with pleuro-pulmonary cancer. Am. Ind. Hyg. Assoc. J. 57(4):370â375. Edling, N.P.G. 1961. Aluminum pneumoconiosis: A roentgendiagnostic study of five cases. Acta. Radiol. 56:170â178. Eklund, A., R.Arns, E.Blaschke, J.Hed, S.O.Hjertquist, K.Larsson, H.Lowgren, J. Nystrom, C.M.Skold, and G.Tornling. 1989. Characteristics of alveolar cells and soluble components in bronchoalveolar lavage fluid from nonsmoking aluminium potroom workers. Br. J. Ind. Med. 46(11):782â786. Elinder, C.G., L.Ahrengart, V.Lidums, E.Pettersson, and B.Sjogren. 1991. Evidence
ALUMINA TRIHYDRATE 125 of aluminum accumulation in aluminium welders. Br. J. Ind. Med. 48(11):735â738. Ellenhorn, M.J. 1997. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd Ed. Baltimore: Williams & Wilkins. EPA (U.S. Environmental Protection Agency). 1992. Dermal Exposure Assessment: Principles and Applications. EPA/600/8â91â011B. Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC. Exley, C. 1998. Does antiperspirant use increase the risk of aluminium-related disease, including Alzheimer's disease? Mol. Med. Today 4 (3): 107â109. FairweatherâTait, S., K.Hickson, B.McGaw, and M.Reid. 1994. Orange juice enhances aluminium absorption from antacid preparation. Eur. J. Clin. Nutr. 48(1):71â73. Ferrante, J. 1999. Toxicity review for alumina trihydrate. Memorandum, dated March 9, 1999 from Jacqueline Ferrante, Pharmacologist, Division of Health Sciences to Ronald Medford, Assistant Executive Director for Hazard Identification and Reduction, U.S. Consumer Product Safety Commission, Washington, DC. Forbes, W.F., and G.B.Hill. 1998. Is exposure to aluminum a risk factor for the development of Alzheimer disease? âYes. Arch. Neurol. 55 (5):740â741. Ganrot, P.O. 1986. Metabolism and possible health effects of aluminum. Environ. Health Perspect. 65:363â441. Gibbs, G.W. 1985. Mortality of aluminum reduction plant workers, 1950 through 1977. J. Occup. Med. 27(10):761â770. Gibbs, G.W., and I.Horowitz. 1979. Lung cancer mortality in aluminum reduction plant workers. J. Occup. Med. 21(5):347â353. Gitelman, H.J., F.R.Alderman, M.Kurs-Lasky, and H.E.Rockette. 1995. Serum and urinary aluminum levels of workers in the aluminum industry. Ann. Occup. Hyg. 39(2):181â191. Golub, M.S., and J.L.Domingo. 1996. What we know and what we need to know about developmental aluminum toxicity. J. Toxicol. Environ. Health 48(6):585â597. Golub, M.S., M.E.Gershwin, J.M.Donald, S.Negri, and C.L.Keen. 1987. Maternal and developmental toxicity of chronic aluminum exposure in mice. Fundam. Appl. Toxicol. 8(3):346â357. Golub, M.S., J.M.Donald, M.E.Gershwin, and C.L.Keen. 1989. Effects of aluminum ingestion on spontaneous motor activity of mice. Neurotoxicol. Teratol. 11(3):231â235. Golub, M.S., B.Han, C.L.Keen, and M.E.Gershwin. 1992a. Effects of dietary aluminum excess and manganese deficiency on neurobehavioral endpoints in adult mice. Toxicol. Appl. Pharmacol. 112(1):154â160. Golub, M.S., C.L.Keen, and M.E.Gershwin. 1992b. Neurodevelopmental effect of aluminum in mice: Fostering studies. Neurotoxicol. Teratol. 14(3): 177â182. Golub, M.S., B.Han, C.L.Keen, and M.E.Gershwin. 1994. Auditory startle in Swiss Webster mice fed excess aluminum in diet. Neurotoxicol. Teratol. 16(4):423â425. Golub, M.S., B.Han, C.L.Keen, M.E.Gershwin, and R.P.Tarara. 1995. Behavioral performance of Swiss Webster mice exposed to excess dietary aluminum during development or during development and as adults. Toxicol. Appl. Pharmacol. 133(1):64â72.
