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ENCL OSED I

NFO RMATI ON: Attachment 1: PRO V I S I ONAL PEER REVI EW ED TOXI CI TY

V A L U E S F O R AL U M INU M ( C A SR N 7429-90-5)

BE ADVI SED: Unless spec ifically indicated to have be en pee r reviewe d, it is t o be noted that the

attached Provisional Toxicity Value Pape r( s) have not be en through the U.S. EPA’ s for ma l re v ie w pr oc e ss; the re for e , th e y do no t re

pr e se nt a U. S. EP

A v e rif ie d a sse ssm e nt.

I f y ou have a

ny questions reg arding this transmissi on, please contac t 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 Envi ronmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268

### Acronyms and Abbreviations

bw body weight

cc cubic cen tim e ters

CD Caesarean D e livered

CERCLA Com p rehensive Environm en tal Response, Com p ensation and Liability Act of 1980

CNS central nervous system

cu.m cubic m e ter

DW EL Drinking Water Equivalent Level

FEL frank-effect level

FIFRA Federal Inse ctic ide, Fun g icide, and Rodenticid e Act

g gram s GI gastro inte stinal

HEC hum a n equivalent concentration Hgb hem oglobin

i.m

. intr am uscular i.p. intraperitoneal

IRIS Integrated R i sk Inform ation System

i.v. intravenous

IUR inhala tion u n it r i sk kg kilogram

L liter

LEL lowest-effect level

LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adj u sted to continuous exposure duration LOAEL(HEC) LOAEL adj u sted for dosim e tr ic differences across species to a hum an

m m e ter

MCL m a xi m u m c ontam inant level

MCLG m a xi m u m c ontam inant level goal

MF modifying factor

mg m illigram mg/kg m illigram s per kilogram mg/L m illigram s per lite r
MRL m i nim a l risk level

MTD m a xi m u m tolerated dose

MTL m e dian threshold lim it NAAQS National A m bient Air Quality Stan dards

NOAEL no-observed-adverse-effect level

NOAE L(ADJ) NOAE L adjusted to continuous exposure duration

NOAE L(HE C) NOAE L adjusted for dosim e tric differences across species to a hum an NOEL no-observed-effect level

OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhala tion ref e rence concentration

ip-RfD provisional oral reference dose

PBPK physiologically based pharm acokinetic ppb parts per billion

ppm parts pe r m illion

PPRTV Provisional Peer Re view ed Toxicity Value

RBC red blood cell(s)

RCRA Resource Conservation and Recovery Act

RDDR Regional deposited dose rati o (for the indicated lung region)

REL rela tive exp o sure lev e l

RfC inhalation refe rence concentration

RfD oral reference dose

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

s.c. subcutaneou s SCE sister chrom a tid ex chang e SDWA Safe Drinking W a ter Act

sq.cm

. square centim eters

TSCA Toxic Substances Control Act

UF uncertainty f actor

μg m i crogram

μm ol m i crom oles

VOC volatile organic com pound

ii10-23-2006

PROVISIONAL P E E R REVIEW E D TOXICI TY VALUES FOR ALUMINUM (CASRN 7429-90-5)

Background

On Dece m b er 5, 2003, the U.S. Environm enta l Protection Agency' s (EPA's) Office of Superfund Rem e diation and Technology Innovation (OSRTI) revised its hierarchy of hum a n health toxicity values for Superfund risk assessm e n ts, establishing the follow ing three tiers as the new hierarchy:

1. EPA' s Integrated Risk In form ation System (IRIS).

2. Provisional Peer-Reviewed Toxicity Va lues (P PRTV) used in EPA' s Superfund Program

.

3. Other (pe e r-reviewed ) to xicity values, including:

< Minim a l Risk Levels produced by the Agency for Toxic Substances and D i sease Registry (ATSDR),

< California E nvironm ental Protecti on Agency (CalEPA) values, and

< EPA Health Effects Assessm ent Summ ary Table (HEAST) values.

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

such a valu e is not av ailable in EPA' s Integrated Risk Information Syste m (IRIS). PPRTVs are developed according to a Standard Operating P r ocedure (S OP) and are derived after a review of

the relevant scientific literatu re using the sam e m e thods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provi siona l tox i c ity va lues

rece ive in ter n al rev i ew b y two EPA scientists and external peer review by three independently

selec t ed sc ie ntif ic expe rts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-p r ogra m consensus review prov ided f o r IRI S values. T h is is be caus e IRIS value s are generally intended to be used in all E P A program s, while PPRTVs are developed specifically for the Superfund Program

.

Because science and av ailab l e inform ation evolve, PPRTVs are in itially derived with a three-year life-cycle. H o wever, EPA Regi ons or the EPA Headquarters Superfund Program

som e ti m e s request that a frequently used PPR TV be reassessed. Once an IRIS value for a specific chem ical becom e s available for Agency review, the analogous PPRTV for that sam e chem ical is retired. It should also be noted that som e PPRTV m a nuscripts conclude that a

PPRTV cannot be derived ba sed on inadequate data.

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Disclaimers

Users of this docum ent should first check to se e if any IRIS values exist f o r the chem i cal of concern before proceeding to use a PPRTV. I f no IRIS valu e is ava ilab l e, staf f in th e region al Superfund and RCRA program offices are advised to carefully re view the inform ation provided

in this docum e nt to ensure that the P P RTVs us ed are appropriate for the types of exposures and

circum stances at the Sup e rfund site o r RCRA f acility in question. PPRTVs are period ically updated; therefore, users should en sure that the values contained in the P P RTV are current at the

tim e of use.

It is im portant to rem e mber that a provi sional value alone tells very little about the

adverse effects of a chem ical or the quality of evidence on w h ich the v a lue is based. Therefore, users are strongly encouraged to read the enti re PPRTV manuscript and understand the strengths

and lim itations of the derived provisional valu es. PPRTVs ar e developed by the EPA Office of Research and Development’s Nati onal Center for Environm e n tal Assessm ent, Superfund Health Risk Technical Support Center for OSRTI. Ot her EPA program s or external parties who m a y choose of their own initi ative to use these PPRTVs are advise d that Superfund resources will not generally be used to respond to challenges of PPR TVs used in a context outside of the Superfund Program

.

Questions Regarding PPRTVs

Questions regarding the contents of th e PPRTVs and their ap propriate use (e.g., on

chem icals not covered, or whether chem icals have pending IRIS toxicity values) m a y be directed

to the EPA Office of Research and Devel opm ent’s National Center for E nvironm ental

Assessm ent, Superfund Health Risk Technica l Support Center (513-569-7300), or OSRTI.

This document has passed the STSC quality re v i ew and peer review evaluation indicating that the quality is consistent w ith the SOPs and standards of the STSC and is suitable for use by registered users of the PPRTV syste m

.

INTRODUCTION

Verified toxicity values for alum inum (Al) and its com pounds are unavailable on IRIS or HEAST (U.S. EPA, 2006, 1997), except for a chronic oral RfD of 4E-4 mg/kg-day for alum inum phosphide. However, occupational guidelines and standards have been established for a num ber

of che m ical and physical for m s of Al, incl uding, from ACGIH, 8- hour TWA-TLVs of 10 m g / m 3

for the com p ound as a metal dust or oxide, 5 m g /m 3 as “pyro” powders or welding fum e s, and 2 mg/ m 3 for soluble salts or organic form s of th e m e tal (ACGIH, 1998). From NIOSH, 10-hour

TW A-RELs of 10 m g / m 3 are specified for “total” Al dust versus 5 m g / m 3 f o r the re s p irab le portion (NIOSH, 1994). NIOSH covers all other form s of the m e tal by identical values to those specified by ACGIH (ACGIH, 1998). OSHA PELs for Al include an 8-hour TW A value of 15 mg/ m 3 for “total” m e tal dust, versus 5 m g / m 3 for the respirable por tion (NIOSH, 1994). The U.S. EPA’s CARA list (U.S. EPA, 1994) cites a HEA for Al (U.S. EP A, 1987), and ATSDR has updated its toxicological profile of the elem ent (ATSDR, 1998).

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The U.S. FDA (2000) has speci fied a m a xim u m a l um inum co ncentration of 25 m c g/L in large-volum e parenterals (LVP) used in total pa renteral nutrition (TPN). The FDA regulation applies to all LVPs used in TPN, including but not lim ited to parenteral am ino acid solutions, highly concentrated dextrose solutions, pare nteral lipid em ulsions, sodium chloride and electrolyte solutions, and st erile water for injection.

Research pa pers per tin e n t to th e potentia l to xicological and carcinog enic effects of Al were sought through com puter searches of the HSDB, RTECS, MEDLINE and TOXLI N E (and its subfiles) databases, covering the tim e period 1995-1999. The literature searches were conducted in June, 1999.

REVIEW OF PERTI N ENT DATA

The review by Stokinger (1981) g i v e s an accoun t of Al as an all-pervasiv e com ponent of products that are central to the da ily lives of m o st Am ericans. Fo r exam ple, the m e tal is a crucial part of m a nufactured products for the building, au tom obile and container industries, while Al as powder or flake is a component in a num b er of consum er products, such as paints, fireworks, etc.

Al com p lexes and m i nerals are used in the brew ing and paper industries, and as coagulants for water purification. Alum inum oxide finds applica tion in abrasives, as a catalyst or absorbent, and as a component in fillers. Alum inum chloride is included in cosm etic for m ulations such as

deodorants.

Hum a n exposure to Al arises principally fr om food and water, through its widespread use in food additives, packaging and cooking utens ils and Al-containing m e dications, particularly antacid, buffered aspirin, anti-ulcer and anti -diarrheal form ulations (Marquis, 1989; Lione, 1985). Pennington and S c hoen (1995) estim a ted daily Al intakes of 0.1-0.3 m g /kg-day for

infants and children 6 m o nths-6 years of ag e and 0.1-0.18 m g / 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 Surv ey (1987-1988). These data ar e in broad agreement with

those of W ilhelm et al. (1995) w ho reported the dietary intake of Al in Germ an children (living

in the Duisb e rg area) as ranging fro m 0.008 to 0.11 m g Al/kg-day. In ad dition, these values are

consistent w ith a range of 1-20 m g /day (0.014-0. 3 m g /kg -day) for norm a l oral daily Al intake

from food a nd water reported by other investigat ors (Ganrot, 1986; Iyenga r et al., 1987; W ilhelm et al., 1990). However, users of Al-containing m e dications can ingest much larger amounts of

the elem ent, possibly as high as 840-5000 m g /d ay (12-71 m g /kg-day) from antacids, 126-728 mg/day (1.8-10.4 m g /kg-day) from buffered aspi rins and 828 mg/day ( 11.8 m g /kg-day) from anti-ulcer compounds when taken at recomm ended dosages (Lione, 1985).

