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Robert Truesdale

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ASSISTANCE REQUESTED: PPRTV for Aluminum.

ENCLOSED INFORMATION: Attachment 1: PROVISIONAL PEER REVIEWED TOXICITY

VALUES FOR ALUMINUM (CASRN 7429-90-5) 

BE ADVISED: Unless specifically indicated to have been peer reviewed, it is to be noted that the

attached Provisional Toxicity Value Paper(s) have not been through the U.S. EPA’s

formal review process; therefore, they do not represent a U.S. EPA verified assessment.

If you have any questions regarding this transmission, please contact the STSC at (513) 569-7300.

Attachments (1)

cc: STSC files. 
10-23-2006 

Provisional Peer Reviewed Toxicity Values for 

Aluminum 

(CASRN 7429-90-5) 

Superfund Health Risk Technical Support Center 

National Center for Environmental Assessment 

Office of Research and Development 

U.S. Environmental Protection Agency 

Cincinnati, OH 45268
Acronyms and Abbreviations 

bw body weight 

cc cubic centimeters 

CD Caesarean Delivered 

CERCLA Comprehensive Environmental Response, Compensation and 

Liability Act of 1980 

CNS central nervous system

cu.m cubic meter 

DWEL Drinking Water Equivalent Level 

FEL frank-effect level 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

g grams 

GI gastrointestinal 

HEC human equivalent concentration 

Hgb hemoglobin 

i.m. intramuscular 

i.p. intraperitoneal 

IRIS Integrated Risk Information System

i.v. intravenous 

IUR inhalation unit risk 

kg kilogram

L liter 

LEL lowest-effect level 

LOAEL lowest-observed-adverse-effect level 

LOAEL(ADJ) LOAEL adjusted to continuous exposure duration 

LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human 

m meter 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

mg milligram

mg/kg milligrams per kilogram

mg/L milligrams per liter 

MRL minimal risk level 

MTD maximum tolerated dose 

MTL median threshold limit 

NAAQS National Ambient Air Quality Standards 

NOAEL no-observed-adverse-effect level 

NOAEL(ADJ) NOAEL adjusted to continuous exposure duration 

NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human 

NOEL no-observed-effect level 

OSF oral slope factor 

p-IUR provisional inhalation unit risk 

p-OSF provisional oral slope factor 

p-RfC provisional inhalation reference concentration 

i
p-RfD provisional oral reference dose 

PBPK physiologically based pharmacokinetic 

ppb parts per billion 

ppm parts per million 

PPRTV Provisional Peer Reviewed Toxicity Value 

RBC red blood cell(s) 

RCRA Resource Conservation and Recovery Act 

RDDR Regional deposited dose ratio (for the indicated lung region) 

REL relative exposure level 

RfC inhalation reference concentration 

RfD oral reference dose 

RGDR Regional gas dose ratio (for the indicated lung region) 

s.c. subcutaneous

SCE sister chromatid exchange

SDWA Safe Drinking Water Act 

sq.cm. square centimeters 

TSCA Toxic Substances Control Act 

UF uncertainty factor 

μg microgram

μmol micromoles 

VOC volatile organic compound 

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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 

ALUMINUM (CASRN 7429-90-5) 

Background

On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of 

Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human 

health toxicity values for Superfund risk assessments, establishing the following three tiers as the 

new hierarchy: 

1. EPA's Integrated Risk Information System (IRIS). 

2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund 

Program. 

3. Other (peer-reviewed) toxicity values, including: 

< Minimal Risk Levels produced by the Agency for Toxic Substances and Disease 

Registry (ATSDR), 

< California Environmental Protection Agency (CalEPA) values, and 

< EPA Health Effects Assessment Summary Table (HEAST) values. 

A PPRTV is defined as a toxicity value derived for use in the Superfund Program when 

such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are 

developed according to a Standard Operating Procedure (SOP) and are derived after a review of 

the relevant scientific literature using the same methods, sources of data, and Agency guidance 

for value derivation generally used by the EPA IRIS Program. All provisional toxicity values 

receive internal review by two EPA scientists and external peer review by three independently 

selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the 

multi-program consensus review provided for IRIS values. This is because IRIS values are 

generally intended to be used in all EPA programs, while PPRTVs are developed specifically for 

the Superfund Program. 

Because science and available information evolve, PPRTVs are initially derived with a 

three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program

sometimes request that a frequently used PPRTV be reassessed. Once an IRIS value for a 

specific chemical becomes available for Agency review, the analogous PPRTV for that same

chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a 

PPRTV cannot be derived based on inadequate data. 

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Disclaimers

Users of this document should first check to see if any IRIS values exist for the chemical 

of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional 

Superfund and RCRA program offices are advised to carefully review the information provided 

in this document to ensure that the PPRTVs used are appropriate for the types of exposures and 

circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically 

updated; therefore, users should ensure that the values contained in the PPRTV are current at the 

time of use. 

It is important to remember that a provisional value alone tells very little about the 

adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, 

users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths 

and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of 

Research and Development’s National Center for Environmental Assessment, Superfund Health 

Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may 

choose of their own initiative to use these PPRTVs are advised that Superfund resources will not 

generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund 

Program. 

Questions Regarding PPRTVs

Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on 

chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed 

to the EPA Office of Research and Development’s National Center for Environmental 

Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI. 

This document has passed the STSC quality review and peer review evaluation indicating 

that the quality is consistent with the SOPs and standards of the STSC and is suitable for use by 

registered users of the PPRTV system. 

INTRODUCTION

Verified toxicity values for aluminum (Al) and its compounds are unavailable on IRIS or 

HEAST (U.S. EPA, 2006, 1997), except for a chronic oral RfD of 4E-4 mg/kg-day for aluminum

phosphide. However, occupational guidelines and standards have been established for a number 

of chemical and physical forms of Al, including, from ACGIH, 8-hour TWA-TLVs of 10 mg/m3

for the compound as a metal dust or oxide, 5 mg/m3

 as “pyro” powders or welding fumes, and 2 

mg/m3

 for soluble salts or organic forms of the metal (ACGIH, 1998). From NIOSH, 10-hour 

TWA-RELs of 10 mg/m3

 are specified for “total” Al dust versus 5 mg/m3 for the respirable 

portion (NIOSH, 1994). NIOSH covers all other forms of the metal by identical values to those 

specified by ACGIH (ACGIH, 1998). OSHA PELs for Al include an 8-hour TWA value of 15 

mg/m3

 for “total” metal dust, versus 5 mg/m3 for the respirable portion (NIOSH, 1994). The 

U.S. EPA’s CARA list (U.S. EPA, 1994) cites a HEA for Al (U.S. EPA, 1987), and ATSDR has 

updated its toxicological profile of the element (ATSDR, 1998). 

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The U.S. FDA (2000) has specified a maximum aluminum concentration of 25 mcg/L in 

large-volume parenterals (LVP) used in total parenteral nutrition (TPN). The FDA regulation 

applies to all LVPs used in TPN, including but not limited to parenteral amino acid solutions, 

highly concentrated dextrose solutions, parenteral lipid emulsions, sodium chloride and 

electrolyte solutions, and sterile water for injection. 

Research papers pertinent to the potential toxicological and carcinogenic effects of Al 

were sought through computer searches of the HSDB, RTECS, MEDLINE and TOXLINE (and 

its subfiles) databases, covering the time period 1995-1999. The literature searches were 

conducted in June, 1999. 

REVIEW OF PERTINENT DATA

The review by Stokinger (1981) gives an account of Al as an all-pervasive component of 

products that are central to the daily lives of most Americans. For example, the metal is a crucial 

part of manufactured products for the building, automobile and container industries, while Al as 

powder or flake is a component in a number of consumer products, such as paints, fireworks, etc. 

Al complexes and minerals are used in the brewing and paper industries, and as coagulants for 

water purification. Aluminum oxide finds application in abrasives, as a catalyst or absorbent, 

and as a component in fillers. Aluminum chloride is included in cosmetic formulations such as 

deodorants. 

Human exposure to Al arises principally from food and water, through its widespread use 

in food additives, packaging and cooking utensils and Al-containing medications, particularly 

antacid, buffered aspirin, anti-ulcer and anti-diarrheal formulations (Marquis, 1989; Lione, 

1985). Pennington and Schoen (1995) estimated daily Al intakes of 0.1-0.3 mg/kg-day for 

infants and children 6 months-6 years of age and 0.1-0.18 mg/kg-day for older children and 

adults, based on the FDA Total Diet Study (1993) and the U.S. Department of Agriculture 

Nationwide Food Consumption Survey (1987-1988). These data are in broad agreement with 

those of Wilhelm et al. (1995) who reported the dietary intake of Al in German children (living 

in the Duisberg area) as ranging from 0.008 to 0.11 mg Al/kg-day. In addition, these values are 

consistent with a range of 1-20 mg/day (0.014-0.3 mg/kg -day) for normal oral daily Al intake 

from food and water reported by other investigators (Ganrot, 1986; Iyengar et al., 1987; Wilhelm

et al., 1990). However, users of Al-containing medications can ingest much larger amounts of 

the element, possibly as high as 840-5000 mg/day (12-71 mg/kg-day) from antacids, 126-728 

mg/day (1.8-10.4 mg/kg-day) from buffered aspirins and 828 mg/day (11.8 mg/kg-day) from

anti-ulcer compounds when taken at recommended dosages (Lione, 1985). 

Toxicokinetics of Aluminum

There is a large amount of information available on the absorption, transfer from tissue to 

tissue and elimination of Al from the body, including data that have been amassed from studies 

on either human volunteers or laboratory animals. In general, the chemical appears to be poorly 

absorbed from the gastrointestinal tract, though the portion of the load that is retained will vary 

depending on the concentration, the chemical species administered, the fasting or fed state of the 

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host, gastrointestinal pH, animal model, etc. For example, Yokel and McNamara (1988) 

administered single oral doses of a number of Al compounds (both water soluble and insoluble) 

to New Zealand white rabbits and obtained absorbed proportions of the load ranging from 0.27% 

to 27%. Fractional uptake of Al in humans under normal conditions (i.e., with no intake of large 

quantities of Al from medicine) was estimated to be 0.1-0.3% assuming an intake of 20 mg

Al/day (0.3 mg Al/kg-day) and urinary excretion of 20-50 μg Al/day (0.3-0.7 μg Al/kg-day) 

(Ganrot, 1986). However, little information is available on the actual mechanism by which the 

element and its compounds are transported across the brush border. (Wilhelm et al., 1990; Lione, 

1985). 

Although the overall extent of Al absorption is poor following oral exposure, there may 

be significant intake of the compound by those taking large amounts of Al compounds in 

patented remedies. As stated, absorption of Al is influenced by gastrointestinal conditions and 

content because Al can form various complexes with different solubilities and oxidation states 

depending on pH and interactions with dietary constituents. At low pH (3-5) in aqueous 

solutions, the soluble (ionic) forms of the Al prevail (Al3+); at high pH (>8), Al in the form of 

soluble aluminum oxide is present; and at pH 5-8, the element is predominantly in the form of 

aluminum hydroxide, which is insoluble (van der Voet and de Wolff, 1986; Wilhelm et al., 

1990). Ingested constituents that can influence absorption by forming complexes with Al 

include phosphate, fluoride, calcium, citrate and lactate. For example, Al is used to bind dietary 

phosphorus and decrease its absorption as a control for hyperphosphatemia, and citrate and 

lactate are complexing agents that can significantly increase Al absorption (Slanina et al., 1984, 

1985, 1986; Partridge et al., 1989; Domingo et al., 1991; Ittel et al., 1991; Lione, 1985; Wihelm

et al., 1990). 

A number of recent reports of studies on the gastrointestinal absorption of Al have 

examined the influence of organic anions such as citrate. In general, the presence of such 

components appears to enhance the absorption of Al, within narrow limits. For example, Deng 

et al. (1998) administered a single oral dose of either distilled water, 2 mmoles/L aluminum 

chloride or 2 mmoles/L aluminum chloride plus 2 mmoles/L sodium citrate to six male Wistar 

rats/group. Animals were bled at 1, 2 and 4 hours after dosing, then terminated after 6 hours. 

Inductively coupled plasma (ICP) was used to measure Al concentrations in blood, bone (tibia), 

kidney, liver and the intestinal wall. Irrespective of treatment, the appearance of Al in the blood 

of dosed groups peaked after 1 hour, with the concentration of the element at higher levels in 

those animals receiving citrate in addition to aluminum chloride. In those animals receiving 

aluminum chloride alone, significant tissue concentrations of the element were restricted to the 

gastrointestinal wall. Those receiving citrate displayed measurable quantities of the element in 

several of the other monitored tissues, including bone. 