ALUMINA TRIHYDRATE 126 Gomez, M., J.L.Domingo, J.M.Llobet, J.M.Tomas, and J.Corbella. 1986. Short-term oral toxicity study of aluminum in rats. Arch. Farmacol. Toxicol. 12(2â3): 145â151. Gomez, M., J.L.Domingo, and J.M.Llobet. 1991. Developmental toxicity evaluation of oral aluminum in rats: Influence of citrate. Neurotoxicol. Teratol. 13(3):323â328. Gorsky, J.E., A.A.Dietz, H.Spencer, and D.Osis. 1979. Metabolic balance of aluminum studied in six men. Clin. Chem. 25(10): 1739â1743. Greger, J.L., and M.J.Baier. 1983. Excretion and retention of low or moderate levels of aluminum by human subjects. Food Chem. Toxicol. 21(4):473â477. Greger, J.L., and S.E.Donnaubauer. 1986. Retention of aluminum in the tissues of rats after the discontinuation of oral exposure to aluminum. Food Chem. Toxicol. 24(12):1331â1334. HÃ¤nninen, H., E.Matikainen, T.Kovala, S.Valkonen, and V.Riihimaki. 1994. Internal load of aluminum and the central nervous system function of aluminum welders. Scand. J. Work Environ. Health 20(4):279â285. Hicks, J.S., D.S.Hackett, and G.L.Sprague. 1987. Toxicity and aluminium concentration in bone following dietary administration of two sodium aluminium phosphate formulations in rats. Food Chem. Toxicol. 25(7):533â538. Hosovski, E., Z.Mastelica, D.Sunderic, and D.Radulovic. 1990. Mental abilities of workers exposed to aluminum. Med. Lav. 81(2):119â123. HSDB (Hazardous Substances Data Bank). 1990. National Library of Medicine. [Online]. Available: http://sis.nlm.nih.gov/cgi-bin/sis/ htmlgen?HSDB Jenkins, R.O., P.J.Craig, W.Goessler, and K.J.Irgolic. 1998. Antimony leaching from cot mattresses and sudden infant death syndrome (SIDS). Hum. Exp. Toxicol. 17(3):138â139. Jouhanneau, P., G.M.Raisbeck, F.Yiou, B.Lacour, H.Banide, and T.B.Drueke. 1997. Gastrointestinal absorption, tissue retention, and urinary excretion of dietary aluminum in rats determined by using 26A1. Clin. Chem. 43(6 Pt. 1):1023â1028. Kaehny, W.D., A.P.Hegg, and A.C.Alfrey. 1977. Gastrointestinal absorption of aluminum from aluminum-containing antacids. N. Engl. J. Med. 296(24): 1389â1390. Kanematsu, N., M.Hara, and T.Kada. 1980. rec assay and mutagenicity studies on metal compounds. Mutat. Res. 77(2): 109â116. Koo, W.W., S.K.Krug-Wispe, P.Succop, R.Bendon, and L.A.Kaplan. 1992. Sequential serum aluminum and urine aluminum: Creatinine ratio and tissue aluminum loading in infants with fractures/rickets. Pediatrics 89(5 Pt. 1):877â881. Krasovskii, G.N., L.Y.Vasukovich, and O.G.Chariev. 1979. Experimental study of biological effects of leads and aluminum following oral administration. Environ. Health Perspect. 30:47â51. Lansdown, A.B. 1973. Production of epidermal damage in mammalian skins by some simple aluminum compounds. Br. J. Dermatol. 89 (1):67â76. Lide, D.R. 1991â1992. Handbook of Chemistry and Physics, 72nd Ed. Boca Raton, FL: CRC Press. Manna, G.K., and R.K.Das. 1972. Chromosome aberrations in mice induced by aluminum chloride. Nucleus 15:180â186. Marzin, D.R., and H.V.Phi. 1985. Study of the mutagenicity of metal derivatives with