Toxicokin e tics of Aluminum

There is a large am ount of infor m ation availa ble on the absorption, transf er from tissue to

tissue and elim ination of Al from the body, includi ng data that have been am assed from studies

on either hum a n volunteers or laborat ory anim als. In general, the chem ical appears to be poorly

absorbed fro m the gastro intes tinal tract, though th e portion of the load that is retain ed will vary depending on the concentration, the chem ical species adm i nistered, the fasti ng or fed state of the

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host, gastrointestinal pH, anim al m o del, etc. For exam ple, Yokel and McNa m a ra (1988)

adm i nistered single oral doses of a num b er of Al com pounds (both water soluble and insoluble)

to New Zealand white rabbits and obtained abso rbed proportions of the load ranging f r om 0.27% to 27%. Fractional uptake of Al in hum a ns under norm a l conditions (i. e ., with no intake of large quantities of Al from m e dicine) was estim ated to be 0.1-0.3% assum i ng an intake of 20 m g 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 inform ation is availab l e on th e actua l m echanism by which the

elem ent and its com pounds are transported across the brush border. (W ilhelm et al., 1990; Lione, 1985).

Although the overall extent of Al absorption is poor followi ng oral exposure, there may be significant intake of the com pound by t hose taking large amounts of Al com pounds in patented rem e dies. As stated, absorption of Al is influenced by gastroin testinal conditions and

content because Al can form various com p lexes with different solubili ties and oxidation states depending o n pH and interac tions with die t ary co nstitu ents. At low pH (3-5) in aqu e ous solution s , th e soluble (io n ic) f o rm s of the Al prev ail (Al 3+ ); at high pH (>8), Al in the for m of

soluble alum inum oxide is presen t; and at pH 5-8, the elem e n t is predominantly in the for m of

alum inum hydroxide, w h ich is insoluble (van de r Voet and de W o lff, 1986; W ilhelm et al., 1990). Ingested constituents th at can influence absorption by for m ing complexes with Al include phosphate, fluoride, calcium

, citrate and lactate. For exam pl e, Al is used to bind dietary phosphorus and decrease its absorption as a c ontrol for hyperphosphatem i a, and citrate and

lactate are com p lexing agents that can significan tly increase Al absorption (Slanina et al., 1984, 1985, 1986; Partridge et al., 1989; D o m i ngo et al., 1991; Ittel et al., 1991; Lione, 1985; W i hel m et al., 1990).

A num b er of recen t repo rts of studies on th e gas t rointes tinal absorption of Al have

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

com ponents appears to enhance the absorption of Al, within narrow lim its. For exam ple, Deng et al. (1998) adm i nistered a si ngle oral dose of either distill ed water, 2 mmoles/L alum inum

chloride or 2 mm oles/L alum inum chl o ride plus 2 mmoles/L sodium citrate to six m a le W i star rats/group. Ani m als were bled at 1, 2 and 4 hours after dosing, th en term inated after 6 hours. Inductively coupled plasm a (ICP) wa s used to m easure Al concentrations in blood, bone (tibia), kidney, liver and the in testinal wall. Irrespective of treatm e nt, the appearance of Al in the blood of dosed groups peaked after 1 hour, with the con centration of the elem ent at higher levels in

those an im als receiving citrate in addition to alum inum chlori d e . In those anim als receiving

alum inum c h loride alone, significant tissue concen tra tions of the elem ent were res t r i c t ed to the

gastro inte stinal wall. Th ose rec e ivin g citrate d i s p layed m easurable qu antities of the elem ent in

several of the other m onitore d tissues, includ ing bone.

Sutherland and Greger (1998a) used a sim ilar dosing regim e n to exam ine the kinetics of absorption and elim ination of Al in m a le Spra gue-Dawley rats that ha d received a single oral dose of 0, 0.25, 0.5 or 1 mmoles/L/kg body weight alum inum lactate in 1 mL of 16% citrate.

Concentrations of Al in serum

, liver, kidney or bone (tibia) were m easur ed at various post-dosing

tim e intervals up to 6 hours. Depending on the do se, absorption factors for Al of up to 4.2% of

the adm i nistered dose w e re observed, with the greater proportion retained in bone. The authors reported a slower rate of absorption in those an imals receiv i ng Al at the higher doses, an

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observation potentially indicating re duced gut motility and / o r satu ration of the trans c ellu lar absorption processes at the hi gher concentrations. Alum inum deposited in kidney and bone appeared to turn-over at a slow er r a te than in the liver.

The influence of citrate on the gastrointest inal absorption of Al in m a n was exam ined directly by Taylor et al. (1998) who adm i nistered a drink cont aining Al and citrate to three

volunteers. Alum inum and citrat e concentrations were m onito red in serial blood and urine

sam p les for up to 24 hours. The kinetics of citrat e and Al differed m a rkedly, the former peaking in plasm a after 32 m i nutes, versus 87 m i nutes fo r Al. This suggests th at Al probably does not

cross th e gas t roin tes tinal barrier as th e citrate. Furtherm ore, the author s r e ported that the over a ll extent of Al absorption h a d probably not exceed ed 1% in th eir experim e nt, a finding th at contrasts with the higher values reported by Su therland and Greger (1998a) in Sprague-Dawley rats and by Deng et al. (1998) in W i star rats.

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

aqueous m e dia will be alm o st i m possible to pred ict, because of the lik elihood that the elem ent
will becom e absorbed to food particles in th e intestinal lum e n. According l y, dependin g on the dose, m ode of delivery and caloric s t ate of the ex perim e ntal anim al (fed/fasted), sign ificant

am ounts of aqueous form s of Al wil l be absorbed only when available binding sites on food have

becom e saturated. This presents an inhere ntly complex overall pict ure of the elem ent’s absorption s i nce, add itio nally, the no rm al dietary c ontent of Al will b e sub s tantial. Th us, it m a y be assum e d that som e sequestered Al will be ab so rbed along with non-sequestered water so luble

f o rm s of the elem ent, while th e re st will be reta ined within the gastro intestin al trac t.

Sutherland and Greger (1998b) used their alum inum lactate in 16% citrate dosing regim e n to exam ine the com p arative importance o f biliary v e rs us urina r y e x cretion of Al. Five

to seven m a le Sprague-D awley rats/group who ha d previously received an im planted bile cannula were treated by gavage. Another sim ilarly-treated cohort of five anim als/group were housed in metabolic cages imm e diately after dosi ng to provide 0- to 3-hour and 3- to 6-hour urine specim ens. At term ination, all anim als were sacrificed and exsangui nated, and tissue, bile and urine samples were m easured by graphite furnace atom ic absorption spectroscopy. Am ong the key findings to em erge from this study was the increm ental appearance of Al in bile as early

as 15 m i nutes after dosing. However, overall am ounts of Al were greater in the 3-hour urine

sam p les than those th at had accum u lated in b ile s a m p les collected with in a sim ilar time fram e. The fact that control rats excret ed 3 tim es more Al in bile than in urine during the first 3 hours after dosing led the authors to c onclude that, at low exposure to Al (in controls receiving Al solely from food), the liver is capable of excr eting the elem ent to the bile, a m echanism that

becom e s saturated as the level of Al adm i nist ration becom e s increased. Thereafter, urinary

excretion becom e s the prim ary route of elim ination in circumstances of Al overload.

Alum inum can also be absorbed by inhalati on as indicated by age- related deposition in the lungs of the general population and exposure-relate d increased blood and urine concentrations in workers exposed to Al (Bas t-Pettersen et al., 1994; Sjogren et al., 1996; Hosovski et al., 1990; Wilhelm et al., 1990; U.S. EPA, 1987). Alum inum occurs primarily in particulate form in the ambient atm o sphere a nd as various dusts and fum e s during its production

and use. Common for m s of inhaled Al include alum inum oxide (alum i na; Al 2 O 3 ), pyro powders

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(powder and flake Al-treated to redu ce surface o x idation), Al we lding fum e and soluble salts (e.g., alum inum chloride a nd sulfate) (ACGIH, 1998).

Neurotoxicity as a Primary Toxi cological Effect of Aluminum

One of the greatest health concerns regarding Al is its neurological effect s. The fi rst evidence for Al-induced neurotoxicity in hum ans was seen in patien t s who

, as a resu lt of receiving long-term hemodialysis f o r chr onic renal failure, developed a degenerative neurolog ical syndrom e (dialysis dem e ntia) char acterized by the gradual loss of m o tor, speech and cognitive functions (Alfrey, 1993). This dem e n tia, attributable to Al in the dialysate, is usually fatal within 6-9 months after the first clinical signs appear. In addition, m a ny patients received high oral doses of Al to act as phosphate binders. A u tops ies of these patients revealed

incre a sed co ncentr ation s of Al in the gray m a tte r and cereb ral spinal flu i d (CSF) but no evidence of neurofibrillary degeneration (NFD) despite th e eleva t ed Al levels. Once the connection between Al and dialysis dem e ntia was established, Al was remove d from dialysis fluid and the

incidence of dem e ntia rapidly de clin ed, thereby s t reng thening the argum ent that Al was a caus a l agent in dialysis dem e ntia (Ganrot, 1986).

Am yotrophic Lateral Sclerosis (ALS) a nd Parkinson’s Disease (PD) are other neurological diseases which have been associat ed with Al exposure. ALS is a progressive disease of the Central Nervous System (CNS) that is characterized by an accum u lation of neurofibrillary tangles. In Gua m , southern W e st New Guinea and parts of Japan, there is an unusually high prevalence of ALS a nd PD. This m a y be related to the na tural abundance of Al coupled with the virtual lack of m a gnesium and calcium in the drinking water supplies and soil of these areas. In a study designe d to evaluate effects of high Al and low calc ium levels in th e diet, m u ch like the conditions associated w ith Guam and other sim ilar areas, cynom olgus monkeys were placed on a low calcium diet either with or without supplem ental Al and

m a nganese (Garruto et al., 1989). Chronic calciu m deficiency alone produced neurodegenerative effects, although neurofibrillary changes were most frequently seen in the m onkeys on a low

calcium diet supplem ented with Al and m a nganese.