Sutherland and Greger (1998a) used a similar dosing regimen to examine the kinetics of 

absorption and elimination of Al in male Sprague-Dawley rats that had received a single oral 

dose of 0, 0.25, 0.5 or 1 mmoles/L/kg body weight aluminum lactate in 1 mL of 16% citrate. 

Concentrations of Al in serum, liver, kidney or bone (tibia) were measured at various post-dosing 

time intervals up to 6 hours. Depending on the dose, absorption factors for Al of up to 4.2% of 

the administered dose were observed, with the greater proportion retained in bone. The authors 

reported a slower rate of absorption in those animals receiving Al at the higher doses, an 

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observation potentially indicating reduced gut motility and/or saturation of the transcellular 

absorption processes at the higher concentrations. Aluminum deposited in kidney and bone 

appeared to turn-over at a slower rate than in the liver. 

The influence of citrate on the gastrointestinal absorption of Al in man was examined 

directly by Taylor et al. (1998) who administered a drink containing Al and citrate to three 

volunteers. Aluminum and citrate concentrations were monitored in serial blood and urine 

samples for up to 24 hours. The kinetics of citrate and Al differed markedly, the former peaking 

in plasma after 32 minutes, versus 87 minutes for Al. This suggests that Al probably does not 

cross the gastrointestinal barrier as the citrate. Furthermore, the authors reported that the overall 

extent of Al absorption had probably not exceeded 1% in their experiment, a finding that 

contrasts with the higher values reported by Sutherland and Greger (1998a) in Sprague-Dawley 

rats and by Deng et al. (1998) in Wistar rats. 

As discussed in a report by Glynn et al. (1999), gastrointestinal absorption of Al from 

aqueous media will be almost impossible to predict, because of the likelihood that the element 

will become absorbed to food particles in the intestinal lumen. Accordingly, depending on the 

dose, mode of delivery and caloric state of the experimental animal (fed/fasted), significant 

amounts of aqueous forms of Al will be absorbed only when available binding sites on food have 

become saturated. This presents an inherently complex overall picture of the element’s 

absorption since, additionally, the normal dietary content of Al will be substantial. Thus, it may 

be assumed that some sequestered Al will be absorbed along with non-sequestered water soluble 

forms of the element, while the rest will be retained within the gastrointestinal tract.

Sutherland and Greger (1998b) used their aluminum lactate in 16% citrate dosing 

regimen to examine the comparative importance of biliary versus urinary excretion of Al. Five 

to seven male Sprague-Dawley rats/group who had previously received an implanted bile 

cannula were treated by gavage. Another similarly-treated cohort of five animals/group were 

housed in metabolic cages immediately after dosing to provide 0- to 3-hour and 3- to 6-hour 

urine specimens. At termination, all animals were sacrificed and exsanguinated, and tissue, bile 

and urine samples were measured by graphite furnace atomic absorption spectroscopy. Among 

the key findings to emerge from this study was the incremental appearance of Al in bile as early 

as 15 minutes after dosing. However, overall amounts of Al were greater in the 3-hour urine 

samples than those that had accumulated in bile samples collected within a similar time frame. 

The fact that control rats excreted 3 times more Al in bile than in urine during the first 3 hours 

after dosing led the authors to conclude that, at low exposure to Al (in controls receiving Al 

solely from food), the liver is capable of excreting the element to the bile, a mechanism that 

becomes saturated as the level of Al administration becomes increased. Thereafter, urinary 

excretion becomes the primary route of elimination in circumstances of Al overload. 

Aluminum can also be absorbed by inhalation as indicated by age-related deposition in 

the lungs of the general population and exposure-related increased blood and urine 

concentrations in workers exposed to Al (Bast-Pettersen et al., 1994; Sjogren et al., 1996; 

Hosovski et al., 1990; Wilhelm et al., 1990; U.S. EPA, 1987). Aluminum occurs primarily in 

particulate form in the ambient atmosphere and as various dusts and fumes during its production 

and use. Common forms of inhaled Al include aluminum oxide (alumina; Al2O3), pyro powders 

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(powder and flake Al-treated to reduce surface oxidation), Al welding fume and soluble salts 

(e.g., aluminum chloride and sulfate) (ACGIH, 1998). 

Neurotoxicity as a Primary Toxicological Effect of Aluminum

One of the greatest health concerns regarding Al is its neurological effects. The first

evidence for Al-induced neurotoxicity in humans was seen in patients who, as a result of

receiving long-term hemodialysis for chronic renal failure, developed a degenerative 

neurological syndrome (dialysis dementia) characterized by the gradual loss of motor, speech 

and cognitive functions (Alfrey, 1993). This dementia, attributable to Al in the dialysate, is 

usually fatal within 6-9 months after the first clinical signs appear. In addition, many patients 

received high oral doses of Al to act as phosphate binders. Autopsies of these patients revealed 

increased concentrations of Al in the gray matter and cerebral spinal fluid (CSF) but no evidence 

of neurofibrillary degeneration (NFD) despite the elevated Al levels. Once the connection 

between Al and dialysis dementia was established, Al was removed from dialysis fluid and the 

incidence of dementia rapidly declined, thereby strengthening the argument that Al was a causal 

agent in dialysis dementia (Ganrot, 1986). 

Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s Disease (PD) are other 

neurological diseases which have been associated with Al exposure. ALS is a progressive 

disease of the Central Nervous System (CNS) that is characterized by an accumulation of 

neurofibrillary tangles. In Guam, southern West New Guinea and parts of Japan, there is an 

unusually high prevalence of ALS and PD. This may be related to the natural abundance of Al 

coupled with the virtual lack of magnesium and calcium in the drinking water supplies and soil 

of these areas. In a study designed to evaluate effects of high Al and low calcium levels in the 

diet, much like the conditions associated with Guam and other similar areas, cynomolgus 

monkeys were placed on a low calcium diet either with or without supplemental Al and 

manganese (Garruto et al., 1989). Chronic calcium deficiency alone produced neurodegenerative 

effects, although neurofibrillary changes were most frequently seen in the monkeys on a low 

calcium diet supplemented with Al and manganese. 

Though a cause and effect relationship between Al and three forms of chronic 

encephalopathy in humans: senile dementia of the Alzheimer type (SDAT, Alzheimer's Disease), 

endemic Amyotrophic Lateral Sclerosis (ALS) and endemic Parkinsonism-dementia (PD, a 

mixture of Parkinsonism and senile dementia) has been suggested, there is no firm evidence that 

it plays a causal role in the development of these diseases (Ganrot, 1986; Lione, 1985). The 

condition is degenerative and characterized by the progressive loss of speech, motor and 

cognitive functions, with death typically occurring within 1-6 months. Autopsies of patients 

revealed increased concentrations of Al in the gray matter and cerebral spinal fluid (CSF), 

though with no conclusive evidence of NFD or other neuropathological changes despite the 

elevated Al levels. 

The neurotoxicity of Al is well documented in certain animal species. Aluminum induces 

a spectrum of behavioral abnormalities and brain neurofibrillary degenerative changes in rabbits 

and cats when injected intracranially or parenterally in high doses, though hamsters and monkeys 

are less sensitive (Ganrot, 1986; Lione, 1985). Such studies have been designed as models for 

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the possible neurotoxicological effects of Al in humans. However, it should be noted that the 

neurofibrillary changes in affected animals differ in morphological detail from those associated 

with SDAT. As discussed further in the Oral Toxicity section, oral doses of Al can also induce 

neurobehavioral effects in adult mice and rats and in their developing offspring. In general, such 

neurotoxic effects of Al appear to be more subtle than those induced through routes of 

administration that by-pass the gastrointestinal tract, perhaps reflecting the lower doses of Al 

reaching the brain. 

Recent reports of studies on the effects of Al on neurotoxicity in animals have sought to 

define the biochemical mechanisms that are impaired when Al crosses the blood-brain barrier. 

However, a unifying concept has yet to emerge, though the passage of the element into various 

regions of the brain has been clearly demonstrated (Deloncle et al., 1995). Among the many 

biochemical functions and processes that appear to be perturbed by the presence of Al in the 

brain are the peroxidation status of biological membranes (Katyal et al., 1997; Deloncle et al., 

1999), inhibition of the neuronal glutamate-nitric oxide-cyclic GMP pathway (Cucarella et al., 

1998), and the marked reduction of protein- and non-protein-bound thiols and the specific 

activity of Na+

/K+ and Mg++ ATPases (Katyal et al., 1997). The relative importance of each of 

these mechanisms and how (or whether) they interact to bring about the observed physiological 

changes remains unclear. 

Other Effects of Aluminum 

Osteomalacia was frequently observed among long-term dialysis patients with 

neurological signs and is commonly attributed to Al overload (Ganrot, 1986; Lione, 1985). This 

bone condition is characterized by widened osteoid (unmineralized bone matrix) with no fibrosis, 

reduced mineralization rate, skeletal pain and a strong tendency for fractures, lack of response to 

vitamin D therapy and increased Al concentration in bone. Effects on bone histology and 

elevated bone Al levels have also been observed in patients with normal renal function who 

received total parenteral nutrition with Al-contaminated casein as a protein source, and in 

parenteral Al loading induced osteomalacia in rats and dogs (Lione, 1985). 

There are a number of published reports of studies in which the carcinogenicity of 

aluminum compounds has been evaluated. These include oral exposure studies in which the 

compounds were made available to experimental animals in the drinking water or diet 

(Schroeder and Mitchener, 1975a,b: Oneda et al., 1994), and inhalation epidemiological studies, 

in which the incidence of tumor formation in persons exposed to aluminum-containing dusts and 

fumes in an occupational setting was compared to unexposed individuals (Spinelli et al., 1991; 

Thériault et al., 1984, 1990; Armstrong et al., 1986; Tremblay et al., 1995; Selden et al., 1997; 

Cullen et al., 1996; Dufresne et al., 1996; Ronneberg and Langmark, 1992). However, it has 

been generally concluded that the inferential association between exposure to Al and marginally 

increased incidences of tumors of the bladder and/or lung are confounded because of the coexposure of subjects in such settings to other harmful and potentially carcinogenic substances, 

such as polycyclic aromatic hydrocarbons (PAHs and coal tar pitch volatiles (CTPV) (Ronneberg 

and Langmark, 1992). Therefore, the issue of the potential carcinogenicity of Al compounds 

remains uncertain. 

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Human Studies

Oral Exposure

Few reports have been identified that address the toxicological effects of Al in humans 

exposed orally. Furthermore, in a review, Reiber et al. (1995) pointed to the conflicting findings 

that have been reported when the incidence of neurological symptoms has been assessed in 

relation to Al exposure in either cross-sectional, ecological or case-control epidemiological 

studies. Among the more recent studies that have used this approach, Martyn et al. (1997) 

discussed the findings of a case-control study involving 441 men in England and Wales who 

were afflicted with either Alzheimer’s disease, brain cancer, dementia or other neurological 

conditions. Assessing the historical exposure of these subjects failed to establish a link between 

Al in drinking water at the prevailing concentrations (below 0.2 mg/L) and the incidence of one 

or more of the conditions under investigation. No data were located regarding the oral 

carcinogenicity of aluminum compounds in humans. 

Inhalation Exposure

Neurobehavioral effects were evaluated in a group of 87 Al foundry workers who were 

occupationally exposed to 4.6-11.5 mg/m3

 Al fumes and dust for a mean of 12.0 years [standard 

deviation (SD) 4.5 years, shortest exposure 6 years] compared to an unexposed control group 

(n=60) who were matched for age, job seniority and social status to exposed subjects (Hosovski 

et al., 1990). It is reported that environmental Al concentrations were measured for each worker 

separately during the winter and summer, implying that personal sampling may have been used 

and that the contributing concentrations are time-weighted averages. In certain places, the 

number of particles ranged as high as 329-1020/cm2

 air, and dust particle sizes were ≤1, 1-5 and 

≤5 microns in 65.6, 26.6 and 7.6% of the samples, respectively. Tests of psychomotor ability 

(simple and complex reaction time, oculomotor coordination), intellectual ability (Wechsler 

intelligence, performance intelligence and verbal intelligence quotients and Wechsler subtests on 

information processing, memory, understanding, calculation, coding, picture completion, picture 

grouping, object assembling, assembling of cubes and common concepts) and cerebral damage 

(Bender visual motor test) were conducted. Performance of the exposed workers was found to 

be significantly (p<0.02) impaired on the complex reaction time, oculomotor coordination, 

memory, coding, picture completion and object assembling tests. However, the investigators 

noted that the performance deficits had no clinical manifestations, and that additional studies 

were probably needed to confirm the possibility of cerebral damage. The study yielded a lowest 

available non-duration adjusted LOAEL of 4.6 mg Al/m3

 for psychomotor and cognitive 

impairment during repeated 8-hour occupational exposures (Hosovski et al., 1990), that could be 

corrected for discontinuous exposure (10 m3

/20 m3 and 5 days/7 days) to yield a LOAELHEC of

1.64 mg/m3

 Al. 