ALUMINA TRIHYDRATE 127 Salmonella-typhimurium TA-102. Mutat. Res. 155:49â52. McLaughlin, A.I.G., G.Kazantzis, E.King, D.Teare, R.J.Porter, and R.Owen. 1962. Pulmonary fibrosis and encephalopathy associated with the inhalation of aluminum dust. Br. J. Ind. Med. 19:253â263. Meiklejohn, A., and E.Posner. 1957. The effect of the use of calcined alumina in china biscuit placing on the health of the workman. Br. J. Ind. Med. 14:229â231. Milham, S., Jr. 1979. Mortality in aluminum reduction plant workers. J. Occup. Med. 21(7):475â480. Miller, R.R., A.M.Churg, M.Hutcheon, and S.Lom. 1984. Pulmonary alveolar proteinosis and aluminum dust exposure. Am. Rev. Respir. Dis. 130(2):312â315. Misawa, T., and S.Shigeta. 1993. Effects of prenatal aluminum treatment on development and behavior in the rat. J. Toxicol. Sci. 18(1):43â48. Mitchell, J., G.B.Manning, M.Molyneux, and R.E.Lane. 1961. Pulmonary fibrosis in workers exposed to finely powdered aluminum. Br. J. Ind. Med. 18:10â20. Moore, P.B., J.A.Edwardson, I.N.Ferrier, G.A.Taylor, D.Lett, S.P.Tyrer, J.P.Day, S.J.King, and J.S.Lilley. 1997. Gastrointestinal absorption of aluminum is increased in Down's syndrome. Biol. Psychiatry 41(4):488â492. Munoz, D.G. 1998. Is exposure to aluminum a risk factor for the development of Alzheimer disease?âNo. Arch. Neurol. 55(5):737â739. Musk, A.W., H.W.Greville, and A.E.Tribe. 1980. Pulmonary disease from occupational exposure to an artificial aluminum silicate used for cat litter. Br. J. Ind. Med. 37(4):367â372. Mussi, I., G.Calzaferri, M.Buratti, and L.Alessio. 1984. Behaviour of plasma and urinary aluminum levels in occupationally exposed subjects. Int. Arch. Occup. Environ. Health 54(2):155â161. Nolan, C.R., J.J.DeGoes, and A.C.Alfrey. 1994. Aluminum and lead absorption from dietary sources in women ingesting calcium citrate. South Med. J. 87(9):894â898. Oneda, S., T.Takasaki, K.Kuriwaki, Y.Ohi, Y.Umekita, S.Hatanaka, T.Fujiyoshi, A.Yoshida, and H.Yoshida. 1994. Chronic toxicity and tumorigenicity study of aluminum potassium sulfate in B6C3F1 mice. In Vivo 8(3):271â278. OSHA (Occupational Safety and Health Administration). 1974. Occupational Safety and Health Standards. Code of Federal Regulations. 29 CFR 1910.1000. Occupational Safety and Health Administration. U.S. Department of Labor. Oteiza, P.I., C.L.Keen, B.Han, and M.S.Golub. 1993. Aluminum accumulation and neurotoxicity in Swiss-Webster mice after long-term dietary exposure to aluminum and citrate. Metabolism 42(10): 1296â1300. Park, H.S., S.T.Uh, and C.S.Park. 1996. Increased neutrophil chemotactic activity is noted in aluminum-induced occupational asthma. Korean J. Intern. Med. 11(1):69â73. Partridge, N.A., F.E.Regnier, W.M.Reed, J.L.White, and S.L.Hem. 1992. Contribution of soluble aluminum species to absorption of aluminum from the rat gut in situ. Clin. Sco. (Colch.) 83(4):425â430. Paternain, J.L., J.L.Domingo, J.M.Llobet, and J.Corbella. 1988. Embryotoxic and teratogenic effects of aluminum nitrate in rats upon oral administration. Teratology 38(3):253â257.