Though a cause and effect relationship be tween Al and three for m s of chronic encephalopathy in hum ans: senile dem e ntia of the Alzheim e r type (SDAT, Alzheim e r' s Disease),

endem i c Amyotrophic Lateral Sc lerosis (ALS) and endem i c Parkinsonism -de m entia (PD, a

m i xture of Parkinsonism and senile dem e ntia) has been suggested, there is no firm evidence that it plays a causal ro le in the de velop m ent of these diseas es (G anrot, 1986; Lione, 1985). The condition is degenerative and ch aracterized by the progressive loss of speech, m o tor and cognitive functions, with death typically occurr ing within 1-6 m onths. Autopsies of patients

revealed increased concentrations of Al in the g r ay m a tter an d cereb ral sp inal fluid (CSF), though with no conclusive evidence of NFD or other neuropathological changes despite the

elevated Al levels.

The neurotoxicity of Al is well docum e nted in certa in anim al species. Alum inum induces

a spectrum of behavioral abnorm a lities and brain neurofib rillary degenerative changes in rabb its and cats when injected intracrani ally or parenterally in high do ses, though ham s ters and m onkeys

are less sens itiv e (Ganro t, 1986; Lio n e, 1985). Such studies have been d e signed as models for

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the possible neurotoxicological eff ects of Al in hum ans. However, it should be noted that the neurofibrillary changes in affected anim als diffe r in m o rphological detail from those associated

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

neurobehavioral effects in adult m i ce and rats and in their developi ng offspring. In general, such neurotoxic effects of Al app ear to be m o re subtle than those induced through routes of

adm i nistration that by -p ass the ga str o intes tina l tract, perhaps reflecting the lower doses of Al

reach ing the brain.

Recent repo rts of studies on the effects of Al on neurotox icity in anim als have sought to

define the biochem i cal m echanis m s that are im pa ired when Al crosses th e blood-brain barrier. However, a unifying concept has yet to em erge, though the passage of the elem ent into various regions of the brain has been clearly dem ons trated (Deloncle et al., 1995). Am ong the m a ny biochem i cal functions and processes that appear to be perturbed by the presence of Al in the brain are the peroxidation status of biological m e mbranes (Katya l et al., 1997; Deloncle et al., 1999), inhib ition of the neuronal g l u t am ate-nitric oxide-cy c lic GMP pathway (Cucarella et al., 1998), and the m a rked reduction of protein- and non-protein-bound thiols and the specific

activ ity of Na + /K + and Mg ++ ATPases (Katyal et al., 1997). T h e relativ e importance o f each of

these m echanism s and how (or whether) they inte ract to bring about th e observed physiological changes remains unclear.

Other Effects of Aluminum

Osteom alacia was frequently observed am ong long-term dialysis patients with neurological signs and is commonly attributed to Al overload (Ganrot, 198 6; Lione, 1985). This bone condition is characterized by widened osteoid (unm ineralized bone m a trix) with no fibrosis,

reduced m i neralization rate, skeletal pain and a strong tendency for fractures, lack of response to

vitam i n D therapy and increased Al concentr ation in bone. Effects on bone histology and

elevated bone Al levels have also been obser ved in patients with norm a l renal function who received total parenteral nutrition with Al-con tam i nated casein as a protein source, and in parenteral Al loading induced osteom alacia in rats and dogs (L ione, 1985).

There are a num b er of pub lished reports of studies in which the carcinogenicity of

alum inum c o m pounds has been evaluated. These include oral exposure studies in which the

com pounds were m a de available to experim e nt al anim als in the drinking water or diet (Schroeder and Mitchener, 1975a,b: Oneda et al., 1994), and inhalation epidem iological studies,

in which the incidence of tum o r for m ation in persons exposed to alum inum -containing dusts and

fum e s in an occupational setting was com p ared to unexposed individuals (Spinelli et al., 1991; Thériault et al., 1984, 1990; Arm s tr ong et al., 1986; Trem blay et al., 1995; Selden et al., 1997; Cullen et al., 1996; Dufresne et al., 1996; Ronneberg and Langm a rk, 1992) . However, it has been generally concluded that the inf e rential a ssociation betw een exposure to Al and m a rginally

increased incidences of tum o rs of the bladde r and/or lung are confounded because of the coexposure of subjects in such settings to othe r harmful and potentially carcinogenic substances, such as polycyclic arom atic hydrocarbons (PAHs and coal tar pitch volat iles (CTPV) (Ronneberg and Langm a r k, 1992). T h erefore, the issue of th e potential carcinogeni city of Al com p ounds

rem a ins uncerta in.

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Human Studies

Oral Exposure

Few reports have been identified that addre ss the toxicological effects of Al in hum ans exposed orally. Furthermore, in a review, Reiber et al. (1995) pointed to the conflicting findings that have been reported when the incidence of neurological sym p tom s has been assessed in relation to Al exposure in eith er cross-sectional, ecological or case-control epidem iological studies. Among the m o re recen t stud ies th at have used this ap proach, Martyn et al. (19 97) discussed the findings of a case-control study involving 441 m e n in Engl and and W a l e s who

were afflicted with either Alzheim e r’s diseas e, brain cancer, dem e ntia or other neurological conditions. Assessing the historical exposure of these subjects faile d to establish a link between

Al in drink i ng water at the prevailin g concentrat ions (below 0.2 m g /L) and the incid e nce of one

or m o re of t h e conditions under investigation. N o data were located regarding the oral carcinogenicity of alum inum com p ounds in humans.

Inhalation E xposure

Neurobehavioral effects were evaluated in a group of 87 Al foundry workers who were occupationally exposed to 4.6-11.5 mg/m 3 Al fumes and dust f o r a m ean of 12.0 years [standard deviation (S D) 4.5 years, shortest exposure 6 ye ars] com p ared to an unexposed control group (n=60) who were m a tched for age, job seniority a nd social status to exposed subjects (Hosovski et al., 1990). It is repor ted that environm ental Al concentratio ns were m easured for each worker separately during the winter and summer, i m plyi ng that personal sam p ling m a y have been used and that the contributing concentrations are ti m e -weighted averages. In certain places, the

num b er of particles ranged as high as 329-1020/cm 2 air, and dust particle sizes were ≤ 1, 1-5 and

≤ 5 m i crons in 65.6, 26.6 and 7.6% of the sam p les, respectively. Tests of psychom otor ability (sim ple and com p lex reaction tim e, oculom otor coordination), intellect ual ability (W echsler intellig ence, perform a nc e intelligence and verbal intellig ence quotien t s an d W echsler subtests on

inform ation processing, m e mory, understanding, calculation, coding, picture com p letion, picture grouping, object assem b ling, assem b ling of cube s and common concepts) and cerebral dam a ge (Bender visual m o tor test) were conducted. Pe rf orm a nce of t h e exposed workers was found to be significantly (p<0.02) im paired on the co m p lex reaction tim e , oc ulomotor coordination,

m e mory, coding, picture com p letion and object asse m b ling tests. However, the investigators noted that the perform a nce deficits had no clinic al m a nifestations, and that additional studies were probably needed to confirm the possibility of cerebral dam a ge. The study yielded a lowest available non-duration adju sted LO AEL of 4.6 mg Al/ m 3 for psychom otor and cognitive

im pair m e nt during repeated 8-hour occupational e xposures (Hosovski et al ., 1990), that could be

corrected for discontin uous exposure (10 m 3 /20 m 3 and 5 days/7 days) to yield a LO AEL HEC of

1.64 m g / m 3 Al.

Alum inum oxide powders were adm i nistered to C a nadian m i ners (m ainly underground gold and uranium m i ners) in known exposures as a m eans of prophylaxis against silicosis (Stokinger, 1981; Rifat et al., 1990 ). Data in which m o re than 42 m illion Al treatm ents ( ≈ 150,000 m a n-years) had been given over a period of 27 years ending in 1971 were reviewed

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by Stokinger (1981). The effectiven ess of this treatm e nt is un certain but no lung damage or

other ill ef f ects (no t spec if ied) were o b served. Th e powders ( M cInty r e po wder) were prepar ed by grinding Al pellets so that 96% of the particles were ≤ 1.2 μm in diam eter. During this

process m o st of the particles becam e oxidized to alum inum oxide; the powder contained 85%

alum inum oxide and 15% elem ental Al. Accord ing to Stokinger (1981), recomm ended exposure concentrations were 30,000 part icles of respirable size per cubic centim eter (ppcc) for 10

m i nutes/day or 10,000-20,000 ppcc for 20 m i nutes/day (t otal treatm e nt days not indicated). Rifat et al. (1990) stated that the recomm ended exposure was to an Al dust concentration of 20,000- 34,000 parts per m l air in the m i ners' changing room s before each shift f o r 10 m i nutes. Stokinger (1981) reported that the 30 ,000 ppcc concentrati on corresponds to ≈ 350 m g /m 3 , which is equivalent to an 8-hour av erage co ncentration of 2 m g / m 3 . Based on the Stokinger (1981) data and the fact that one unspecified study used le vels 30 tim es higher than advised, the TLV of 10 mg/ m 3 is recomm ended for Al dust (ACGIH, 1998).

The increasing awarenes s of the potential neur otoxicity of Al has resulted in a num ber of investigations of the inciden ce of neurotoxicological sym p tom s in Al workers. Although

treatm ent with McIntyre powder had not produced apparent a dverse effects, a neurobehavioral

evaluation of m a le m i ners (261 exposed to McIntyre powder, 346 unexposed) who started working between 1940 and 1979 (ad d ition a l durati on data not reported) w a s perform e d in 1988-1989 (Rifat et al., 1990). There were no si gnificant differences between exposed and unexposed m i ners in reported diagnoses of neurol ogical disorder. Results of cognitive testing (Mini-Men t al State Exam ination for general cog n itiv e function, Ravens colored p r og ressiv e

m a trices test for reasoning and Sym b ol Digit Mo dalities Te st f o r spatia l p e rcep tual a c curacy and

inform ation processing), however, showed th at the exposed group had significantly (p ≤ 0.001)

im paired perfor m ance on at least one test, and wh en all test scores were summed. Als o, the

likelihood of scores in the im paired range increased with duration of exposure.