Aluminum oxide powders were administered to Canadian miners (mainly underground 

gold and uranium miners) in known exposures as a means of prophylaxis against silicosis 

(Stokinger, 1981; Rifat et al., 1990). Data in which more than 42 million Al treatments 

(≈150,000 man-years) had been given over a period of 27 years ending in 1971 were reviewed 

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by Stokinger (1981). The effectiveness of this treatment is uncertain but no lung damage or 

other ill effects (not specified) were observed. The powders (McIntyre powder) were prepared 

by grinding Al pellets so that 96% of the particles were ≤1.2 μm in diameter. During this 

process most of the particles became oxidized to aluminum oxide; the powder contained 85% 

aluminum oxide and 15% elemental Al. According to Stokinger (1981), recommended exposure 

concentrations were 30,000 particles of respirable size per cubic centimeter (ppcc) for 10 

minutes/day or 10,000-20,000 ppcc for 20 minutes/day (total treatment days not indicated). Rifat 

et al. (1990) stated that the recommended exposure was to an Al dust concentration of 20,000-

34,000 parts per ml air in the miners' changing rooms before each shift for 10 minutes. 

Stokinger (1981) reported that the 30,000 ppcc concentration corresponds to ≈350 mg/m3

, which 

is equivalent to an 8-hour average concentration of 2 mg/m3

. Based on the Stokinger (1981) data 

and the fact that one unspecified study used levels 30 times higher than advised, the TLV of 10 

mg/m3

 is recommended for Al dust (ACGIH, 1998). 

The increasing awareness of the potential neurotoxicity of Al has resulted in a number of 

investigations of the incidence of neurotoxicological symptoms in Al workers. Although 

treatment with McIntyre powder had not produced apparent adverse effects, a neurobehavioral 

evaluation of male miners (261 exposed to McIntyre powder, 346 unexposed) who started 

working between 1940 and 1979 (additional duration data not reported) was performed in 

1988-1989 (Rifat et al., 1990). There were no significant differences between exposed and 

unexposed miners in reported diagnoses of neurological disorder. Results of cognitive testing 

(Mini-Mental State Examination for general cognitive function, Ravens colored progressive

matrices test for reasoning and Symbol Digit Modalities Test for spatial perceptual accuracy and 

information processing), however, showed that the exposed group had significantly (p≤0.001) 

impaired performance on at least one test, and when all test scores were summed. Also, the 

likelihood of scores in the impaired range increased with duration of exposure. 

A neurologic syndrome was described in Al smelting plant potroom workers (White et 

al., 1992). Twenty-five men were evaluated for suspected work-related neurologic illness based 

on findings in three patients studied previously. The average duration of employment was 18.7 

years (SD, 3.6; range, 12-23 years), 15 of the patients were working at the time of evaluation, 

and 10 had taken early retirement or medical leave due to workplace-related symptoms (mean 

length of time since exposure was 1.3 years ranging from 0.2-5 years). Quantitative exposure 

level data were not reported, but 21 of the workers had been employed in the potroom prior to 

installation of fume hoods for a mean duration of 5.3 years (range 3-7 years). Symptoms most 

often reported by the patients were frequent loss of balance (88%), memory loss (84%) and joint 

pain (84%); other symptoms included dizziness (80%), numbness (80%), parasthesias (72%) and 

tremor (68%). Neurologic examinations showed mild to moderate signs of lack of coordination 

(tremor, dyssynergy of upper extremity limb movement or ataxia) in 84% of the patients. 

Neuropsychologic effects were evaluated in 21 of the patients using the Wechsler Adult 

Intelligence Scale-Revised (intellectual functioning), Wide Range Achievement Test-Revised 

(academic functioning), Halstead-Reitan Neuropsychological Test Battery (neuropsychological 

assessment) and Minnesota Multiphasic Personality Inventory (personality functioning). 

Memory function was assessed with the Wechsler Memory Scale (14 patients) and Wechsler 

Memory Scale-Revised (8 patients). The memory function evaluation showed mild to moderate 

impairment on subtests of immediate recall for verbal or visual information (70-75% of the 

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tested patients) and delayed verbal or visual recall (50-70%). Other effects included mild or 

moderate impairment on Halstead-Reitan tests of abstract reasoning and flexible thinking (42% 

of the tested patients), memory for tactile information (53%) and sustained attention and 

discrimination of tonal and speech patterns (44 and 64%, respectively). On the Wechsler 

memory and Halstead-Reitan tests, mild and moderate impairment was defined as scores 1.5-2 

and ≥2 standard deviations below the mean of the normal population, respectively. Most (89%) 

of the patients tested with the Minnesota Multiphasic Personality Inventory had abnormally 

elevated scores (≥2 SDs above the population mean) indicative of clinical depression. 

Significant positive correlations were found between severity of incoordination (signs and 

symptoms) and degree of exposure (qualitative) before the introduction of the ventilation hoods. 

White et al. (1992) noted two other studies that described neurologic problems among Al 

smelter workers. Thus, an evaluation of 444 electrolysis workers found neuropsychiatric 

changes in 123 (28%), “neurotic syndromes” in 89 (20%) and “slight pyramidal and cerebellar 

changes” in 39 (9%) (Langauer-Lewowicka and Braszczynska, 1983). In the second study, 

symptoms including mental confusion, concentration and memory problems were described in 

six potroom workers (Cawthon, 1988). 

In another study of Al production workers, neuropsychological effects were assessed in 

38 elderly men who had been exposed for at least 10 years exclusively in the potroom (n=14), 

foundry (n=8) or other manual labor departments of the same plant (n=16, control group) (BastPettersen et al., 1994). The mean ages and employment durations of the groups were in the 

ranges of 62.5-63.5 and 19.2-19.6 years, respectively. The men were examined soon after or just 

before retirement in 1991. Limited environmental monitoring data indicates that the degree of 

Al exposure varied between the subgroups and over the years. Average annual total dust 

concentrations in the potroom were reduced significantly from 9.5 mg/m3

 in 1977 to 3.0 mg/m3

in 1990. Aluminum levels were not specifically reported, but the average Al content in the total 

potroom dust was approximately 20% by weight; other constituents of the dust included fluoride 

and coal tar pitch components. Data from an Al uptake/excretion study of workers from the 

same plant indicated that the level of Al exposure was approximately 8 times higher in the 

potroom than in the foundry (0.48 and 0.06 mg/m3

, respectively) (Drablos et al., 1992). Medical 

examinations (including lung function, standard laboratory tests and serum and urine Al 

concentrations) and a neuropsychological test battery were performed. The battery assessed six 

mental functions (neuropsychiatric symptoms, motoric/sensoric, reaction time, psychomotor 

speed/efficiency, memory/learning and intelligence) using a questionnaire and 15 different 

objective tests. Some subtle deficits were found in potroom workers that were not considered to 

be indicative of a significant neurological syndrome. The findings in potroom workers included 

a subclinical tremor as indicated by results of a static steadiness test [time scores on one of two 

test indices were significantly worse in comparison with the control group (84% slower, 

p=0.03)], and possible tendencies (i.e., test results that were about 1 SD below normal mean 

values but not statistically significant) for increased risk of impaired visuospatial organization 

(Block Design subtest of the Wechsler Adult Intelligence Scale) and psychomotor tempo (one 

Halstead ReitanTrail Making test). Although these findings were not considered to be indicative 

of a neurologic syndrome, it was suggested that they may be early signs of CNS impairment. 

Additionally, the finding of a subclinical tremor seems to be consistent with the tremor and other 

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signs of incoordination observed in 84% of the patients in the White et al. (1992) study 

summarized above. 

Studies of Al welders are consistent with those of Al smelter workers in indicating that 

occupational exposure to Al can be neurotoxic. CNS function was evaluated in 17 welders who 

had an average of 15 years (range 5-27 years) experience, with the last 4 years exclusively with 

Al (Hanninen et al., 1994). Most of the welders had equipment that ventilated the welding 

masks but the respiratory protection was not always used. The assessment included 

measurements of serum and urinary Al, neuropsychological tests (simple reaction time, three 

tests for psychomotor speed, two tests for visual and spatial ability, four memory tests and two 

verbal ability tests), a symptom questionnaire and neurological interview, quantitative 

electroencephalography (QEEG) and P-300 event-related auditory-evoked responses. Serum and 

urine Al levels were 3.5 and 8.5 times higher, respectively, than an unexposed reference 

population. The welders performed normally on the neuropsychological tests, although 

correlation analysis of test scores and exposure parameters showed weak negative associations 

between the four memory tests and urinary Al level and a positive association between the 

variability (standard deviation) of visual reaction times and serum Al levels. Analysis of the 

QEEG data showed that serum Al levels were positively correlated with the amount of delta and 

theta activity in the brain frontal region and negatively correlated with the amount of alpha 

activity in the frontal region. Results of this study (disturbances of memory and attention, QEEG 

changes similar to those in patients with Al encephalopathy) were interpreted as consistent with 

known CNS effects of Al, but insufficient for establishing a definite relationship between Al 

exposure and effects. 

In another study of Al welders, CNS evaluations were performed on 38 men who had at 

least 5 years exposure (mean 17.1 years) and a control group of 44 railway track welders 

exposed to metal fumes other than Al (mean 13.8 years) (Sjogren et al., 1996). Limited 

monitoring data indicated that the median exposure to welding fumes was 10 mg/m3

 and that the 

Al content was 40% of the total fumes. Symptom questionnaires, psychological tests (simple 

reaction time, finger tapping speed and endurance, digit span, vocabulary, tracking, symbol digit 

coding, cylinders, olfactory threshold and Luria-Nebraska motor scale), neurophysiological 

indices [electroencephalography, P-300 auditory-evoked responses, brain-stem auditory evoked 

responses and diadochokinesis (ability to perform rapidly alternating movements with one limb)] 

and blood and urine Al levels were assessed. The blood and urine Al concentrations were 

approximately 3 and 7 times higher in the Al welders than in the controls, but there were no clear 

correlations between duration of exposure to Al and concentration of Al in blood or urine. The 

Al welders reported more acute CNS symptoms (e.g., concentration difficulties) and had 

decreased motor function in five tests (finger tapping in non-dominant hand, two tasks from the 

Luria-Nebraska motor scale, pegboard peg movement with dominant hand, amplitude of 

diadochokinesis in dominant hand) when compared to the control group. Urinary Al 

concentration was significantly correlated with acute CNS symptoms, but not with any of the 

performance measures. To further study possible dose-effect relationships of Al exposure, the 

Al welders were combined with the control group and divided into three exposure categories 

according to urinary Al levels, using the 50th and 75th percentiles as category dividers. The 

group with the highest mean urinary Al level had significantly more acute CNS symptoms and 

significantly reduced performance on one of the motor function tests (a Luria-Nebraska motor 

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scale task) when compared to the group with the lowest Al level. In an earlier study of 65 

welders with ≥10 years of exposure to Al fumes, the highest exposure category (based on 

exposure duration) was 2.8 times more likely than unexposed workers to have three or more 

neuropsychiatric symptoms (Sjogren et al., 1990). 

A body of epidemiological evidence has pointed to an increased incidence of cancers of 

various kinds in workers employed in the aluminum production industry. However, as discussed 

in a review by Ronneberg and Langmark (1992), the concern about potential cancer hazards in 

the aluminum industry has primarily arisen because of exposures to polycyclic aromatic 

hydrocarbons (PAHs) and coal tar pitch volatiles (CTPVs) rather than to Al per se. Thus, while 

a number of studies have provided inferential data linking occupationally exposed aluminum 

workers with an increased risk of developing tumors of the bladder or lung (Gibbs, 1985; 

Thériault et al., 1984, 1990; Armstrong et al., 1986; Spinelli et al., 1991; Pearson et al., 1993; 

Tremblay et al., 1995), it would be unwise to ascribe any excess tumor formation to the effects of 

Al in view of the concurrent exposure to well-documented carcinogenic PAHs such as 

benzo(a)pyrene. The issue is further complicated by the likely exposure of production workers 

to other substances such as fluorides, sulfur dioxide, aromatic amines and asbestos (Ronneberg 

and Langmark, 1992; Tremblay et al., 1995; Dufresne et al., 1996), and to the possible effects of 

cigarette smoking in affected individuals. Consequently, these studies have failed to provide 

direct evidence for the carcinogenicity of Al fumes and dusts. 

Animal Studies

Oral Exposure

Numerous subchronic animal studies were located in the biomedical/toxicological 

literature but only those that define the threshold region of the oral dose-response relationship are 

summarized in this paper. A major limitation of many of the studies of Al toxicity is the lack of 

complete information on total dietary (e.g., food and drinking water) intake of Al and of other 

elements that are known to effect Al biokinetics and toxicity (e.g., calcium and magnesium). 