ALUMINA TRIHYDRATE 128 Pennington, J.A., and S.A.Schoen. 1995. Estimates of dietary exposure to aluminum. Food Addit. Contam. 12(1): 119â128. Pierre, F., F.Baruthio, F.Diebold, and P.Biette. 1995. Effect of different exposure compounds on urinary kinetics of aluminum and fluoride in industrially exposed workers. Occup. Environ. Med. 52(6):396â403. Pigott, G.H., B.A.Gaskell, and J.Ishmael. 1981. Effects of long term inhalation of alumina fibres in rats. Br. J. Exp. Pathol. 62(3):323â331. Pivnick, E.K., N.C.Kerr, R.A.Kaufman, D.P.Jones, and R.W.Chesney. 1995. Rickets secondary to phosphate depletion. A sequela of antacid use in infancy. Clin. Pediatr. 34(2):73â78. Poisindex (PoisindexÂ® System). 1998. Toxicologic Managements: Aluminum. Micromedex, Inc. Volume 97, expiration date 8/31/98. Posner, E., and M.C.Kennedy. 1967. A further study of china biscuit placers in Stokeon-Trent. Br. J. Ind. Med. 24(2): 133â142. Priest, N.D., R.J.Talbot, J.G.Austin, J.P.Day, S.J.King, K.Fifield, and R.G.Cresswell. 1996. The bioavailability of 26Al-labelled aluminum citrate and aluminum hydroxide in volunteers. Biometals 9(3):221â8. Recker, R.R., A.J.Blotcky, J.A.Leffler, and E.P.Rack. 1977. Evidence of aluminum absorption from the gastrointestinal tract and bone deposition by aluminum carbonate ingestion with normal renal function. J. Lab. Clin. Med. 90(5):810â815. Reiber, S., W.Kukull, and P.Standish-Lee. 1995. Drinking water aluminium and bioavailability. J. Am. Water Works Assoc. 87(5):86â100. Rifat, S.L., M.R.Eastwood, D.R.McLachlan, and P.N.Corey. 1990. Effect of exposure of miners to aluminum powder. Lancet 336(8724): 1162â1165. Rockette, H.E., and V.C.Arena. 1983. Mortality studies of aluminum reduction plant workers: Potroom and carbon department. J. Occup. Med. 25(7):549â557. Rollin, H.B., P.Theodorou, and T.A.Kilroe-Smith. 1991. Deposition of aluminum in tissues of rabbits exposed to inhalation of low concentrations of Al2O3 dust. Br. J. Ind. Med. 48(6):389â91. Ronneberg, A., and F.Langmark. 1992. Epidemiologic evidence of cancer in aluminum reduction plant workers. Am. J. Ind. Med. 22(4):573â 590. Salib, E., and V.Hillier. 1996. A case-control study of Alzheimer's disease and aluminum occupation. Br. J. Psychiat. 168(2):244â249. Savory, J., C.Exley, W.F.Forbes, Y.Huang, J.G.Joshi, T.Kruck, D.R.McLachlan, and I.Wakayama. 1996. Can the controversy of the role of aluminum in Alzheimer's disease be resolved? What are the suggested approaches to this controversy and methodological issues to be considered? J. Toxicol. Environ. Health 48(6):615â35. Schonholzer, K.W., R.A.Sutton, V.R.Walker, V.Sossi, M.Schulzer, C.Orvig, E. Venczel, R.R.Johnson, D.Vetterli, B.Dittrich-Hannen, P.Kubik, and M.Suter. 1997. Intestinal absorption of trace amounts of aluminum in rats studied with 26 aluminum and accelerator mass spectrometry. Clin. Sci. (Colch.) 92(4):379â383. Sedman, A.B., G.L.Klein, R.J.Merritt, N.L.Miller, K.O.Weber, W.L.Gill, H.Anand, and A.C.Alfrey. 1985. Evidence of aluminum loading in infants receiving intravenous therapy. N. Engl. J. Med. 312(21):1337â1343.