A neurologic syndrom e was describ e d in Al sm elting p l ant p o troom wor k ers (W hite et al., 1992). Twenty-five m e n were evaluated for suspected w o rk-related neurologic illness based on findings in three patients studied previousl y. T h e average duration of employm e nt was 18.7 years (SD, 3.6; range, 12-23 years), 15 of the patients were w o rking at the tim e of evaluation, and 10 had taken early retirem e nt or m e dical leave due to workplace-related sym p toms (m ean length of tim e since exposure was 1.3 years ra nging from 0.2-5 years )

. Quantitativ e exposure level data w e re not reported, but 21 of the work ers had been employed in the potroom prior to

installation of fume hoods for a m e a n duration of 5.3 years (range 3-7 years). Sym p tom s most often reported by the patients were f r equent loss of balance (88%), m e mo ry loss (84 %) and jo int pain (84%); other sym p tom s in cluded dizziness (80%), num bness ( 80%), parasthesias (72%) and

trem or (68%). Neurologic exam inations showed m ild to m o derate signs of lack of coordination (trem o r, dyssynergy of upper extrem ity lim b m o ve m e nt or ataxia) in 84% of the patients. Neuropsychologic effects were evaluated in 21 of the patients using the W echsler Adult

Inte llig ence Scale-Rev i s e d (in t ellec t ual f unction i ng), W i de Range Achiev em ent Test-Revised (academ ic function i ng), Halstead -Reitan Neurop sychological Test Battery (neuropsy c hological

assessm ent) and Minnes o ta Multiph a sic Per s ona lity Invento r y (persona lity f unctionin g ).

Mem o ry function was assessed with the W echsler Mem o ry Sc ale (14 patients) and W e chsler

Mem o ry Scale-Rev i sed (8 patients ). The m e mory function evaluation showed m ild to m oderate

im pair m e nt on subtests of i m m e diate recall for verbal or visual info rm ation (70-75% of the

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

moderate im pairm e nt on Halstead -Reitan tests of abst ract reasoning and flexible thinking (42%

of

the tested patien t s), m e m o ry f o r ta ctile information (53%) and su stained attention and

discrim i nation of tonal and speech p a tterns ( 44 and 64%, res p ectiv ely). On the W echsler

m e mory and Halstead-Reitan tests, m ild and m o derate im pairm e nt was defined as scores 1.5-2

and ≥ 2 standard deviations below the m ean of the norm a l population, respectively. Most (89%) of the patien t s tes t ed with the Minn esota Mu ltiph a sic Personality Invento r y had abnorm a lly

elevated sco r es ( ≥ 2 SDs above the population m e an) in dicative of clinical depression. Significant positiv e correlations were found between severity of incoordination (s ign s and

sym p tom s ) and degree of exposure (qualitative) before the introduction of the ventilation hoods.

White et al. (1992) noted two other studies that described neurologic problem s a m ong Al

sm elter workers. Thus, an evaluation of 444 electrolysis workers found neuropsychiatric changes in 123 (28%), “neurotic syndrom e s” in 89 (20%) and “slight pyram idal and cerebellar changes” in 39 (9%) (Langauer-Lew owicka and Braszczynska, 1983). In the second study,

sym p tom s i n cluding m e ntal confusion, concentra tion and m e m o ry problem s 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 leas t 10 years exclusively in the potroom (n=14), foundry (n=8) or other m a nual labor departm e nts of the same plant (n=1 6, control group) (BastPettersen et al., 1994). The m ean a g es and em ploym ent durations of the groups were in the ranges of 62.5-63.5 and 19.2-19.6 years, respectively. The men were exam ined soon after or just

before retirem e nt in 1991. Lim ited environm ental m onitoring data indicates that the degree of Al exposure varied betw een the subgroups and over the years. Average annual total dust concentrations in the potroom were reduced significantly from 9.5 m g / m 3 in 1977 to 3.0 m g / m 3

in 1990. Alum inum levels were no t specifically reported, but the av erage Al content in the total

potroom dus t was approxim ately 20% by weight; ot her constituents of the dust included fluoride and coal tar pitch com ponents. Data from an Al uptake/excretion study of workers from the

sam e plant indicated that the level of Al e xposure was approxim a tely 8 times higher in the

potroom than in the foundry (0.48 and 0.06 m g / m 3 , respectively) (Drablos et al., 1992). Medical

exam inations (including lung function, standard laboratory tests and serum and urine Al concentrations) and a neuropsychol ogical test battery were perf orm e d. The battery assessed six

m e ntal functions (neuropsychiatric symptom s , m o toric/sensoric, reaction tim e , psychomotor speed/ef f i cie n cy, m e mory/lea r ning a nd inte llig en ce) using a q u estionn air e and 15 dif f e rent objective tests. Som e subtle defi cits were found in potroom worker s that were not considered to be indicative of a significant neur ological syndrom e. The findings in potroom workers included

a subclinical trem or as indicated by results of a s t atic stead ine ss tes t [ tim e scores on one of two test indices were significantly wors e in com p arison with th e control group (84% slow er, p=0.03)], and possible tendencies (i .e., test results that were about 1 SD below norm a l m ean values bu t n o t sta tis tic ally signif i can t) f o r incr eas ed risk of im paired visuospatial organization (Block Design subtest of the W echsler Adult In te llig ence Sca l e) and psy c hom o tor te mpo (one Halstead ReitanTrail Making test). Although these findings were not considered to be indicative of a neurologic syndrom e, it was suggested that they m a y be early signs of CNS i m pairm e nt. Additionally, the finding of a subclinical trem or seem s to be consistent with the trem or 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 cons istent with those of Al s m e lter workers in indicating th at occupational exposure to Al can be neurotoxic. CNS function was evaluated in 17 w e lders who had an average of 15 years (range 5-27 years) ex p e rien ce, with the last 4 y ears ex clus ively with Al (Hanninen et al., 1994). Most of the weld ers had equipment that ventilated the welding

m a sks but the respiratory protection was not alw a ys used. T h e assessm ent included

m easure m ents of serum and urinary Al, neurops ychological tests (sim ple reaction time, three tests for psychom otor speed, two tests for visual and spatial ability, four m e mory tests and two verbal ability tests), a symp tom questionnaire and neurologic al interview, quantitative electroencephalography (QEEG) a nd P-300 event-related auditory-evoked responses. Serum and

urine Al levels were 3.5 and 8.5 tim es higher, respectively, than an unexposed reference population. The welders perform e d norm a lly on the neuropsychological tests, although correlation analysis of test scores and exposure param e ters showed weak negative associations

between the four m e m o r y tests and urinary Al lev e l and a pos itive a ssociation between the

variab ility ( s tandard d e viation ) of visual reaction tim es and seru m Al levels. Analysis of the QEEG data showed that serum Al levels were po sitiv ely co rrelated with the am ount of delta and theta activity in the brain frontal region and ne gatively correlated with the am ount of alpha activity in the frontal region. Re sults of this study (d isturbances of m e m o ry and attention, QEEG changes sim ila r to tho s e in patients w ith Al enc e pha l opa t h y) we r e i n te r p re ted as consistent with known CNS effects of Al, but insufficient for es tablishing a definite relationship betw een Al exposure and effects.

In another study of Al welders, CNS eval uations were perform e d on 38 m e n who ha d at least 5 years exposure (m ean 17.1 years) and a control group of 44 ra ilway track welders exposed to m e tal fum e s other than Al (m ean 13.8 years) (Sjogren et al., 1996). Lim ited monitoring data indicated that the medi an exposure to welding fum e s wa s 10 m g / m 3 and that the Al content was 40% of the total fumes. Sym p tom questionnaires, psychological tests (sim ple reaction time, finger tapping speed and endurance, digit span, vocabulary, tracking, symbol digit coding, cylinders, olfactory threshold and Luri a-Nebraska motor scale), neurophysiological indices [electroencephalography, P-300 auditory-evoked responses, brain-stem auditory evoked responses and diadochokinesis (ab ility to perform rapidly alternating m ovem e nts with one lim b)]

and blood and urine Al levels were assessed. The blood and urine Al concentrations were approxim a tely 3 and 7 tim es higher in the Al welder s than in the controls, but there were no clear correlations between duration of exposure to Al a nd concentration of Al in blood or urine. The Al welders reported m o re acute CNS sym p to m s ( e .g., concentration difficulties) and had

decreased motor function in five tests (finger tapping in non-do m i nant hand, two tasks from the

Luria-Neb r aska m o tor scale, pegboard peg m ove m e nt with dom i nant han d, am plitude of

diadochokinesis in dom inant hand) when com p ared to the control group. Urinary Al

concentratio n was significantly co rrelated with acute CNS sympto m s , but not with any of the perform a nce m easures. To further study possible dose-effect relationships of Al exposure, the

Al welders were com b ined with the control gr oup and divided into three exposure categories

accord ing to urinary Al levels, us ing the 50 th and 75 th percentiles as category dividers. The group with the highest mean urinary Al level had significantly m o re acu te CNS sym p tom s and significantly reduced perfor m ance on one of the mo tor function tests (a L u ria-Nebraska m o tor

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scale task) when com p ared to th e group with the lowest Al leve l. In an earlier study of 65

welders with ≥ 10 years of exposure to Al fum e s, th e highest exposure category (based on exposure duration) was 2.8 tim es more likely th an unexposed workers to have three or m o re neuropsychiatric sym p tom s (Sjogren et al., 1990).

A body of e p idem iological evidence has pointed to an increased incidence of cancers of

various kinds in workers em ployed in the alum in um production industry. However, as discussed

in a rev i ew by Ronneberg and Lang m a rk (1992), the concern about poten tial cancer hazards in

the alum inum industry h a s prim arily arisen b ecau se of exposures to po lycyclic arom atic hydrocarbons (PAHs) and coal tar pitch vol atiles (CTPVs) rather than to Al per se . T hus, while

a num ber of studies have provi ded inferential data linking oc cupationally exposed alum inum workers with an increased risk of developing tumors of the bladder or lung (Gibbs, 1985; Thériault et al., 1984, 1990; Arm s trong et al., 19 86; Spinelli et al., 1991 ; Pearson et al., 1993;

Trem blay et al., 1995), it would be unwise to ascribe any excess tum o r for m ation to the effects of Al in view of the concurrent exposure to well-docum ented carcinogenic PAHs such as benzo(a)pyrene. The issue is further com p licat ed by the likely exposure of production workers

to other substances such as fl uorides, sulfur dioxide, arom atic am ines and asbestos (Ronneberg and Langm a r k, 1992; Trem blay et al., 1995; Dufresne et al., 1996), and to the possible effects of cigarette smoking in affected individuals. Cons equently, these studies have failed to provide

direct evid ence for the carcinog enicity of Al fumes and dusts.