Estimated or reported dosages used in studies in which Al content of the basal diets are not 

reported must be assumed to underestimate the actual experimental dosages. The magnitude of 

the underestimate may be considerable. For example, a range of Al contents of 200-1200 mg

Al/kg for commercial grain-based diets (Golub et al., 1992b) would provide 30-200 mg Al/kg 

bw-day in a subchronic or chronic mouse bioassay [based on U.S. EPA (1988) default values for 

body weight and food intake]. On this basis, studies in which complete dietary Al intakes were 

not reported or could not be estimated may provide some information about the hazards of oral 

exposure to Al but are inappropriate for establishing NOAELs or LOAELs for the critical effect 

of Al. NOAELs and LOAELs from studies that provide estimates of total Al dosages, or 

otherwise provide information relevant to determining the NOAEL/LOAEL boundary for the 

critical effect of Al are presented in Table 1 and are summarized below. 

Systemic toxicity 

Groups of 10 female Sprague-Dawley rats were administered aluminum nitrate 

nonahydrate in sugar-containing drinking water at doses of 360, 720 and 3600 mg/kg-day (26, 52 

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and 259 mg Al/kg bw-day, respectively) for 100 days (Domingo et al., 1987). A control group 

received sugar-containing distilled water only. Sugar had been added to the drinking water of all 

groups to reduce the taste-aversive effects of Al. The level of Al in the diet was not reported. 

Animals were housed in metabolic cages to facilitate the collection of fecal and urine samples. 

Food and water consumption were measured daily, body weights were noted weekly and blood 

samples were taken at monthly intervals and at termination to monitor clinical chemistry and 

hematological parameters. At termination, all animals were necropsied, and the weights of major 

organs (brain, heart, lungs, kidneys, liver and spleen) were monitored. Aluminum concentrations 

were measured in various tissues, pieces of which were processed for histopathological 

examination. A significant decrease (p<0.05) in body weight gain was observed in the 259 mg

Al/kg-day group, attributed by the authors to decreased food intake. Overall, no consistent 

variations in hematological (hemoglobin, hematocrit) or clinical chemistry (SGOT, SGPT, 

alkaline phosphatase, urea, creatinine, total protein, cholesterol, glucose) parameters were 

observed. No histopathological alterations in the heart, liver, kidney, spleen, brain and 

cerebellum were observed. Interpretation of these data was complicated by the concurrent 

exposure of the rats to high doses of nitrate of up to 475 times the RfD for nitrate (1.6 mg nitratenitrogen/kg-day) which is based on methemoglobinemia in humans (U.S. EPA, 1999). 

Therefore, because of nitrate co-exposure, the absence from the study design of a food-restricted 

control group and uncertainty surrounding the contribution of Al in food, the apparent effect of 

Al on body weight gain cannot be conclusively attributed to Al alone. 

Some recent studies have identified a number of potential toxicological responses in 

laboratory animals exposed orally to Al compounds in a subchronic or chronic dosing regimen. 

In most cases, however, only one dose level was employed in the study compared to controls, 

and since the amount of Al in the diet was not given, the resulting dose level represents an 

incremental dose of Al compared to that of controls as baseline. However, while these studies 

may offer inadequate quantitative dosimetric information for NOAEL/LOAEL identification and 

consequent RfD development, they provide an qualitative indication of a range of potential 

toxicological responses that might be induced in humans exposed to the element. For example, 

Garbossa et al. (1998) studied the potential for water-soluble Al to affect the erythropoietic 

integrity of late erythroid progenitor cells in the bone marrow. Three groups of five male Wistar 

rats/group were either (1) gavaged with citrate at a dose of 1.0 μm Al/g-day (27 mg/kg-day), 5 

days/week, for 15 weeks, (2) had drinking water containing 100 mmol Al/L made available to 

them as the citrate for the same length of time or (3) maintained as controls. As calculated by the 

authors, the dose associated with the applied concentration of Al in drinking water approximated 

to 14-17 μmol/g-day (420 mg/kg-day). Rats had access to a standard chow diet, though with no 

indication of the baseline concentration of Al provided therein. At the end of the in-life phase of 

the study, all rats were sacrificed, and samples of blood were obtained for hematological 

investigation. Femoral bone marrow cells were flushed with physiological medium, stimulated 

with recombinant human erythropoietin, then monitored for the comparative incidence of 

colony-forming units-erythroid (CFU-E). Further tests were carried out to monitor the osmotic 

fragility and average life-span of erythrocytes from each test group. The animals in the group 

receiving Al at the higher dose showed decreased hematocrit, hemoglobin concentration, median 

osmotic fragility and erythrocyte life-span values compared to controls. The content of Al 

increased in the serum and bone of both exposed groups, the distribution of concentrations in 

bone correlating inversely with the extent of an animal’s CFU-E development. 

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That Al in drinking water may have the ability to cause histopathological changes and 

altered hepatic enzyme activities was suggested by Basu et al. (1997) who made available 

aluminum chloride in drinking water to groups of eight male Sprague-Dawley rats at a dose of 50 

mg/kg-day (10.1 mg Al/kg-day) for 40 days. Additionally, other groups of similarly-treated rats 

received drinking water containing either 0, 50, 100, 200 or 400 ppm (mg/L) added calcium

(Ca), as the chloride. The authors reported increased specific activities of acid and alkaline 

phosphatases in liver 10,000 x g supernatants from Al-receiving animals versus controls, and in 

alkaline phosphatase activity in equivalent kidney preparations. The presence of Ca in the 

drinking water appeared to reverse these changes, plus the accompanying histopathological 

features associated with them. 

Konishi et al. (1996) examined the ability of Al and Ca to cause opposite and potentially 

harmful effects in laboratory animals, in relation to the well-documented association between Al 

and the onset of osteomalacia. Male STD Wistar rats were divided into four groups (n=4), 

receiving either (1) a normal diet (Group I), (2) a normal diet supplemented with Al (Group II), 

(3) a Ca-deficient diet (Group III) or (4) a Ca-deficient diet with supplemental Al (Group IV), for 

10 weeks. Blood samples were taken at termination, and then animals were perfused with 

paraformaldehyde/glutaraldehyde fixative. Levels of Ca, iron (Fe) and Al in serum and bone 

were measured by atomic absorption spectrophotometry, and sections of the resected right tibia 

were prepared for histopathological examination after decalcification in 5% formic acid in 10% 

formalin. 

 There were statistically-significant changes in body weight gain when those of groups 3 

and 4 were compared to animals from groups 1 and 2, the values for the latter groups remaining 

constant from about 4 weeks of dosing. In discussing their histopathological findings, the 

authors described no decrease in the thickness of cortical bone in Group II compared to control, 

while bone specimen from Groups III and IV showed “an increase in osteoid as well as

osteoblasts and osteoclasts”, in addition to other disturbances of ossification. Such effects were 

considered to suggest bone fragility, with changes being more marked in Group IV compared to 

III. The amount of Al in the tibia of exposed rats was significantly greater in Group II than in 

Group I, whereas the average levels in Groups III and IV showed a further increase in Al 

deposition, most notably in group IV. There were also differences among the groups in the 

concentration of Fe in bone (tibia), and in the concentrations of Al, Ca, Fe and the levels of 

parathyroid hormone in blood. The authors concluded that Ca deficiency appeared to potentiate 

the deposition of orally administered Al in bone, and the attendant inhibition of ossification. 

Iron deposition was also thought to play a role in the osteogenic disturbance, where Ca is 

deficient. 

A histopathological investigation indicated profound changes in the cerebrovascular and 

neuronal integrity when male Long-Evans rats (n=9) were exposed for 52 weeks to 0.5 ppm

aluminum fluoride in drinking water (Varner et al., 1998). This corresponded to an Al dose of 

0.019 mg/kg-day, based on a default drinking water consumption of 0.057 L/day, and a default 

body weight of 0.472 kg for male Long-Evans rats (U.S. EPA, 1988). Duel control groups 

received either NaF (fluoride controls) or double distilled deionized water. Tissue levels of Al 

were measured in brain, liver and kidney by the use of a direct current plasma technique. 

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Animals receiving aluminum fluoride showed poor survival compared to the other groups, with 

6/9 having died by week 48. The tissue concentrations of Al were increased in the brain and 

kidney compared to both the control groups, with Al-fluorescence being used to demonstrate that 

Al deposition was mostly in the vasculature. Morphological and histopathological changes due 

to treatment were apparent in the liver, kidney and spleen. Some changes in neuronal integrity 

were also evident in the hippocampus and neocortex. Other cytological changes in the brain 

were associated with chromatid clumping, pyknosis and vacuolation. 

A report by Somova et al. (1997) describes a study in which 10 male Wistar rats/group 

received either 0, 5 or 20 mg/kg-day aluminum chloride by gavage in water for 6 months. At 

termination, all animals were exsanguinated, then subjected to a necropsy in which excised 

pieces of liver, kidney and cardiac and skeletal muscle were taken for histopathological 

examination. Pieces of brain were examined by electron as well as light microscopy, and all 

tissues were monitored for Al concentration by atomic absorption spectrophotometry. As 

tabulated by the authors, Al in plasma and all of the listed tissues was dose-dependently 

increased to levels that were statistically significantly greater than controls. However, though 

described in qualitative terms and illustrated photographically, the Al-induced lesions did not 

receive a quantitative treatment in the report. Thus, while at least some of the low dose rats 

displayed NFD (neuro fibrillar degeneration) of the hippocampal region of the brain, insufficient 

data are provided in the report to apply this observation to the identification of a NOAEL or 

LOAEL. 

Dietary experiments 

Six Beagle dogs/sex/group were fed a diet providing either, in males, 0, 118, 317 or 1034 

mg/kg-day sodium aluminum phosphate (0, 3.4, 9.0 or 29.4 mg Al/kg-day, respectively) or, in 

females, 0, 112, 361 or 1087 mg/kg-day sodium aluminum phosphate (0, 3.2, 10.3 or 30.9 mg

Al/kg bw-day, respectively), for 6 months (Katz et al., 1984). No information was available on 

the level of Al in the diet, and no compound-related effects on body weight gain, hematological 

and clinical chemistry parameters (parameters not specified) or histopathological endpoints 

(major organs and tissues examined) were observed. A highest NOEL of 30.9 mg Al/kg-day 

could be tentatively identified in this study, but this would not include the contribution of Al 

from the basal diet, nor reflect the identification of any toxicological effects, since the NOEL 

occurred at the upper limit of the dose-response curve. 

Neurotoxicity 

A number of studies have been reported in which neurotoxicological/neurobehavioral 

effects have been explicitly evaluated. In others, the effects of Al on neurological developmental 

have been addressed. For example, Golub et al. (1989) fed diets containing Al as the lactate at 

25 (controls), 500 or 1000 mg Al/kg diet (3.3, 65 or 130 mg Al/kg-day) to groups of 15 female 

Swiss-Webster mice for 6 weeks (Golub et al., 1989). No mice were exposed to lactate alone. 

While no statistically significant differences in food intake or body weight gain were observed, 

mice fed the highest Al concentration gained less weight than the controls or low-dose group. 

As reported by the authors, a significant decrease (20%) in spontaneous motor activity (i.e., total, 

vertical and horizontal movement) was observed in the 130 mg Al/kg-day group. Activity in the 

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65 mg Al/kg-day group was not significantly different than the controls. Thus, the highest 

NOAEL is 65 mg Al/kg-day and the LOAEL is 130 mg Al/kg-day. 

 Neurobehavioral effects of aluminum lactate were evaluated in groups of 12 female 

N:NIH Swiss-Webster mice (4.5-5.5 weeks old) that were fed 25 (controls) or 1000 mg Al/g diet 

for 90 days (Golub et al., 1992a). Based on a food factor of 0.19 kg diet/kg body weight/day 

calculated using an algorithm relating food consumption to body weight (U.S. EPA, 1988) and 

reported body weight data (the time-weighted average weight is 25.4 g), the dosage in the treated 

mice is estimated to be 190 mg Al/kg bw-day. No mice were exposed to lactate alone. A 

neurobehavioral test battery used by Donald et al. (1989) was administered at the beginning of 

the experiment (day 0) and after 45 and 90 (±3) days, with motor activity evaluated at the latter 

two time points. Aluminum levels were measured in brain, femur and liver at the end of the 

exposure period. 

Body weight was significantly increased in the treated mice but no exposure-related 

changes in food intake or overt signs of neurotoxicity were observed. Results of the 

neurobehavioral tests showed significantly decreased hindlimb grip strength at 90 days, 

decreased air puff startle response at 90 days and decreased auditory startle response at 45 days 

in the treated mice. Spontaneous motor activity was reduced at 90 days as indicated by 

decreased total activity counts, horizontal activity counts and percentage of intervals with high 

activity counts. Aluminum concentrations in the brain and liver were increased approximately 

3-fold in the treated mice, but brain and liver lipid peroxidation indices were not altered. 