ALUMINA TRIHYDRATE 129 Selden, A.I., H.B.Westberg, and O.Axelson. 1997. Cancer morbidity in workers at aluminum foundries and secondary aluminum smelters. Am. J. Ind. Med. 32(5):467â477. Sideman, S., and D.Manor. 1982. The dialysis dementia syndrome and aluminum intoxication. Nephron 31(1):1â10. Sim, M., R.Dick, J.Russo, B.Bernard, P.Grubb, E.Krieg Jr., C.Mueller, and C. McCammon. 1997. Are aluminum potroom workers at increased risk of neurological disorders? Occup. Environ. Med. 54(4):229â235. Sjogren, B., V.Lidums, M.Hakansson, and L.Hedstrom. 1985. Exposure and urinary excretion of aluminum during welding. Scand. J. Work Environ. Health 11(1):39â43. Sjogren, B., C.-G.Elinder, V.Lidums, and G.Chang. 1988. Uptake and urinary excretion of aluminum among welders. Int. Arch. Occup. Environ. Health 60(2):77â79. Sjogren, B., K.G.Ljunggren, O.Almkvist, W.Frech, and H.Basun. 1996. A follow-up study of five cases of aluminosis. Int. Arch. Occup. Environ. Health 68(3):161â164. Smith, M.A., and G.Perry. 1998. What are the facts and artifacts of the pathogenesis and etiology of Alzheimer disease? J. Chem. Neuroanat. 16(1):35â41. Spinelli, J.J., P.R.Band, L.M.Svirchev, and R.P.Gallagher. 1991. Mortality and cancer incidence in aluminum reduction plant workers. J. Occup. Med. 33(11):1150â1155. Steinhagen, W.H., F.L.Cavender, and B.Y.Cockrell. 1978. Six month inhalation exposures of rats and guinea pigs to aluminum chlorhydrate. J. Environ. Pathol. Toxicol. 1(3):267â277. Taylor, G.A., I.N.Ferrier, I.J.McLoughlin, A.F.Fairbaim, I.G.McKeith, D.Lett, and J.A.Edwardson. 1992. Gastrointestinal absorption of aluminium in Alzheimer's disease: Response to aluminum citrate. Age Ageing 21 (2):81â90. Teraoka, H. 1981. Distribution of 24 elements in the internal organs of normal males and the metallic workers in Japan. Arch. Environ. Health 36(4):155â165. Testolin, G., D.Erba, S.Ciappellano, and G.Bermano. 1996. Influence of organic acids on aluminium absorption and storage in rat tissues. Food Addit. Contam. 13(1):21â27. Theriault, G., L.De Guire, and S.Cordier. 1981. Reducing aluminum: An occupation possibly associated with bladder cancer. Can. Med. Assoc. J. 124(4):419â422; 425. Thorne, B.M., A.Cook, T.Donohoe, S.Lyon, D.M.Medeiros, and C.Moutzoukis. 1987. Aluminum toxicity and behavior in the weanling Long- Evans rat. Bull. Pyschon. Soc. 25(2):129â132. Ueda, M., Y.Mizoi, Z.Maki, R.Maeda, and R.Takada. 1958. A case of aluminum dust lung: A necropsy report. Kobe J. Med. Sci. 4:91â99. Vandenplas, O., J.P.Delwiche, M.L.Vanbilsen, J.Joly, and D.Roosels. 1998. Occupational asthma caused by aluminum welding. Eur. Respir. J. 11(5):1182â1184. Weberg, R., and A.Berstad. 1986. Gastrointestinal absorption of aluminum from single doses of aluminum containing antacids in man. Eur. J. Clin. Invest. 16(5):428â32. Wedrychowski, A., W.N.Schmidt, and L.S.Hnilica. 1986. The in vivo cross-linking of proteins and DNA by heavy metals. J. Biol. Chem. 261 (7):3370â3376.
ALUMINA TRIHYDRATE 130 White, D.M., W.T.Longstreth, Jr., L.Rosenstock, K.H.Claypoole, C.A.Brodken, and B.D.Townes. 1992. Neurologic syndrome in 25 workers from an aluminum smelting plant. Arch. Intern. Med. 152(7): 1443â1448. Yokel, R.A., and P.J.McNamara. 1989. Elevated aluminum persists in serum and tissues of rabbits after a six-hour infusion. Toxicol. Appl. Pharmacol. 99(1): 133â138. Yokel, R.A., V.Lidums, P.J.McNamara, and U.Ungerstedt. 1991. Aluminum distribution into brain and liver of rats and rabbits following intravenous aluminum lactate or citrate: A microdialysis study. Toxicol. Appl. Pharmacol. 107(1):153â163. Yokel, R.A., D.D.Allen, and J.J.Meyer. 1994. Studies of aluminum neurobehavioral toxicity in the intact mammal. Cell. Mol. Neurobiol. 14 (6):791â808. Zafar, T.A., C.M.Weaver, B.R.Martin, R.Flarend, and D.Elmore. 1997. Aluminum (26Al) metabolism in rats. Proc. Soc. Exp. Biol. Med. 216 (1):81â85. Zatta, P., M.Favarato, and M.Nicolini. 1993. Deposition of aluminum in brain tissues of rats exposed to inhalation of aluminum acetylacetonate. Neuroreport 4(9): 1119â1122.