Animal Stu d ies

Oral Exposure

Num e rous subchronic anim al studies were loc a ted in the b i o m edical/toxicologic a l literature but only those that defi ne the threshold region of the or al dose-response relationship are

summarized in this p a pe r. A m a jor lim itation of m a ny of the studies of Al toxicity is the lack of

com p lete inform ation on total dietary (e.g., food a nd drinking water) intake of Al and of other

elem ents that are known to effect Al biokinetic s and toxicity (e.g., calcium and m a gnes i um ).

Estim ated or reported dosages used in studies in which Al content of the basal d i ets are not reported m u st be assum e d to underestim ate the actu al experim e ntal dosages. The m a gnitude of

the underestim ate m a y be considerable. For ex ample, a range of Al contents of 200-1200 m g Al/kg for commercial grain-based diets (Gol ub et al., 1992b) would provide 30-200 mg Al/kg bw-day in a subchronic or chroni c mouse bioassay [based on U.S. EPA (1988) default values for body weight and food intake]. On this basis, studi es in which com p lete dietary Al intakes were not reported or could not be esti m a ted m a y provide som e infor m a tion about the hazards of oral exposure to Al but are inappropria te for establishing NOAEL s or L OAEL s for the critical effect

of Al. NOAELs and LOAELs fr om studies that provide estim a tes of total Al dosages, or otherwise provide inform ation relevant to determ ining the NOAE L/LOAEL bound ary for the critical effect of Al are p r esented in Table 1 and are summ arized below.

Systemic tox i city

Groups of 10 fe m a le Sprague-Dawley rats were adm i nistered alum inum ni trate nonahydrate in sugar-containing drinking water at doses of 360, 720 and 3600 m g /kg-day (26, 52

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and 259 m g Al/kg bw-day, respectively) for 100 days (Dom ingo et al., 1987). A control group

rece ived sug a r-con tain in g distille d water only. S ugar 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.

Ani m als were housed in m e tabolic cages to facilitate th e collection of fecal and urine sam p les. Food and water consumption were m easured da ily, body weights were noted weekly and blood

sam p les were taken at monthly intervals and at term ination to m onitor clinica l chem istry and

hem a tological param e ters. At term ination, all an im als were necropsied, and the weights of m a jor organs (brain, heart, lungs, kidneys, liver and sp leen) were m onitored. Alum inum concentrations

were m easured in various tissues, pieces of which were processed for histopathological

exam ination. A significant decrease (p<0.05) in body weight gain was observed in the 259 m g Al/kg-day group, attributed by the authors to de creased food intake. Overall, no consistent

variations in hem a tological (hem ogl obin, hem a tocrit) or clin ical chem istry (SGOT, SGPT, alkaline phosphatase, urea, crea tin in e, tota l pro t e i n, chole s te r o l, glucose) param e ters were
observed. N o histopathological alterations in the heart, live r , ki dney, spleen, brain and

cerebellum were observed. Interpretation of th ese data was com p licated by the concurrent exposure of the rats to high doses of nitrate of up to 475 tim es the RfD for nitrate (1.6 m g nitratenitrogen/kg-day) which is based on m e the m oglobinem ia in hum a ns (U.S. EPA, 1999). Therefore, b ecause of nitrate co-expo sure, the ab sence from the study design of a food-restricted control group and uncertainty surro unding the contribution of Al in food, the apparent effect of Al on body weight gain cannot be conc lusively attributed to A l alone.

Som e recent studies h a v e identified a num be r of potential tox i colog i cal responses in laboratory anim als exposed orally to Al com pou nds in a subchronic or chronic dosing regim e n.
In m o st cases, however, only one dose level was em ployed in the study compared to controls,

and since th e am ount of Al in the d i et was not given, the resu lting dos e level rep r esen ts an
increm ental dose of Al com p ared to that of cont rols as baseline. However, while these studies

m a y o f fer inadequate quantitative dosim e tric inform ation for NOAE L/LOAEL identification and consequent RfD developm ent, they provide an q u alitative in dication of a range of potential toxicological responses that m i ght be induced in hum a ns exposed to the elem ent. For exam ple, Garbossa et al. (1998) studied th e potential for w a ter-soluble Al to affect the erythropoietic integ r ity of late e r ythro i d progenitor c e lls in the bone m a rrow. Three groups of five male W i star rats/group w e re either (1) gavage d w ith citrate at a dose of 1.0 μm Al/g-day (27 m g /kg-day), 5 days/week, for 15 weeks, (2) had drinking water containing 100 mm ol Al/L m a de available to
them as the citrate for th e sam e length of tim e or (3) m a intain ed as controls. As calculated by th e authors, the dose associated with the applied c oncentration of Al in dr inking water approxim a ted to 14-17 μmol/g-d ay (42 0 m g /kg-day ) . Rats ha d access to a s t andard cho w diet, thou gh with no

indication of the baseline concentration of Al provi ded therein. At the end of the in-life phase of the study, all rats were sacrif iced, and sam p les of blood were obtained for hem a tological investigation. Fe m o ral bone m a rrow cells were flushed with physiological m e dium , stim ulated

with recom b inant hum an erythr opoietin, then m o nitored for th e com p arative incidence of colony-forming units-erythroid (CFU -E). Further tests were carri ed out to m onitor the osm o tic fragility and average life-span of erythrocytes fro m each test group. The anim als in the group receiving Al at the higher dose show ed decrease d hem a tocrit, hem oglobin concentration, m e dian

osm o tic fragility and erythrocyte life-span values com p ared to contro ls. T h e conten t o f Al

increased in the serum and bone of both exposed groups, the distribution of concentrations in bone correlating inversely with the extent of an anim al’s CFU-E developm ent.

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That Al in drinking water m a y have the ab ility to cause his t op at hological changes and altered hepatic enzym e a c tivities was suggested by Basu et al. (1997) who m a de available

alum inum c h loride in drinking water to groups of eight m a le Sprague-Dawley rats at a dose of 50 mg/kg-day (10.1 m g Al/kg-day) for 40 days. Add ition a lly, o t her groups o f si m ilarly

- treated rats received drinking water containing either 0, 50, 100, 200 or 400 ppm ( m g/L) added calcium (Ca), as th e chloride. T h e aut hors reported increased specific activities of acid and alkaline phosphatases in liv er 10, 000 x g supernatan ts fro m Al-receiv i ng anim als versus con t ro ls, and in alkaline phosphatase activity in equivalent kidney preparations. The presence of Ca in the drinking water appeared to re verse th ese changes, plus the accom panying histopathological

features ass o ciated with them

.

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

harmf u l ef f e cts in labor a t ory an im als, in re lati on to the well-docum ented association between Al

and the onset of osteom a l acia. Male STD W i star rats were divided into four groups (n=4), receiving either (1) a norm a l diet (Group I), (2) a norm a l diet s upplem ented with Al (Group II), (3) a Ca-deficient diet (Group III) or (4) a Ca-deficient diet with supplem ental Al (Group IV), for

10 weeks. Blood sam p l e s were taken at term in ation, and then anim als were perfused with paraform aldehyde/glutaraldehyde fixative. Levels of Ca, iron (Fe) and Al in serum and bone

were m easured by atom ic absorption spectrophotom e try, and sections of th e resected right tibia were prepared for histopathologi cal exam ination after decalcification in 5% form ic acid in 10%

for m alin.

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

and 4 were com p ared to anim als from groups 1 and 2, the values for the latter groups rem a ining constant from about 4 weeks of dosing. In di scussing their histopathol ogical findings, the

authors described no decrease in th e thickness of cortical bone in Group II com p ared to control,

while bone s p ecim e n from Groups III and IV sho w ed “an increase in os teo i d as well as osteoblasts and osteoclasts”, in a ddition to other disturbances of ossification. Such effects were considered to suggest bone fragility, with cha nges being m o re m a rked in Group IV compared to

III. The amount of Al in the tibia of exposed rats was significantly g r ea ter in Group II than in Group I, whereas the average levels in Groups III and IV showed a fu rther increase in Al deposition, most notably in group IV. There we re also differences am ong the groups in the concentration of Fe in bone (tibia ), and in the concentrations of Al, Ca, Fe and the levels of parathyroid horm one in blood. The authors concluded that Ca defi ciency appeared to potentiate the deposition of orally adm i nistered 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 investiga tion indicated profound changes in the cerebrovascular and neuronal integrity when m a le Long-Evans rats (n=9) were exposed for 52 weeks to 0.5 ppm

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

0.019 m g /kg-day, based on a defau lt drinking water consum ption of 0.057 L/day, and a default body weight of 0.472 kg for m a le Long-Evans rats (U.S. EPA, 1988). Duel control groups received either NaF (fluoride cont rols) or double distilled deionized water. Tissue levels of Al

were m easured in brain, liver and kidney by th e use of a direct current plasm a technique.

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Ani m als receiving alum inum fluoride showed poor survival com p ared to the other groups, with 6/9 having died by week 48. The tissue concentra tions of Al were increased in the brain and kidney compared to both the control groups, with Al-fluorescence being used to dem onstrate that Al deposition was m o stly in th e vasculature. Morphological a nd histopathological changes due

to treatm e nt were apparent in the liver, kidney and spleen. Som e changes in neuronal integrity were also evident in the hippocam pus and neocor tex. Other cytological changes in the brain

were associated with chrom a tid clum ping, pyknosis and vacuolation.

A report by Som ova et al. (1997) describes a study in which 10 m a le W i star rats/group received either 0, 5 or 20 m g /kg-day alum inum c h loride by gavage in water for 6 m o nths. At

term ination, all anim als were exsanguinated, th en subjected to a necropsy in which excised pieces of liv e r, kidney and cardiac and skelet al muscle were taken for histopatho l ogical

exam ination. Pieces of brain were exam ined by electron as well as light m i croscopy , and all

tissues were monitored for Al concentrati on by atom ic absorption spectrophotom etry. As tabulated by the authors, Al in plasm a and all of the lis ted tiss ue s was dose-dependently increased to levels that were statistically sign ificantly greater than controls. However, though described in qualitative term s and illustrated photographically, the Al-i nduced lesions did not

rece ive a qu antitative tre a tm ent in th e repor t. Th us, while a t least som e of the low dos e rats displayed NFD (neuro fibrillar degeneration) of the hippocampal region of the brain, insufficient

data a r e pro v ided in the report to app l y this ob ser v ation to the identi fication of a NOAEL or

LOAEL.