Male Wistar rats (6-8 per group) were exposed continuously for 6 months to food 

containing 1.52 mg Al/kg (normal diet) or 1000 mg Al/kg as aluminum chloride with citrate 

(Florence et al., 1994). The average daily Al intake was estimated to be 0.13 or 84 mg Al/kg 

bw-day, assuming a body weight of 0.305 kg (arithmetic mean of default mature weight of male 

Wistar rats and the starting weight in this study of 0.11 kg) and a food intake of 0.026 kg food/kg 

bw-day, calculated using an algorithm relating food intake to body weight (U.S. EPA, 1988). 

The citrate content of the diet was in a 1:1 stoichiometric proportion to Al, therefore, the 

estimated daily intake was 598 mg/kg-day. Rats exposed to Al developed histopathological 

abnormalities in brain tissue, not specific to any brain region, characterized by extensive 

cytoplasmic vacuolization in astrocytes, swelling of astrocytic processes, particularly of astrocyte 

end-feet abutting blood vessels. Neurons also exhibited vacuolization and nuclear inclusions. 

Although no specific behavioral assays were reported, the investigators noted that "no significant 

behavioral changes were observed". Accordingly, the functional significance of the 

histopathological lesions is uncertain. The lesions appear to differ from the NFD observed with 

parenteral Al exposures (Kowall et al., 1989; Wakayama et al., 1993); or from exposures to Al in 

combination with calcium deprivation (Garruto et al., 1989; Kihira et al., 1995; Mitani, 1992). 

The LOAEL for histopathological changes in the brain was 84 mg Al/kg-day. 

Male Sprague-Dawley rats (40 per group) were exposed in drinking water to 0, 50 or 100 

mg Al/kg bw-day as aluminum nitrate with citric acid for 6.5 months beginning at 21 days of 

age, 8 months of age or 16 months of age (Domingo et al., 1996). The citric acid dosage was 

355 or 710 mg/kg-day in the 50 or 100 mg Al/kg bw-day groups, respectively. Controls did not 

receive citric acid. Dietary Al intake was not reported; the rats were maintained on Panlab rat 

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chow. Animals from control and exposed groups were subjected to a number of neurobehavioral 

tests, and at termination, Al levels were measured in various excised regions of the brain. The 

authors observed the highest Al levels in the olfactory bulb and rhachidical bulb, while the cortex 

and thalamus were the regions showing the lowest Al content. However, compared to controls, 

there were no significant effects (p>0.05) of Al (with citric acid) on spontaneous motor activity 

(open-field) or passive avoidance operant training or performance (grid floor shock, light/dark 

shuttle box). Thus, the NOAEL was 100 mg Al/kg-day with citric acid; although this does not 

include the Al contribution from food. This study is listed on Table 1 because the NOAEL, 

although probably underestimated because of unreported Al intake from food, is still lower than 

the LOAELs from other studies. 

Groups of six male albino rats were administered 0 or 25 mg Al/kg bw-day as aluminum 

nitrate in normal saline by gavage, 10% ethanol in drinking water, or 25 mg Al/kg bw-day by 

gavage combined with 10% ethanol in drinking water, 6 days/week for 6 weeks (Flora et al., 

1991). The level of Al in the diet was not reported. Urinary ∆-aminolevulinic acid (ALA), 

blood ALA-dehydratase (ALAD), blood zinc protoporphyrin (ZPP), glutamic oxaloacetic 

transaminase (GOT) and glutamic pyruvic transaminase (GPT) in serum and liver and brain 

biogenic amines and their metabolites [dopamine (DA), norepinephrine (NE), 

5-hydroxytryptamine (5-HT), homovanillic acid (HVA) and 5-hydroxyindolacetic acid 

(5-HIAA)] were evaluated at the end of the treatment period. Treatment with Al alone caused 

significantly increased blood ALAD (p<0.01), decreased liver GPT (p<0.05), decreased brain 

DA (p<0.01), increased brain NE (p<0.05) and decreased brain 5-HT (p<0.05). Compared to 

treatment with Al alone, concurrent exposure to ethanol and Al produced significantly decreased 

ALAD, increased ALA, increased ZPP, increased liver GPT, increased serum GOT and 

increased brain HVA. Significant changes found only in the combined Al and ethanol group 

included increased serum GPT, increased brain NE and decreased brain 5-HT. Treatment with 

ethanol alone only inhibited blood ALAD. The rats were co-exposed to relatively high levels of 

nitrate [comparable to those in the Domingo et al. (1987) subchronic study], but it seems likely 

that some of the changes (i.e., effects on brain chemicals) are related to aluminum which is 

known to be neurotoxic. Because the toxicological significance of the changes is unclear due to 

lack of evaluation of neurobehavioral performance and other endpoints, there is uncertainty 

whether the 25 mg Al/kg-day dose is a NOAEL or a LOAEL, an uncertainty compounded by the 

absence of information about the level of Al in the basal diet. 

Reproductive/developmental toxicity 

A number of studies have been carried out to examine the effects of Al compounds on 

developmental toxicity, particularly their effects on postnatal neurobehavioral development. For 

example, Bernuzzi et al. (1989) exposed groups of 6-12 pregnant Wistar rats to aluminum

chloride or aluminum lactate in the diet on gestational days 1 through 21. The rats received 

nominal daily doses of 0, 100, 300, 400 mg Al/kg as aluminum chloride or 0, 100, 200 or 400 mg

Al/kg as aluminum lactate. No rats were exposed to lactate alone, and information regarding 

level of Al in the basal diet was not reported. On the average, there was a less than 10% 

decrease in maternal body weight gain and no effect on food or water intake. No significant 

difference in litter size was observed. However, postnatal mortality increased 55% and 26% in 

offspring of the rats exposed to 300 or 400 mg Al/kg-day, respectively. The offspring of dams

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fed ≥300 mg Al/kg-day weighed significantly less than controls on postnatal day 1. Decreased 

body weight was also observed on postnatal days (PD) 4 and 14 in the offspring of rats fed 400 

mg Al/kg-day as aluminum lactate. The following tests were used to assess neuromotor 

development (maturation): righting reflex, grasping reflex, negative geotaxis, suspension test 

and locomotor coordination. The tests were performed on PDs 4, 6, 9, 12 and 20, respectively. 

Impairment of neuromotor development (righting and grasping reflexes) was observed in the 

pups exposed to ≥200 mg Al/kg-day. Impaired grasping reflex was also observed in the 100 

mg/kg-day aluminum lactate group. Offspring of rats fed 400 mg/kg-day also exhibited altered 

performance on the locomotor coordination test. 

A follow-up study by the same research group found that ingestion of 400 mg Al/kg bwday as aluminum lactate had no effect on postnatal mortality, body weight and righting and 

grasping reflex tests (Muller et al., 1990), although significant differences between control and 

exposure groups were noted in locomotor coordination and operant conditioning tests. 

Significant differences between controls and exposed groups in the negative geotaxis test were 

limited to those pups of dams treated during the second and third weeks of gestation, a finding 

interpreted by the authors to indicate the possibility of long-term effects on the central nervous 

system of trans-placenta exposure to Al during a later organogenic phase. According to Muller 

et al. (1990), the contradictions between this and their earlier study (Bernuzzi et al., 1989) could 

be related to environmental modifications. In particular, the mothers and pups were much more 

protected in the Muller et al. (1990) study than in the previous one because they were housed in 

plastic cages instead of wire mesh cages and received cotton to build nests. Body temperature of 

the pups, therefore, may have been more adequately maintained in the Muller et al. (1990) study. 

As discussed in this study, toxicity in pups can be confounded by insufficient body temperature, 

and delayed pup weight gain could explain the differences in neuromotor performance. 

Muller et al. (1990) administered diets supplemented with 0 or 400 mg Al/kg bw-day as 

aluminum lactate to groups of 6-9 pregnant Wistar rats on days 1-7, 1-14 or 1-21 of gestation. 

No rats were exposed to lactate alone, and information regarding level of Al in the basal diet was 

not reported. Neuromotor development was assessed on postnatal days 4, 6, 9, 12 and 20 using 

tests of righting reflex, grasping reflex, negative geotaxis, suspension and locomotor 

coordination, respectively. Learning ability was also tested on PD 65 using operant 

conditioning. No effects on maternal body weight or food intake were observed in dams exposed 

on gestational days 1-7 or 1-14. In the dams exposed on gestational days (GD) 1-21, a 

significant decrease in maternal body weight (26 and 35%, respectively) was observed on days 

16 and 19 of gestation. Decreased food intake was also observed on day 19 of gestation. No 

effects on litter size, postnatal mortality or postnatal body weight were observed. Impairment of 

neuromotor development (p<0.05) was observed in two of the five tests (negative geotaxis and 

locomotor coordination); no differences between the three treated groups were observed. For the 

operant conditioning test, there were significant differences (p<0.05) between the treated and 

control young rats. No differences between the three treated groups were observed. The 

LOAEL for developmental toxicity is 400 mg Al/kg-day, but this does not include the 

contribution of Al from the basal diet. 

Groups of 10 pregnant Sprague Dawley rats were administered 180, 360 or 720 mg/kgday aluminum nitrate nonahydrate by gavage (13, 26, 52 mg Al/kg bw-day) on GDs 6-14 

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(Paternain et al., 1988). A vehicle (water) only control group was used. The level of Al in the 

diet was not reported. Aluminum exposed dams gained significantly less weight than the 

controls. No significant effects on the numbers of litters, corpora lutea, total implants, live 

fetuses, resorptions or runt fetuses were observed. Significant decreases in fetal body weight and 

tail length were observed at all three Al doses; decreased fetal body length was also observed at 

the 52 mg Al/kg-day dose level. No dose-related external or visceral malformations were 

observed in the offspring. However, a significant increase in the incidence of skeletal 

malformations (delayed ossification, hypoplastic deformed ribs) was observed at all three 

treatment levels. In addition, the incidence of hematomas was significantly increased at the high 

dose. Because the rats were co-exposed to relatively high levels of nitrate [comparable to those 

in the Domingo et al. (1987) subchronic study], the effects of treatment cannot be conclusively 

attributed to Al alone, in the absence of a nitrate-exposed control group. 

By contrast to the striking findings of potentially teratogenic effects of aluminum nitrate 

in Sprague-Dawley rats, as described above (Paternain et al., 1988), equivalent experiments by 

Domingo et al. (1989) in Swiss mice did not reveal any reproductive, developmental or 

teratogenic effects of Al, when administered to dams as the hydroxide. Domingo et al. (1989) 

administered by gavage 0, 66.5, 133 or 266 mg/kg-day aluminum hydroxide (0, 23.9, 47.8 or 

95.5 mg Al/kg bw-day) to groups of 20 pregnant Swiss mice on GD 6-15. The level of Al in the 

diet was not reported. The dams were killed on GD 18. No compound-related effects were 

observed on maternal mortality, clinical signs, body weight, food intake or absolute or relative 

heart, lung, spleen, liver, kidney and brain weights. In addition, no compound-related effects 

were observed on numbers of implantations, resorptions, live and dead fetuses, sex ratio and the 

incidences of external malformations, internal soft-tissue defects or skeletal abnormalities. 

Therefore, this study identifies a NOEL of 95.5 mg Al/kg-day by default for reproductive, 

developmental and teratogenic toxicity in mice. However, neuromotor development was not 

assessed and the contribution of Al from the basal diet was not stated in the report. 

A number of studies have been designed to evaluate the influence of citrate or lactate on 

the potential developmental toxicity of Al. For example, Gomez et al. (1991) exposed groups of 

15-19 pregnant Sprague-Dawley rats to either distilled water (controls) or 133 mg Al/kg bw-day 

in the form of either aluminum hydroxide (384 mg/kg-day), aluminum citrate (1064 mg/kg-day) 

or aluminum hydroxide (384 mg/kg-day) concurrent with citric acid (62 mg/kg-day) by gavage 

on GD 6-15. The level of Al in the diet was not reported and no rats were exposed to citric acid 

alone. Terminations were performed on GD 20. Maternal and fetal evaluations showed 

exposure-related effects only in the group exposed to aluminum hydroxide and citric acid 

concurrently. Significant changes included reduced maternal body weight gain on GDs 6-20 (but 

not at sacrifice on day 20), reduced fetal body weight and some skeletal variations (increased 

delayed occipital and sternebrae ossification and increased absence of xiphoides). No effects 

were seen on maternal food consumption or clinical signs, maternal absolute or relative liver, 

kidney or brain weights, gravid uterine weight, corpora lutea/dam, implantations/litter, pre- or 

postimplantation loss/litter, viable or nonviable implants/litter, fetal sex ratio or fetal 

malformations (external, visceral or skeletal). This study identified a stand alone minimum

LOAEL of 133 mg Al/kg-day for non-neurobehavioral developmental toxicity of aluminum

hydroxide and aluminum citrate in rats. Although confidence in this LOAEL is low (because 

aluminum hydroxide administered concurrently with citric acid induced did developmental 

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effects and because the dose does not include a contribution of Al from the basal diet) the value 

is consistent with the developmental NOAEL of 95.5 mg Al/kg-day for aluminum hydroxide in 

mice (Domingo et al., 1989). 