Dietary exp e riments

Six Beagle dogs/sex/group were fed a diet providing either, in m a les, 0, 118, 317 or 1034 mg/kg-day sodium alum i n um phosphate (0, 3.4, 9.0 or 29.4 mg Al/kg-day, respectively) or, in

fe m a les, 0, 112, 361 or 1087 m g /kg-day sodium alum inum phosphate (0, 3.2, 10.3 or 30.9 m g Al/kg bw-day, respectively), for 6 m o nths (Katz et al., 1984). No infor m ation was available on the level of Al in the diet, and no compound-rela ted effects on body weight gain, hem a tological

and clin ical chem istry param e ters (p aram eters not specified) or hist opathological endpoints (m ajor organs and tissues exam ined) were observed. A highest NO EL of 30.9 m g Al/kg-day could be tentatively identified in this study, but this would not include the contribution of Al

f r om the basal die t , nor r e f l ect th e id entif ica ti on of any toxicological effects, sin ce th e NOEL occurred at the upper limit of the dose-response curve.

Neurotoxicity

A num b er of studies have been reported in which neurotoxicol ogical/neurobehavioral effects have been explicitly evaluated. In othe rs, the effects of Al on neurological developm ental

have been addressed. F o r exam ple, Golub et al. (1989) fed diets containing Al as the lactate at 25 (controls), 500 or 1000 m g Al/kg diet (3.3, 65 or 130 m g A l/kg-day) to groups of 15 fe m a le

Swiss-W e bs ter m i ce for 6 weeks (Golub et al., 1989) . No m i ce were exposed to lactate alone. While no statistically significant differences in food intake or body weight gain were observed,

m i ce fed the highest Al concentration gained le ss weight than the cont rols or low-dose group. As reported by the authors, a significant decrease (20%) in sp ontaneous m o tor ac tiv ity (i.e., tota l,

vertical and horizontal m ovem e nt) was observed in the 130 m g Al/kg-day group. Activity in the

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65 m g Al/kg-day group was not sign ificantly different than the controls. Thus, the highest

NOAE L is 65 m g Al/kg-day and th e LOAEL is 1 30 m g Al/kg-day.

Neurobehavioral effects of alum inum lactate were evaluated in groups of 12 fe m a le

N:NIH Swiss-W e bster 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 cons um ption to body weight (U.S. EPA, 1988) and reported body weight data (the tim e-weighted average weight is 25.4 g), the dosage in the treated

m i ce is estim a ted to be 190 m g Al/kg bw-day. No m i ce were exposed to lactate alone. A neurobehavioral test battery used by Donald et al. (1989) was ad m i nistered at the beginning of the experiment (day 0) and after 45 and 90 (±3) d a ys, with motor ac tiv ity evalua ted at the la tte r two tim e points. Alum inum levels w e re m easured in brain, femur and liver at the end of the exposure period.

Body weight was significantly increased in the treated m i ce but no exposure-related changes in f ood intake or overt signs of ne urotoxicity 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 m i ce. Spontane ous m o tor activity was reduced at 90 days as indicated by decreased total activity counts, horizontal activity counts and percentage of intervals with high

activ ity cou n ts. Alum inum concentr ations in th e brain and liver were increased appro x im ately

3-fold in the treated m i ce, but brain and liver lipid peroxidation indi ces were not altered.

Male W i star rats (6-8 per group) were exposed continuously for 6 m onths to food containing 1.52 m g Al/kg (norm a l diet) or 1000 mg Al/kg as alum inum c h loride with citrate (Florence et al., 1994). The aver age daily Al intake was estim ated to be 0.13 or 84 mg Al/kg bw-day, assum i ng a body weight of 0.305 kg (arithm e tic m e an of default m a ture weight of m a le

W i star 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 sto i chiom e tric p r oportion to Al, therefore, the

estim ated daily intake w a s 598 m g /kg-day. Rats exposed to Al deve loped histopathological

abnorm a lities in brain tis s ue, not specific to any brain region, characterized by extens ive cytoplasm i c vacuolization in astroc ytes, swelling of astrocytic proce sses, particularly of astrocyte end-feet abutting blood vessels. Neurons also ex hibited vacuolization a nd nuclear inclusions. Although no specific behavioral assays were reporte d, the investigators note d that "no significant behavioral changes were observed". Accord ingly, the functional significance of the histopathological lesions is uncer ta in . The lesion s appear to d i ffer from the NFD observed with parenteral Al exposures (Kowall et al., 1989; W a ka yam a et al., 1993); or f r om exposures to Al in

com b ination with calcium depriv ation (Garruto et al ., 1989; Kihira et al., 1995; Mitani, 1992). The LOAEL for histopathological changes in the brain was 84 m g Al/kg-day.

Male Sprague-Dawley rats (40 per group) we re exposed in drinking water to 0, 50 or 100 mg Al/kg bw-day as alum inum nitrate with ci tric acid for 6.5 months beginning at 21 days of age, 8 m ont hs of age or 16 m onths of age (Dom ingo et al., 1996). The citric acid dosage was 355 or 710 mg/kg-day in the 50 or 100 m g Al/kg bw -day groups, respective ly. Controls did not receive citric acid. Dietary Al intake was not re ported ; the r a ts were m a intained on P a nlab r a t

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chow. Anim als from c ontrol and exposed groups were subjected to a numb er of neurobehavioral tests, and at term ination, Al leve ls were m easured in various excised regions of the brain. The authors observed the highest Al levels in the olf actory bulb and rhachidical bulb, while the cortex

and thalam us were the regions showing the lowest Al content. However, com p ared to controls, there were no significant effects (p>0.05) of Al (with citric acid) on spontaneous m o tor activity (open-field) or passive avoidance operant training or perf ormance (grid floor shock, light/dark shuttle box). Thus, the NOAE L wa s 100 m g 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 underestim ated because of unrepor ted Al intake from food, is still lower than

the LOAELs from other studies.

Groups of six m a le albino ra ts were adm i nistered 0 or 25 m g Al/kg bw-day as alum inum

nitrate in norm al saline by gava ge, 10% ethanol in drinking w a ter, or 25 mg Al/kg bw-day by gavage combined with 10% ethanol in drinking w a ter, 6 days/week for 6 weeks (Flora et al., 1991). The level of Al in the diet was not reported. Urinary ∆ -am i nolevulinic acid (ALA), blood ALA-dehydratase (ALAD), blood zinc pr o t oporphyrin (ZPP), glutam ic oxaloacetic

transam i nase (GOT) and glutam ic pyruvic transa m i nase (GPT) in serum and liver and brain biogenic amines and their m e tabolites [dopa m i ne (DA), norepinephrine (NE), 5-hydroxytryptam ine (5-HT), hom o v anillic ac id (HVA) and 5-hydroxyindolacetic acid (5-HIAA)] were evaluated at the end of the tr eatm ent period. Treatm e nt with Al alone caused significantly increased blood ALAD ( p <0.01), decr eased liver GPT (p<0.05), decreased brain DA (p<0.01), increased brain NE (p<0.05) and d ecreased brain 5-HT (p<0.05). Compared to

treatm ent with Al alone, concurrent exposure to ethanol and Al produced significantly decreased ALAD, increased ALA, increased Z PP, incr eased liver GPT, increased serum GOT and increased brain HVA. Significant changes found only in the co m b ined Al and ethanol group

included increased s e ru m GPT, increased brain NE and decreased brain 5-HT. Treatm ent with ethanol alone only inhibited blood A L AD. The r a ts were co-exposed to relati vely high levels of nitrate [comparable to those in the Dom i ngo et al. (1987) subchr onic study], but it seem s likely

that som e of the changes (i.e., effects on brain ch em icals) are related to alum inum whi c h is

known to be neurotox ic. Because the toxico logica l sign ifican ce of the cha nges is unclear due to lack of evaluation of neurobehavioral perform a nce and other endpoints, there is uncertainty

whether the 25 m g Al/kg-day dose is a NOAEL or a LOAEL, an uncertainty com pounded by the

absence of infor m ation about the level of Al in the basal diet.

Reproductive/developm ental toxicity

A num b er of studies have been carried out to exam ine the effects of Al compounds on developm ental toxicity, particularly their effect s on postnatal neurobehavior al developm ent. For

exam ple, Be rnuzzi et al. (1989) exposed groups of 6-12 pregnant W i star rats to alum inum

chloride or alum inum lactate in the diet on ge stational days 1 through 21. The rats received

nom i nal daily doses of 0, 100, 300, 400 m g Al/kg as alum inum chloride or 0, 100, 200 or 400 m g Al/kg as alum inum lactate. No rats were e xposed to lactate alone, and inf o rm ation regarding level of Al in the basal diet was not reporte d. On the average, there was a less th an 10 %

decrease in m a ternal body weight gain and no eff ect on food or water intake. No significant

dif f e rence in litter size w a s observed. However, postnatal morta lity incr eased 55% a nd 26% in offspring of the rats exposed to 300 or 400 m g Al/kg-day, respectively. T h e offspring of da m s

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fed ≥ 300 m g Al/kg-day weighed significantly less th an 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 alum inum lactate. T h e follo wing tests were used to assess neurom otor developm ent (m aturation): right ing reflex, grasping reflex, nega tive geotaxis, suspension test

and locom o tor coordination. The tests were perform e d on PDs 4, 6, 9, 12 and 20, respectively.

Im pair m e nt of neurom otor developm ent (rightin g and grasping reflexes) was observed in the pups exposed to ≥ 200 mg Al/kg-day. Im paired grasping reflex was also observed in the 100 mg/kg-day alum inum lactate group. Offspring of rats fed 400 m g /kg-day also exhibited altered perform a nce on the locomotor coordination test.