In a similar experimental protocol, groups of 11-13 pregnant female Swiss albino (CD-1) 

mice were administered 57.5 mg Al/kg bw-day as either aluminum hydroxide (166 mg/kg-day), 

aluminum lactate (627 mg/kg-day) or aluminum hydroxide (166 mg/kg-day) concurrent with 

lactic acid (570 mg/kg-day) by gavage on gestation days 6-15 (Colomina et al., 1992). Other 

groups were treated with lactic acid alone (570 mg/kg-day, equivalent to the amount in 627 

mg/kg of aluminum lactate) or distilled water (controls). The level of Al in the diet was not 

reported. Fetal evaluations were performed on GD 18, including examinations for skeletal and 

visceral abnormalities in approximately two-thirds and one-third of the pups, respectively. The 

investigators noted that the dose of Al (57.5 mg/kg-day) is equivalent to ingestion of 3.5 g 

Al/day by a 60 kg person, which is higher than the usual quantities of Al ingested therapeutically 

for peptic disorders. Maternal body weight gain was significantly lower than control values in 

the aluminum lactate-treated mice when evaluated over GDs 6-9 (92%), 6-12 (55.6%) and 0-18 

(38.5%) and in the mice treated with combined aluminum hydroxide and lactic acid evaluated 

over GDs 6-12 (37.8%), 6-15 (42.7%) and 0-18 (15.7%). The decreased maternal weight gain in 

the aluminum lactate group was accompanied by significantly reduced food consumption during 

gestation days 6-18. Significant developmental and/or teratological effects in the aluminum 

lactate group included 16% reduced fetal body weight (p<0.01) and increased incidences of cleft 

palate (13.2%, p<0.05), dorsal hyperkyphosis (i.e., excessive flexion of spine) (13.5%, p<0.05) 

and delayed parietal ossification (15.4%, p<0.01). These developmental effects were not 

observed in any of the control or aluminum hydroxide exposed pups, and the only other 

significant changes in the other groups were decreased maternal relative liver weight and delayed 

fetal parietal ossification in the lactic acid only exposure group. Other types of internal or 

skeletal malformations or variations were not found in any of the fetuses. Additionally, no 

effects were seen on maternal absolute or relative kidney weight, gravid uterine weight, numbers 

of implantation sites/litter, live or dead fetuses, resorptions, postimplantation loss/litter, litters 

with dead fetuses or fetal sex ratio in any of the groups. By analogy to the findings of the 

Domingo et al. (1989) and Gomez et al. (1991) studies, the lack of developmental effects of 

aluminum hydroxide at the tested dose could be related to low solubility and absorption. 

In a more recent study, pregnant Swiss mice were administered gavage doses of 0 or 104 

mg Al/kg bw-day as aluminum hydroxide on days 6-15 of gestation (Colomina et al., 1994). 

Dietary Al intake was not reported; the mice were maintained on Panlab rodent chow. 

Compared to controls, there were no effects (p>0.05) of Al on maternal body or organ weight, 

number of implantations per litter, number of resorptions per litter, number of dead fetuses per 

litter, percentage of positive post-implantation loss, sex ratio or fetal body weight per litter. 

Gross external, visceral or skeletal examination of fetuses revealed no abnormalities or

developmental variations. Thus, the NOAEL for development effects from this study is 104 mg

Al/kg-day, however, this does not include the Al contribution from food. Thus, based on this 

study and the previous study (Colomina et al., 1992), aluminum lactate appears to be more potent 

as a developmental toxicant in mice than the less water soluble aluminum hydroxide. 

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Groups of 16 pregnant Swiss-Webster mice were fed 25 (control group), 500 or 1000 mg 

Al/kg diet as aluminum lactate throughout gestation and lactation (Donald et al., 1989). The 

control diet was fed to pups that were selected for post-weaning neurobehavioral assessment. 

Reported maternal doses were 5, 100 and 200 mg Al/kg bw-day at the beginning of pregnancy 

and 10.5, 210 and 420 mg Al/kg bw-day near the end of lactation. No mice were exposed to 

lactate alone. There were no treatment-related changes in maternal survival, body weight 

(measured on GD 0 and 16 and PDs 0, 5, 10, 15 and 20), food intake, toxic signs or 

neurobehavior (evaluated after pups were weaned at PD 21 using the same test battery used for 

the pups and described below), or on litter size or postnatal growth and development in pups as 

assessed by body weight, toxic signs on PDs 0-55, and by crown-rump length on PDs 0 and 20. 

Neurobehavioral maturation was tested in two pups per litter on PDs 8-18 with a 12-item test 

battery (fore- and hindlimb grasp, fore- and hindpaw placement on sticks of 2 widths, vibrissa 

placing, visual placing, auditory and air puff startle, eye opening and screen grasp, cling and 

climb). A neurobehavioral test battery was administered to six pups per litter at age 25 days (4 

days postweaning) or 39 days (fore- and hindlimb grip strengths, temperature sensitivity of tail, 

negative geotaxis, startle reflex to air puff and auditory stimuli) or age 21 and 35 days (foot 

splay). The pre-weaning neurobehavioral testing showed that a significant (p=0.007) number of 

pups in the high dose group had impaired vertical screen climb performance. The postweaning 

neurobehavioral assessment showed significantly (p<0.05) altered performance on several tests. 

These included decreased forelimb grip strength at age 39 days in the low dose group, increased 

hindlimb grip strength at age 25 days in both low and high dose groups, increased foot splay 

distance at age 21 days in both low and high dose groups and at age 35 days in the low dose 

group, and increased forelimb grip strength at age 25 days and decreased thermal sensitivity at 

age 25 and 39 days in the high dose group. There were no treatment-related changes in 

concentrations of Al in pup liver or bone (brain tissue was not analyzed). 

In a more recent study of similar design by the same group of investigators, groups of 14 

and 9 female Swiss Webster mice (6-8 weeks old) were fed 25 (control) or 1000 mg Al/g diet as 

aluminum lactate, respectively, during gestation and lactation (Golub et al., 1992b). The 1000 

mg/g concentration was selected based on the demonstration of neurobehavioral effects in 

weanlings at this level (Donald et al., 1989). No mice were exposed to lactate alone. Using food 

intake and body weight values estimated from reported data, maternal doses are estimated to be 

approximately 4.3 and 174 mg Al/kg bw-day at the beginning of gestation and 4.8 and 607 at the 

end of the lactation period. At birth, litters were fostered either within or between groups to 

provide four groups of offspring that were exposed to excess Al via maternal diet during 

gestation, lactation, both or neither (i.e., 25 ppm during gestation and lactation, 1000 ppm during 

gestation and 25 ppm during lactation, 25 ppm during gestation and 1000 ppm during lactation, 

and 1000 ppm during gestation and lactation). Maternal effects included significantly (p≤0.015) 

reduced (10-12%) body weight gain and food intake in the treated group during late pregnancy 

and lactation, and signs of neurotoxicity (hindlimb splaying and dragging) in one treated dam at 

postnatal day 21 (weaning); this dam had seizures and died 4 days later. No treatment-related 

effects on litter size, birth weight, crown-rump length, righting ability at birth, sex ratio or 

postnatal survival were observed. Both gestation-only and lactation-only exposure caused 

significantly (p<0.05) decreased body weight gain in the treated pups beginning on postnatal day 

10; combined gestation and lactation exposure produced the greatest decrease (approximately 

24% at weaning). Neurobehavioral testing using the same battery as Donald et al. (1989) was 

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performed at weaning on the dams and on a total of 12, 16, 12 and 6 pups (1 male and 1 female 

pup per litter) from the control, gestation-only, lactation-only and combined gestation and 

lactation groups, respectively. Results of this testing showed effects only in pups, including 

significantly decreased forelimb grip strength after gestation-only exposure, increased hindlimb 

grip strength after both gestation and lactation exposure, decreased temperature sensitivity after 

lactation-only exposure, and longer negative geotaxis latency after lactation-only exposure. In 

general, the findings of this study are consistent with those of Donald et al. (1989) in showing 

neurodevelopmental effects at the 1000 mg/kg dietary concentration, although intake dosages are 

dissimilar at the end of lactation. Using the dosage at the beginning of gestation, this study 

defines a LOAEL of 174 mg/kg-day for developmental effects. 

The Donald et al. (1989) study differs from that of Golub et al. (1992b) in that offspring 

were not fostered, were tested at a later age (25 vs. 21 days), were allowed 4 days of recovery 

from the treated diet prior to testing, participated in other behavioral tests currently, and 

experienced no growth retardation. The effects found only in the cross-fostered groups in the 

Golub et al. (1992b) study (lower forelimb strength after gestation exposure and altered negative 

geotaxis latencies after lactation only exposure) were not observed by Donald et al. (1989). 

Increased footsplay was observed by Donald et al. (1989) but not by Golub et al. (1992b), 

perhaps due to an opposing effect of smaller pup body size in this study. Neither gestation or 

lactation exposure affected pup brain or liver Al concentrations, but lactation exposure caused 

significantly lower manganese and iron concentrations in liver and manganese concentrations in 

brain. 

In a further extension of the two previous studies (Donald et al., 1989; Golub et al., 

1992b), pregnant female Swiss-Webster mice were exposed continuously to a semi-purified diet 

containing 7 (control), 500 or 1000 mg Al/kg from the time of conception, through pregnancy 

and lactation (Golub et al., 1995). At weaning, pups were exposed to the same Al diet as their 

mothers (500 or 1000 mg Al/kg) until they were 150-170 days of age or were switched to the 

control diet (7 mg Al/kg) for the same time period. Based on reported dosages in previous 

studies by the same investigators, estimated daily dosages for mice exposed to 1000 mg Al/kg 

diet were as follows: 200 mg/kg bw-day in pregnant mice, 420 mg/kg-day in lactating mice and 

130 mg/kg-day in offspring (Golub et al., 1994); doses for the mice exposed to 500 mg Al/kg 

diet were assumed to be approximately half of that of mice fed 1000 mg Al/kg, or 100 mg/kgday in pregnant mice, 210 mg/kg-day in lactating mice and 65 mg/kg-day in offspring. 

Compared to the control diet, the Al diet had no effect on dam weight, gestation length, litter 

size, pup weight, offspring growth or organ weights. Operant conditioning (nose poke) of 

offspring for delayed spatial alternation or discrimination reversal tasks was initiated at 50 days 

of age and continued 5 days/week for a total of 35 sessions. A neurobehavioral test battery was 

conducted when the offspring were 150-170 days of age (forelimb and hindlimb grip strength, 

temperature sensitivity, negative geotaxis, air puff and auditory startle response). Maternal and 

pre-weaning exposure to 500 mg Al/kg significantly affected (p<0.05) operant training in the 

offspring, but not performance after training in delayed spatial alternation or discrimination 

reversal tasks (i.e., decreased number of training sessions to achieve the training criteria). This 

exposure also significantly decreased forelimb and hindlimb grip strength and puff startle 

response (p<0.05). Pre-weaning and combined pre- and post-weaning exposure to 1000 mg

Al/kg significantly increased (p<0.05) incidence of cagemate aggression at the time behavioral 

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testing. No effects were observed on auditory startle response, temperature sensitivity or 

negative geotaxis in offspring. Histopathological examination of the brain and spinal cord 

revealed no treatment-related changes. Thus, the LOAEL for combined maternal and preweaning exposure on neurobehavioral effects in mice would approximate to 100 mg Al/kg-day 

(estimated daily maternal dosage). 

Pregnant Charles River CD rats were administered gavage doses of 0, 250, 500 or 1000 

mg Al/kg bw-day ("experiment A") or 0, 5, 25, 50, 250 or 500 mg Al/kg bw-day ("experiment 

B") as aluminum lactate in distilled water on GDs 5-15 (Agarwal et al., 1996). Dietary Al intake 

was not reported. Offspring were examined for body weight, anogenital distance, oestrus cycle 

regularity (after puberty), duration of pseudopregnancy induced by mechanical stimulation of the 

cervix, oocyte production induced by an injection of human chorionic gonadotropin, and male 

and female gonad weights. Aluminum had no effect on litter size and no consistent effects on 

birth weight were observed. For example, birth weights were decreased in male offspring from

dams that received 250 mg Al/kg-day, but not at higher dosages, and the effect was observed 

only in experiment A. Female offspring birth weights decreased at certain dosage levels in 

experiment A and increased at these same dosage levels in experiment B. Similar 

inconsistencies between experiment A and B were observed for gonadal weights, anogenital 

distance, time to puberty (vaginal opening), duration of pseudopregnancy or numbers of 

superovulated oocytes. A significantly increased (p<0.05) number of abnormal oestrus cycle 

lengths (defined as less than 4 days or greater than 5 days) occurred in offspring from dams that 

received 250 mg Al/kg-day (in experiment A, the endpoint was not measured in experiment B). 

However, the effect was most pronounced in the first three oestrus cycles (of five observed) and 

not detected by the 5th cycle. Thus, the NOAEL for temporary disturbance of the oestrus cycle 

in offspring of dams administered Al is 250 mg Al/kg-day. NOAELs for all other reproductive 

endpoints in this study were 1000 mg Al/kg-day. These NOAELs do not include the 

contribution of Al in food. 

In a three-generation study, Ondreicka et al. (1966) exposed initial groups of seven 

female and three male Dobra Voda mice to either 0 or 19.3 mg Al/kg bw-day as aluminum 

chloride in drinking water. The diet also contained 160 to 180 ppm Al, giving an estimated 

intake of 27-31 mg/kg-day based on default values for food consumption and body weight for 

chronic exposure of mice (U.S. EPA, 1988). Using this estimate, the total Al intakes (drinking 

water and food) were 27 mg/kg-day (controls) and 46.3 mg/kg-day (exposed group). The P0

group produced three litters (designated F1a, F1b and F1c) and the F1a group produced two litters 

(designated F2a and F2b) from which the weanlings were exposed to Al in the drinking water 

starting at 4 weeks of age. There was no difference in body weight gain among the groups in the 

P0 generation, a result that contrasted with the striking decrease in this parameter in the treated 

F1b, F1c, F2a and F2b groups. Though no effects on erythrocyte count, hemoglobin levels or 

histopathology of the liver, spleen and kidneys were observed in the P0, F1 or F2 generations at 

the end of the study and no significant differences were seen in the number of litters or offspring 

between the exposed and control groups, the study identified a LOAEL of 46.3 mg Al/kg-day, 

based on the observed changes in body weight gain. 

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Other toxicological effects of aluminum 

In a study designed to determine the effects of oral Al exposure on susceptibility to 

bacterial infection, female Swiss-Webster mice (13-14 per group) were exposed to a diet 

containing 25 (control), 500 or 1000 mg Al/kg as aluminum lactate during pregnancy, through 

lactation and for 10 days following weaning of the pups (Yoshida et al., 1989). Based on 

reported dosages in previous studies by the same investigators, estimated daily dosages for mice 

exposed to 1000 mg Al/kg diet are as follows: 200 mg/kg-day during pregnancy and 420 mg/kgday during lactation; doses for the mice exposed to 500 mg Al/kg diet are assumed to be 

approximately half of that of mice fed 1000 mg Al/kg, or 100 mg/kg-day in pregnant mice and 

210 mg/kg-day in lactating mice (Golub et al., 1994). At weaning, dams and pups were 

inoculated with a tail vein injection of Listeria monocytogenes and monitored for mortality for 

10 days. In a separate experiment, female mice, 6 weeks of age, were exposed to the same

dietary Al levels for 6 weeks and then inoculated with L. monocytogenes. Estimated Al dosages 

were 5, 98 or 195 mg Al/kg bw-day for the 25, 500 or 1000 mg Al/kg dietary levels, 

respectively, based on a default food factor of 0.195 kg diet/kg bw-day assuming a reference 

"subchronic" food intake and body weight for female B6C3F1 mice over the period from

weaning to 90 days (U.S. EPA, 1988). Inoculation resulted in significantly greater (p<0.025) 

mortality in dams exposed to 500 or 1000 mg Al/kg diet compared to controls. There were no 

differences in mortality between the groups of inoculated pups or between groups of inoculated 

adult mice exposed to Al for 6 weeks. The LOAEL for pregnant mice was 100 mg Al/kg bw-day 

and the NOAEL for adult, non-pregnant mice was 195 mg Al/kg bw-day. Although the exposure 

duration in this study was only 7 weeks, it is included in Table 1 because it provides the only 

dose-response data on the effects of Al on resistance to pathogens. 

Carcinogenicity studies 

Schroeder and Mitchener (1975a) exposed 52 Long-Evans rats/sex/group to 0 or 5 ppm 

Al as potassium aluminum sulfate in drinking water for life. Based on default values for 

drinking water consumption and body weight for this strain of rat in a chronic study (U.S. EPA, 

1988), these values are equivalent to Al doses of 0.472 and 0.67 mg/kg-day, for males and 

females, respectively. Study endpoints included body and heart weight; serum glucose, 

cholesterol and uric acid; and urinary protein, glucose and pH. All animals were necropsied at

the time of natural death, and histological examinations were carried out on heart, lung, kidney, 

liver, spleen and gross tumors, for approximately 50% of the animals in the group. The only 

remarkable finding was a significant increase (p<0.005) in gross tumor incidence in exposed 

male rats [13/25 (52%) compared to 4/26 (15%) in controls], although the tumor sites were not 

reported. Six of the tumors in the exposed males (46% of total) were considered malignant 

compared to two malignant tumors (50% of total) in the male controls. There were no 

significant differences in tumor incidences between exposed and control females. 

In another study by the same investigators, 54 Swiss mice/sex/group were exposed to 

drinking water containing 0 or 5 ppm Al as aluminum potassium sulfate for life (Schroeder and 

Mitchener, 1975b). Based on default values for drinking water consumption and body weight for 

B6C3F1 mice in a chronic study (U.S. EPA, 1988), these values approximate to Al doses of 1.2 

mg/kg-day in both males and females. Study endpoints included body weight, gross pathology, 

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and some limited histology of the heart, lung, liver, kidney and spleen. The incidences of gross 

tumors were 15/41 (36.6%) and 11/38 (28.9%) in exposed and control males, respectively, and 

19/41 (46.3%) and 14/47 (29.8%) in exposed and control females, respectively, differences that 

did not achieve statistical significance by Fisher’s exact test, although incidences of multiple 

tumors and lymphoma leukemia were considered by the authors to be significantly increased in 

females (p<0.025 and p<0.05, respectively). However, a definitive assessment of aluminum 

carcinogenicity in both this and the rat study (Schroeder and Mitchener, 1975a) is precluded by 

the limitations of the pathology examinations and reporting. 

In a more recent study, the tumorigenic potential of aluminum potassium sulfate was 

assessed in B6C3F1 mice chronically exposed in the diet (Oneda et al., 1994). Sixty 

animals/sex/group were fed a diet containing 0, 1.0, 2.5, 5.0 or 10.0% (w/w) for 20 months. 

These concentrations of aluminum potassium sulfate (as the dodecahydrate) are equivalent to 0, 

569, 1422, 2844 and 5687 ppm Al. Using food factors calculated with an algorithm relating food 

consumption to body weight (U.S. EPA, 1988) and body weight data estimated from growth 

curves reported by the investigators, the dosages of aluminum are estimated to be 0, 95, 237, 483 

or 1024 mg Al/kg-day in males and 0, 97, 242, 512 or 1110 mg Al/kg-day in females. Clinical 

signs, food consumption, and body weight were evaluated weekly. Hematology, clinical 

chemistry or urine endpoints were not assessed. Necropsies that included organ weight 

measurements and comprehensive histological examinations (including brain) were performed 

on all animals, including those that died during the course of the study. Survival rates were 

higher than control values in all treated male and female groups, ranging from 86.7-95.0% 

compared to 73.3% in males and 86.7-91.7% compared to 78.3% in females. No changes in 

food consumption were observed, but body weight gain was increased in both sexes at 95-97 and 

237-242 mg Al/kg-day (weights were 10-23% higher than controls at end of study), was similar 

to controls in both sexes at 483-512 mg Al/kg-day, and decreased in both sexes at 1024-1110 mg

Al/kg-day (11-16% lower than controls at end of study). There were no exposure-related 

increased incidences of tumors, other proliferative lesions or non-neoplastic lesions. In fact, the 

incidence of spontaneous hepatocellular carcinomas was significantly decreased in males at 1024 

mg Al/kg-day (5.5% compared to 20.5% in controls, p<0.01). 

Inhalation Exposure

Groups of 20 weanling Fischer 344 rats/sex and 20 weanling Hartley guinea pigs/sex 

were exposed to 0, 0.25, 2.5 or 25 mg/m3

 aluminum chlorhydrate [Al2(OH)5Cl≥x(H2O)] for 6 

hours/day, 5 days/week for 6 months (Steinhagen et al., 1978). Analysis of the aluminum 

chlorhydrate by the investigators showed it to contain 24.5% Al, indicating that the animals were 

exposed to 0, 0.061, 0.61 and 6.1 mg Al/m3

. Body weights were measured weekly for the first 8 

weeks and biweekly thereafter. At the end of the exposure period, 10 animals (5/sex) of each 

species were sacrificed for organ weight measurements (heart, lung, liver, kidney, spleen and 

brain) and histological examination of the lungs, liver and kidney. In addition, comprehensive 

histological examinations were performed on animals in the control and 6.1 mg AL/m3

 groups. 

The remainder of the animals was used for hematology evaluation (RBC, WBC, hematocrit and 

hemoglobin) and Al measurements in blood and tissues. Apparent effects of Al included 

multifocal granulomatous pneumonia in both species at ≥0.61 mg Al/m3

, significantly increased 

absolute and relative lung weights in both species, and decreased body weight gain in rats and 

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minimal lung edema in guinea pigs at 6.1 mg Al/m3

. The granulomatous reaction was 

characterized by foci of giant vacuoled particle-containing macrophages in the lungs and 

macrophages that did not appear to contain vacuoles or other evidence of phagocytized material 

in the peribronchial lymph nodes. There was a significant dose-related accumulation of Al in the 

lungs of both species at ≥0.061 mg Al/m3

. However, a NOAEL of 0.061 mg/m3 could be 

identified for the onset of compound-induced histopathological effects. 

In other studies, groups of 14-30 guinea pigs, rats and hamsters were exposed to fine 

metallic Al powders (pyro, atomized and flaked) at concentrations of 15, 30, 50 or 100 mg

powder/m3

 air for 6 hours/day, 5 days/week for 6 months (Gross et al., 1973). Alveolar 

proteinosis occurred in exposed animals of all three species after 2 months of exposure, but 

fibrosis or other pulmonary changes did not develop. Similarly, groups of 23 or 46 rats and 48 

hamsters were exposed to undetermined concentrations of Al fumes or Al powder (20% Al, 80% 

Al(OH)3) for morning hours only or morning and afternoon for up to 20 months (Christie et al., 

1963). Effects were similar for both forms of Al in both species, including initial increased 

alveolar macrophage proliferation followed by nodular hyalinized areas, with development of 

pneumonia but no fibrosis. 

Exposure to 2.18 mg Al fibers/m3

 for 6 hours/day, 5 days/week for up to 86 weeks 

produced slightly increased alveolar macrophages and some irritation of the nasal passages in a 

group of 50 Alderly Park rats (Pigott et al., 1981). Finally, a study by Drew et al. (1974) 

observed the development of granulomatous nodules also developed in male hamsters that were 

exposed to 8 mg Al/m3

 of Alchlor (a propylene glycol complex of aluminum-chloride-hydroxide) 

for 6 hours/day, 5 days/week for 20 or 30 exposures. The alterations persisted at the longest post 

treatment observation (6 weeks) and consistently developed at the bifurcation of the 

bronchioloalveolar ducts, which is a likely site of particulate deposition. 

DERIVATION OF A PROVISIONAL CHRONIC RfD 

FOR ALUMINUM 

This survey of the toxicological effects of Al in rodents suggests that neurotoxicological 

and developmental (including neurodevelopmental) endpoints are among the most sensitive 

indicators of Al toxicity. However, as vehicles for the development of toxicity values such as a 

provisional chronic RfD, the latter group of studies are considered to be more appropriate, since 

the level of exposure to Al appears to be better characterized. In fact, neurobehavioral deficits 

have been observed in mice and rats exposed during various stages of development and in 

subchronic studies (Bernuzzi et al., 1989; Donald et al., 1989; Golub et al., 1989, 1992a, b, 1995; 

Muller et al., 1990), as described above. These deficits include impaired operant learning, 

changes in grip strength, altered startle response and impaired motor coordination. In addition, 

several studies have shown that oral Al can produce histopathological changes in the CNS, 

although the histopathological lesions have yet to be causally related to the neurobehavioral 

deficits. Thus, Florence et al. (1994) reported histopathological changes in the brain of rats 

exposed to dietary Al for 6 months, the changes including the appearance of vacuolation of the 

cell body and cell processes of astrocytes in the brain and swelling of astrocytic processes. In 

addition, more localized vacuolization of neurons in the brain also was observed. These changes 

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were observed in rats exposed to elevated Al in the diet and are distinct from the NFD that has 

been observed in rats, rabbits and monkeys maintained on elevated dietary Al in combination 

with reduced dietary calcium (Garruto et al., 1989; Kihira et al., 1994; Mitani, 1992; Yano et al., 

1989; Yoshida et al., 1990) or in rabbits administered intracisternal or intraventricular injections 

of Al (Kowall et al., 1989; Wakayama et al., 1993). Interpretation of the low-calcium studies is 

complicated by the observation that NFD was observed in animals maintained on low-calcium

diets without excess Al and was enhanced by the addition of excess Al to these diets (Garruto et 

al., 1989; Kihira et al., 1994). Furthermore, Al has been shown to inhibit the gastrointestinal 

absorption of calcium (Orihuela et al., 1996), an effect that may exacerbate the calcium

deprivation induced by low calcium diets. Thus, it is not clear whether calcium deprivation 

enhances the neurotoxicity of Al or Al exacerbates the adverse effects of calcium deprivation. 