A follow-up study by the sam e research group found that ingestion of 400 m g Al/kg bwday as alum inum lactate had no effect on pos tnatal m o rtality, body we ight and righting and grasping reflex tests (Muller et al., 1990), although significant di fferences between control and

exposure groups were n o ted in loco motor c oord i nation and operant con d ition i ng tes t s. Significant differences between co ntrols and exposed groups in th e negative geotaxis test were

lim ited to those pups of dam s treated during th e second and third weeks of gestation, a finding interpreted by the authors to i ndicate the possibility of long-term e ffects 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 st udy (Bernuzzi et al., 1989) could

be related to environm ental m odifications. In pa rticular, the m o thers and pups were m u ch m o re protected in the Muller et al. ( 1990) study than in the prev ious one because they were h oused in plastic cages instead of wire m e sh cages and rece ived cotton to build nests. Body temperature of the pups, therefore, m a y have been more adequately m a intained 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 coul d explain the differences in neurom otor perform a nce.

Muller et al. (1990) administ ered diets supplem ented with 0 or 400 m g Al/kg bw-day as

alum inum lactate to groups of 6-9 pregnant W i st ar rats on days 1-7, 1-14 or 1-21 of gestation. No rats were exposed to lactate alone, and inform a tion regarding le vel of Al in the basal diet was not reported. Neurom otor developm ent was a ssessed on postnatal days 4, 6, 9, 12 and 20 using tests of righting reflex, gr asping reflex, negative geotaxis, suspension and locom o tor coordination, respectively. Learning ability was also tested on PD 65 using operant conditioning. No effects on m a tern al body weight or food intake were observed in dam s exposed on gestational days 1-7 or 1-14. In the da m s exposed on gestational days (GD) 1-21, a significant decrease in m a ternal body weight (26 and 35%, respectively) was observed on days 16 and 19 of gestation. Decreased f ood intake was also observed on day 19 of gestation. No effects on litter size, postnatal m o rtality or postn atal body weight were observed. Im pairm e nt of

neurom otor developm ent (p<0.05) w a s observed in two of the five tests (negative geotaxis and

locom o tor coordination); no differe nces between the three treated groups were observed. For the

operant con d ition i ng tes t , there were significan t differences (p<0.05) between the treated and control young rats. No differences between the three treated groups were observed. The LOAEL for developm ental toxicity is 400 m g Al/kg-day, but this does not include the

contribution of Al from t h e basal diet.

Groups of 10 pregnant S p rague Dawley rats were adm i nistered 180, 360 or 720 m g /kgday alum inum nitrate nonahydrate by gava ge (13, 26, 52 m g Al/kg bw-day) on GDs 6-14

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(Paternain et al., 1988). A vehicl e (water) only control group was used. The level of Al in the diet was not reported. Alum inum exposed dam s gained significantly less weight than the

contro ls. No signif i can t ef f ects on the num bers of litte rs, co rpora lu tea, total im plants, live fetuses, resorptions or runt fetuses w e re observe d. 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 m g Al/kg-day dose level. No dose-relate d extern al or visceral m a lfor m a tions were observed in the offspring. However, a signifi cant increase in the incidence of skeletal

m a lfor m a tions (delayed ossification, hypoplastic defor m ed ribs) was observed at all three

treatm ent levels. In ad dition, the incidence of he m a tom a s wa s significantly increased at the high

dose. Becau se the rats w e re co -exposed to relati v e ly high lev e ls of nitrate [com parable to those

in the Dom i ngo et al. (1987) subc hronic study], the effects of treat m e nt cannot be conclusively attributed to Al alone, in the abse nce of a nitrate-e xposed control group.

By contrast to the striking findings of poten tially teratogenic effects of alum inum nitrate in Sprague-Dawley rats, as described above (Pat ernain et al., 1988), e quivalent experim e nts by

Dom i ngo et al. (1989) in Swiss m i ce did not reveal any repr oductive, developm ental or teratogenic effects of Al, when adm i nistered to dam s as the hydroxide. D o m i ngo et al. (1989)

adm i nistered by gavage 0, 66.5, 133 or 266 m g /kg-day alum inum hydroxide (0, 23.9, 47.8 or

95.5 m g Al/kg bw-day) to groups of 20 pregnant Swiss m i ce on GD 6-15. The level of Al in the diet was not reported. T h e dam s wer e kill ed on GD 18. No com pound-r e lated effects were

observed on m a ternal m o rtality, clin ical signs, body weight, food inta ke or absolute or relative heart, lung, spleen, liver, kidne y and brain weights. In ad dition, no com p ound-related effects

were observed on num bers of im plantations, resorp tions, live and dead fetuses, sex ratio and the

incidences of external m a lform a tions, internal sof t -tissue defects or skeletal abnorm a lities. Therefore, this study identifies a NOEL of 95.5 mg Al/kg-day by default for reproductive, developm ental and teratogenic toxicity in m i ce. However, neurom otor developm ent was not
assessed and the contribution of Al from the basal diet was not stated in the report.

A num b er of studies have been designed to evalu a te th e influ e nce of citrate or lactate on the potential developm ental toxicity of Al. For exam ple, Gom ez et al. (1991) exposed groups of 15-19 pregnant Sprague-Dawley rats to either di stilled water (controls) or 133 m g Al/kg bw-day

in the form of either alum inum hydroxide (384 mg/kg-day), alum inum c itrate (1064 mg/kg-day)

or alum inum hydroxide (384 m g /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 re ported and no rats were exposed to citric acid

alone. Term inations were perform e d on GD 20. Maternal and fetal evaluations show ed exposure-related effects only in the group expos ed to alum inum hydroxide and citric acid concurrently. Significant change s included reduced m a ternal body weight gain on G D s 6-20 (but not at sacrifice on day 20), reduced fetal body wei ght and some skeletal variations (increased delayed occipital and sternebrae ossification and increased absence of xi phoides). No effects

were seen on m a ternal f ood consumption or clin ical signs, m a ternal abso lute or relative liver, kidney or brain weights, gravid uterine weight, corpora lutea/dam

, i m plantations/litter, pre- or postim plantation loss/litter, viable or nonviable implants/litter, fetal sex ratio or fetal

m a lfor m a tions (external, visceral or skeletal ). This study identifie d a stand alone m i nimum

LOAEL of 133 m g Al/kg-day fo r non-neurobehavioral developm ental toxicity of alum inum hydroxide and alum inum citrate in rats. Alt hough confidence in this L OAEL is low (because

alum inum hydroxide adm i nistered concurrently with citric acid induced did developm ental

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effects and because the d o se does not include a co ntribu tion of Al from the basal d i et) the value is consistent with the developm ental NOAE L of 95.5 m g Al/kg-day for al um inu m hy droxide in

m i ce (Dom i ngo et al., 1989).

In a sim ilar experim e ntal protocol, groups of 11-13 pregnant fe m a le Swiss albino (CD-1)

m i ce were adm i nistered 57.5 m g Al/kg bw-day as either alum inum hydr oxide (166 mg/kg-day),

alum inum lactate (627 mg/kg-day) or alum inum hydroxide (166 m g /kg-da y) concurrent with lactic acid (570 m g /kg-day) by gavage on gesta tion days 6-15 (Colom ina et al., 1992). Other groups were treated with lactic acid alone (570 m g /kg-day, eq uivalent to the am ount in 627 mg/kg of alum inum lactate) or distilled water (c ontrols). The level of Al in the diet was not reported. Fetal evaluations were perf orm e d on GD 18, including exam inations for skeletal and

viscer al abn o rm alities in approxim a tely two- thir ds and one-third of the p ups, respec tively. The investigators noted that the dose of Al (57.5 m g /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 alum inum lactate-treated m i ce when eval uated over GDs 6-9 (92%), 6-12 (55.6%) and 0-18 (38.5%) and in the m i ce treated with com b ined alum inum hydroxide and lactic acid evaluated over GDs 6-12 (37.8%), 6-15 (42.7%) and 0-18 (15.7%). The decreased m a ternal weight gain in

the alum inum lactate group was accom panied by significantly reduced food consumption during gestation days 6-18. Significant developm ental and/or teratological e ffects in the alum inum lactate group included 16% reduced fetal body weight (p<0.01) and increase d incidences of cleft palate (13.2%, p<0.05), dorsal hype rkyphosis (i.e., excessive flexi on of spine) (13.5%, p<0.05) and delayed parietal ossifica tion (15.4%, p<0.01). These deve lopm ental effects were not observed in any of the control or alum in um hydroxide exposed pups, and the only other significant changes in the other gr ou ps were decreased m a ternal re lative liver weig ht and delayed

f e tal par i etal ossif i ca tion in th e lactic acid only exposure group. Other types of internal or

skeletal m a lfor m a tions o r variations were not found in any of the fetuses. Additionally , no effects were seen on m a ternal absolu te or rela tive kidney weight, gravid uterine weight, num bers

of i m plantation sites/litter, live or dead fetuse s, r e sorptions, p o stim plantation loss /litte r , litte rs with dead fetuses or fetal sex ratio in any of the groups. By analogy to the findings of the

Dom i ngo et al. (1989) and Gom ez et al. (1991) studies, the lack of developm ental effects of

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

In a m o re recent study, p r egnant Swiss m i ce were adm i nistered gavage d o ses of 0 or 104 mg Al/kg bw-day as alum inum hydroxide on days 6-15 of gestation (Colom ina et al., 1994). Dietary Al intake was n o t reported ; the m i ce were m a intained on Panlab rodent chow

. Com p ared to controls, there were no effects (p>0.05) of Al on m a tern al body or organ weight,

num b er of implantations per litt er, num b er of resorptions per litter, num ber of dead fetuses per litter, percentage of positive pos t-im plantation loss, sex ratio or fetal body weight per litter.

Gross exte rn al, vis cera l o r skele t a l ex am ination of f

e tuses rev e aled no abno rm alities o r developm ental variations. Thus, the NOAE L for de velopm ent effects from this study is 104 m g Al/kg-day, however, this does not include the Al contribution from food. Thus, based on this study and the previous study (Colom i n a et al., 1992) , alum inum lactate appears to be more potent as a developm ental toxicant in m i ce than the less water soluble alum inum hydroxide.

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Groups of 16 pregnant S w iss-W e bster m i ce were fed 25 (control group), 500 or 1000 mg Al/kg diet as alum inum l actate throughout gest ation and lactation (Dona ld et al., 1989). The control diet was fed to pups that were selected for post-weani ng neurobehavioral assessm e nt. 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 e nd of lactation. No m i ce were exposed to

lactate alone. There were no treatm ent-relate d changes in m a ternal survival, body weight (m easured 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 grow th and developm ent in pups as assessed by body weight, toxic si gns on PDs 0-55, and by crown-rum p le ngth on PDs 0 and 20.