Donald et al. (1989) and Golub et al. (1995) are co-principal studies that identify a 

LOAEL of 100 mg Al/kg-day for minimal neurotoxicity in the offspring of mice exposed to 

dietary aluminum lactate (soluble aluminum) during gestation and lactation. The neurotoxicity 

associated with this LOAEL is consistent with LOAELs from other developmental and 

subchronic neurobehavioral studies in mice and rats which used higher dietary dosages of 

aluminum lactate or aluminum chloride (Golub et al., 1989, 1992a,b; Bernuzzi et al., 1989; 

Muller et al., 1990). Of the above, Golub et al., (1995) is the only study in which a 

histopathological examination of the brain and spinal cord was conducted and no abnormalities 

were reported. The Florence et al. (1994) study indicates that histopathological abnormalities of 

the CNS can occur in rats exposed subchronically to 84 mg/kg-day; although this is lower than 

the LOAEL for neurobehavioral effects, it was not chosen as the principal study because the 

functional significance of the histopathological lesions are uncertain. 

A number of studies were identified that, at face value, appeared to indicate LOAELs at 

lower doses than the 100 mg Al/kg-day value selected herein, for example, Paternain et al. 

(1988) and Colomina et al. (1992). However, in these as in many of the studies under 

consideration, insufficient information on dietary Al (Al content and/or feed type) was reported 

to permit a reliable estimation of the overall dose level to which the animals were subjected. 

Other developmental studies with aluminum hydroxide and/or citrate in mice and rats 

identified a NOAEL which are equivalent (95.5 mg Al/kg-day), or a minimum LOAEL that was 

greater (133 mg Al/kg-day) than the 100 mg Al/kg-day critical LOAEL (Domingo et al., 1989; 

Gomez et al., 1991), an overlap potentially related to differences in effective doses due to 

variations in unreported Al dietary content and factors affecting absorption such as chemical 

form (e.g., the use of less absorbable aluminum hydroxide). In addition, the LOAEL of 43.3 mg

Al/kg-day for decreased body weight gain in mice exposed to aluminum chloride for 180-390 

days (Ondreicka et al., 1966) was thought be inappropriate for risk assessment due to the small 

sample size and to the poor reporting of study details. Aluminum nitrate caused alterations in 

levels of brain biogenic amines and hepatic and hematological indices in rats exposed to 21.4 mg

Al/kg-day for 6 weeks (Flora et al., 1991). This dose is not a LOAEL because insufficient 

information is available to determine if the effects are adverse.

Therefore, the LOAEL of 100 mg Al/kg-day for minimal neurotoxicity in the offspring of 

mice (Donald et al., 1989, Golub et al., 1995) is selected as the basis for the provisional chronic 

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RfD. The LOAEL is considered minimal because the results of the postweaning neurobehavioral 

test battery indicate that performance deficits may be marginal. In particular, of the three 

observed effects (decreased forelimb and increased hindlimb grip strengths, increased hindlimb 

foot splay distance), one effect (increased grip strength) has unclear toxicological significance 

and two effects (increased grip strength and foot splay distance) did not persist after 2 weeks of 

no further exposure. 

Application of an uncertainty factor (UF) of 100 (3 for use of a minimal LOAEL, 10 for 

interspecies extrapolation and 3 for intrahuman variability where the critical effects have been 

observed in a sensitive sub-group) results in a provisional RfD of 

p-RfD = 1E-0 mg Al/kg-day. 

The provisional RfD of 1E-0 mg Al/kg-day is approximately 3-fold higher than estimated 

normal daily Al intake of approximately 0.2-0.3 mg/kg-day (Iyengar et al., 1987; Ganrot, 1986; 

Wilhelm et al., 1990). Chronic users of medications such as antacids, buffered aspirins and 

antiulceratives would be expected to ingest much larger amounts of Al, possibly as high as 10-70 

mg/kg-day. However, these subjects would not represent the most sensitive population 

(developing infants), as indicated by the animal data. 

Low confidence is placed in the co-critical studies, because they only identify a LOAEL 

for a sensitive effect and evaluated comparatively small numbers of animals. Confidence in the 

data base is low because the most reliable supporting data for neurotoxicity of Al in humans are 

of limited general relevance (e.g., dialysis encephalopathy is manifested in patients with 

impaired renal function and excessive Al uptake from intravenous exposure). In fact, 

neurotoxicity remains to be assessed in animals chronically exposed to Al, and developmental 

morphology has not been adequately investigated in two animal species. These limitations in the 

Al data base do not increase uncertainty in the RfD; therefore, a data base uncertainty factor was 

not used. However, reflecting the low confidence in the co-critical studies, there is low overall 

confidence in the RfD. 

DERIVATION OF A PROVISIONAL CHRONIC RfC FOR ALUMINUM

Al seems to be the most likely cause for the generally and consistently reported 

psychomotor and cognitive effects (particularly signs of impaired coordination) in Al production 

workers and welders (Bast-Pettersen et al., 1994; Rifat et al., 1990; Hosovski et al., 1990; White 

et al., 1992; Hanninen et al., 1994; Sjogren et al., 1990, 1996). In addition, there is strong 

evidence that Al is neurotoxic by other routes of exposure. Thus, a degenerative neurological 

syndrome (dialysis dementia) has been documented in humans with chronic renal failure, 

apparently due to an increased exposure to Al from dialysis treatment and/or ingestion of 

phosphate binding agents which contain Al (Alfrey, 1993). This syndrome is characterized by 

gradual loss of motor, speech and cognitive functions. Neurotoxicity, particularly neuromuscular 

effects such as decreased motor activity, startle responsiveness and grip strength, has also been 

observed in mice following subchronic oral exposure and in the offspring of mice and rats 

exposed orally during gestation and/or lactation. Based on this information, as well as evidence 

28
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that Al is absorbed by Al production workers and welders, the hypothesis that the occupational 

studies are indicative of a neurotoxic effect of Al appears to be justified. However, the only 

occupational study that has yielded suitable monitoring data is that of Hosovski et al. (1990), in 

which workers were exposed to presumed time-weighted average (TWA) concentrations of 4.6-

11.5 mg Al/m3

 magnitude for an average of 12 years. Using 4.6 mg Al/m3 as the LOAEL for 

psychomotor and cognitive impairment for an 8-hour occupational exposure (Hosovski et al., 

1990) and corrections for discontinuous exposure (10 m3

/20 m3 and 5 days/7 days), the 

LOAELHEC is 1.64 mg/m3

. Applying an uncertainty factor of 300 for intrahuman variability 

(10), use of a LOAEL (10) and an incomplete database (3) yields a provisional RfC of 

p-RfC = 1.64 mg/m3

/300 = 5E-3 mg/m3.

The lack of inhalation developmental studies may increase uncertainty in the database 

because oral data in animals indicate that neurotoxic and morphological developmental effects 

may occur at lower doses than neurotoxicity in adults. Additionally, there is uncertainty related 

to the lack of corroborating data on air concentrations associated with neurotoxicity. Confidence 

in the critical study is low to medium because only a LOAEL was identified. Confidence in the 

database is medium because (1) there are no corroborating data on effect levels (NOAELs and 

additional LOAELs), (2) no data are available for developmental neurotoxicity by the inhalation 

route and (3) a well-designed two-generation reproduction study is lacking. Reflecting the low 

to medium confidence in the critical study and database, there is low to medium confidence in 

the provisional RfC. 

PROVISIONAL CARCINOGENICITY ASSESSMENT FOR 

ALUMINUM 

Weight-Of-Evidence Classification

A considerable number of epidemiological studies have examined the incidence of excess 

tumor formation in persons occupationally exposed to Al in the form of dusts or fumes. In 

general, a body of inferential evidence exists for an increase in cancer of the bladder and lung 

through such occupational exposure to Al, although conclusions linking these responses to the 

effects of Al are confounded by attendant co-exposure to other harmful emissions such as PAHs 

and by cigarette smoking. A 20-month exposure of B6C3F1 mice to Al potassium sulfate 

dodecahydrate in the diet at concentrations up to 10% w/w displayed no indication of compoundrelated carcinogenicity and, in general, no indication of adverse toxicological effects of any kind 

(Oneda et al., 1994). Similarly, the life-time exposure of Swiss mice and Long-Evans rats to 5 

ppm Al as aluminum potassium sulfate in drinking water provided no convincing evidence for 

the carcinogenicity of Al compounds (Schroeder and Mitchener, 1975a,b). Gene reversion 

experiments on Al compounds resulted in negative results in S. typhimurium (Ahn and Jeffrey, 

1994). Taking all of the evidence of Al carcinogenicity together, and in accordance with the 

U.S. EPA (2005) cancer guidelines, aluminum is classified as inadequate information to assess 

carcinogenic potential. The basis for this classification is insufficient evidence in 

epidemiological/occupational studies, lack of demonstrated carcinogenicity or mutagenicity in 

29
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available animal studies, lack of positive evidence of non-carcinogenicity and lack of mode of 

action data for aluminum. 

Quantitative Estimates of Carcinogenic Risk

Due to insufficient data, a provisional oral slope factor and inhalation unit risk could not 

be developed. 

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Table 1. Summary of oral toxicity data for aluminuma

Study Type Species Al

Exposure 

Concentration 

(ppm) 

Exposure 

Dosage 

(mg Al/kgday) 

Exposure 

Frequency and 

Duration 

Critical Effect 

NO

(mg 

d

Ondreicka et al., 1966 

Subchronic 3-gen dietary

Dobra Voda mice 

chloride -- 27 (control),

46 

Continuous, 180-390 days 

Decreased body weight gainin F1 and F2.

Golub et al., 1989 

Subchronic dietary 

S-W mice lactate 25 (control), 

500,1000

3.3 (control),65,130

Continuous, 6 weeks 

Decreased spontaneous motor activity; decreased weight gain. 

Golub et al., 1992a 

Subchronic dietary 

S-W mice lactate 25 (control), 

1000

190 Continuous, 90

days

Decreased hindlimb grip, decreasedspontaneous motor activity,  decreased startle response. 

Florence et al., 1994 

Subchronic dietary 

Wistar rat chloride 

(with citric acid) 

1.52 (control), 1000

0.13(control), 84

Continuous, 6 months 

Histopathological changes in brain astrocytes and neurons.

Domingo etal., 1996 

Subchronic drinking water

Sprague Dawley rats 

nitrate (withcitric acid)

-- 0, 50, 100 

(plus unreported dietary Al) 

Continuous, 6.5 months 

Operant conditioning andperformance 

Yoshida et al., 1989 

Subchronic dietary 

S-W mice lactate 25 (control), 500, 

1000

5 (control),98, 195 

Continuous, 7 weeks 

Increased mortality from L. monocytogenes inoculation 

Donald et al., 1989 

Developmentaldietary 

S-W mice lactate 25 (control), 500, 

1000

5 (control),100, 200

Continuous, gestation and lactation 

Neurobehavioral effects. 

Golub et al., 1992b

Developmentaldietary 

S-W mice lactate 25 (control), 

1000

4 (control),174 

Continuous, gestation and lactation 

Neurobehavioral effects. 

Golub et al., 1995 

Developmentaldietary 

S-W mice lactate 7, 500, 1000 1 (control), 

100, 200

Continuous, gestation, lactation tomaturity 

Neurobehavioral effects. 

38
Table 1. Summary of oral toxicity data for aluminuma

Study Type Species Al

Exposure 

Concentration 

(ppm) 

Exposure 

Dosage 

(mg Al/kgday) 

Exposure 

Frequency and 

Duration 

Critical Effect 

NO

(mg 

d

Yoshida et al., 1989 

Developmentaldietary 

S-W mice lactate 25 (control), 500, 

1000

4 (control),100, 200

Continuous, gestation and lactation 

Increased mortality of damsfrom L. monocytogenes inoculation 

aStudies for which total dosages were reported or could be estimated (unless otherwise noted).

39