Neurobehavioral m a turation was tested in two pu ps per litter on PDs 8-18 with a 12-item test battery (fore- and hind limb grasp, fore- and h i nd paw placement on sticks of 2 widths, vibris sa placing, visual placing, auditory and air puff startle, eye openi ng and screen grasp, cling and

clim b). A neurobehavioral test battery was adm i ni stered to six pups per litter at age 25 days (4 days postweaning) or 39 days (for e- and hindlimb grip strengths, tem p era t ure sen s itiv ity of tail, negative geotaxis, startle reflex to air puff and auditory stim ul i) or age 21 and 35 days (foot splay). The pre-weaning neurobeha vioral testing showed that a significant (p=0.007) num b er of pups in the high dose group had im paired vertical screen climb perform a nce. The postweaning

neurobehavioral assessm ent showed significantly (p<0.05) altered pe rform a nce on several tests.

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

hindlim b grip strength at age 25 days in bot h low and high dose groups, increased foot splay distance at age 21 days in both low and high dos e groups and at age 35 days in the low dose group, and increas ed forelim b grip strength at ag e 25 days an d decreased therm a l sens itiv ity at age 25 and 39 days in the high dose group. Th ere were no treatm ent-related changes in concentrations of Al in pup liver or bone (brain tissue was not analyzed).

In a m o re recent study o f si m ilar design by the sam e group of investigato r s, groups of 14

and 9 fe m a le Swiss W e bster m i ce (6-8 weeks old) were fed 25 (control) or 1000 m g Al/g diet as

alum inum lactate, respectivel y, during gestation and lactati on (Golub et al., 1992b). The 1000 mg/g concentration was selected based on the demonstration of neurobe havioral effects in weanlings at this level (Donald et al., 1989). No m i ce were exposed to lactate alone. Using food intake and body weight values estim ated from re ported data, m a ternal doses are estimated to be approxim a tely 4.3 and 174 m g Al/kg bw-day at th e 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 e xposed to excess Al via m a ternal diet during gestation, lactation, both or ne ither (i.e., 25 ppm during gesta tion and lactation, 1000 ppm during gestation and 25 ppm during l actation, 25 ppm during gestati on and 1000 ppm during lactation, and 1000 ppm during gestation and lactation). Maternal effects incl uded 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 neurot oxicity (hindlimb splaying and dr agging) in one treated dam at postnatal day 21 (weaning); this da m had seizures and died 4 days la ter. No treatm e nt-re la ted effects on litter size, birth weight, crown-rum p l e ngth, righting ability at birth, sex ratio or postnatal survival were observed. Both ge station-only and lactat ion-only exposure caused significantly (p<0.05) decreased bod y weight gain in the treated pups beginning on postnatal day 10; com b ined gestation and lactation exposure produced the greatest decrease (approxim a tely 24% at weaning). Neurobehavioral testing using the sam e batte ry as Donald et al. (1989) was

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perform e d a t weaning on the dam s and on a total of 12, 16, 12 and 6 pups (1 m a le and 1 fe m a le pup per litter) from the control, gestation-only, lact ation-only and com b ined gestation and lactation groups, respectively. Results of th is testing showed effects only in pups, including significantly decreased forelim b grip strength after gestation- only exposure, increased hindlim b grip strength after both gestation and lactation ex posure, decreased tem p e r atur e sens itivity af ter lactation-only exposure, and longer negative geotax is latency after lacta tion-only exposure. In general, the findings of this st udy are consistent with those of Donald et al. (1989) in showing neurodevelopm ental effects at th e 1000 m g /kg dietary c oncentration, although intake dosages are

dissim ilar at the end of lactation. Using the dosage at the beginning of gestation, this study

defines a L OAEL of 174 m g /kg-da y f o r develop m ental ef f e cts.

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, partic ipated in other behavior al tests currently, and experienced no growth retardati on. T h e effects found only in the cross-fostered groups in the Golub et al. (1992b) study (lower forelim b strength after gestati on exposure and altered negative geotaxis latencies after lactat ion only exposure) w e re not obser ved 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 sm aller pup body size in this study. Neither gestation or lactation exposure affected pup br ain or liver Al concentrations , but lactation exposure caused significan tly lower m a nganese and iron concentrati ons in liver and m a ngane se concentrations in

brain.

In a further extension of the two previous studies (Donald et al., 1989; G o lub et al., 1992b), pregnant fem a le Swiss-W e bs ter m i ce were exposed continuously to a sem i -purified diet containing 7 (control), 500 or 1000 mg Al/kg fr om the tim e of conception, through pregnancy and lactation (Golub et al., 1995). At weaning, pups were exposed to the sam e 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 m g Al/kg) for the sam e tim e period. Based on reported dosages in previous studies by the sam e investigators, estim a ted daily dosages for m i ce exposed to 1000 mg Al/kg

diet were as follows: 200 m g /kg bw-day in preg nant m i ce, 420 m g /kg-day in lactating m i ce and

130 m g /kg-day in offspring (Golub et al., 1994); doses for the m i ce exposed to 500 mg Al/kg

diet were assum e d to be approxim a tely half of that of m i ce fe d 1000 m g Al/kg, or 100 m g /kgday in pregnant m i ce, 210 m g /kg-day in lact ating m i ce and 65 m g /kg-day in offspring.

Com p ared to the control diet, th e Al diet had no effect on dam weight, gestation length, litter size, pup weight, offspring growth or organ we ights. Operant condi tioning (nose poke) of offspring for delayed spatial alte rnation or discrim i nation reversal tasks w a s initiated at 50 days of age and continued 5 days/week for a total of 35 sessions. A neurobehavi oral test battery was

conducted w h en the offspring were 150-170 days of age (forelim b and hindlim b grip strength,

tem p erature sensitivity, negative geotaxis, air puff and auditory startle re sponse). Maternal and pre-weaning exposure to 500 m g A l/kg significantly affected (p< 0.05) operant training in the offspring, but not perform a nce after training in delayed spatial alternat ion or discrim i nation reversal tasks (i.e., decreased num ber of training sessions to achiev e th e tr a i ning c r iteria). This exposure also significantly decreased forelim b and hindlim b grip strength and puff startle response (p<0.05). Pre-weaning and com b ined pre- and post-weaning exposure to 1000 m g Al/kg sign if icantly incr e a sed (p <0.05) incidence of cagem ate a ggression at the tim e behavioral

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testing. No effects were observed on auditory startle response, tem p er ature sensitivity or negative geotaxis in offspring. Histopathological exam ination of the brain and spinal cord

revea l ed no trea tm ent-re lated changes. Thus, the LOAEL fo r com b ined matern al and preweaning exposure on neurobehavioral effects in mice would approxim a te to 100 m g Al/kg-day (estim ated daily m a ternal dosage).

Pregnant Charles R i ver CD rats were ad m i nistered gavage doses of 0, 250, 500 or 1000 mg Al/kg bw-day ("experim e nt A") or 0, 5, 25, 50, 250 or 500 m g Al/kg bw-day ("experim e nt B") as alum inum lactate in distilled water on GDs 5-15 (Agarwal et al., 1996) . Dietary Al intake was not reported. Offspring were exam ined fo r body weight, anogenital distance, oestrus cycle regularity (after puberty), durati on of pseudopregnancy induced by m echa n ical stim ulation of the cervix, oocyte production induced by an injection of hum a n c horionic gonadotropin, and m a le

and fe m a le gonad weights. Alum inum had no eff ect on litter size and no consistent effects on birth weight were observed. For example, birth weights were decr eased in m a le offs pring from

dam s that received 250 mg Al/kg-day, but not at higher dosages, and the effect was observed only in experim e nt A. Fem a le offspring birth weights decreas ed at certain dosage lev e ls in experim e nt A and increased at these sam e dosage levels in experim e nt B. Sim ilar inconsistencies between experim e nt A and B were observed f o r gonadal weights, anogenital distance, time to puberty (vaginal opening), duration of pseudopregnancy or num bers of superovulated oocytes. A signi ficantly increased (p<0.05) numb er of abnorm a l oestrus cycle lengths (defined as less than 4 days or greater than 5 days) occurred in offspring from dam s that

received 250 m g Al/kg-day (in ex perim e nt A, the endpoint was not m e a s ured in experim e nt B). However, the effect was most pronounced in the fi rst three oestrus cycles (of five observed) and not detected by the 5th cycle. Thus, the NOAEL for tem porary disturbance of the oestrus cycle in offspring of da m s ad m i nistered Al is 250 mg Al/kg-day. NOAE Ls for all other reproductive endpoints in this study were 1000 m g 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

fe m a le and three m a le Dobra Voda m i ce to e ither 0 or 19.3 mg Al/kg bw-day as alum inum chloride in drinking water. The diet also contained 160 to 180 ppm Al, giving an estimated

intake of 27-31 m g /kg-day based on default va lues for food consum ption and body weight for chronic exposure of m i c e (U.S. EPA, 1988). Usi ng this estim ate, the total Al intakes (drinking water and food) were 27 mg/kg-day (controls ) and 46.3 m g /kg-day (exposed group). The P 0 group produced three litters (designated F 1a , F 1b and F 1c ) and the F 1a group produced two litters (designated F 2a and F 2b ) from which the weanlings were exposed to Al in the drinking water starting at 4 weeks of age. There was no diffe rence in body weight gain am ong the groups in the

P 0 generation, a result that contra s t ed with the s t r i king decr eas e in th is par a m e ter in th e tre a ted

F 1b , F 1c , F 2a and F 2b groups. Though no effects on erythroc yte count, hemoglobin levels or histopathology of the liv er, spleen and kidneys were observed in the P 0 , F 1 or F 2 generations at the end of the study and no significa nt differences were seen in th e num ber of litters or offspring between the exposed and control groups, the st udy identified a LOAEL of 46.3 m g Al/kg-day, based on the observed changes in body weight gain.

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Other toxico logica l ef fects of alum inum

In a study designed to determ ine the effects of oral Al exposure on susceptibility to bacterial infection, fem a le Swiss-W e bster m i ce (13-14 per group) were exposed to a diet containing 25 (control), 500 or 1000 mg Al/kg as alum inum l actate 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 sam e investigato r s , estim ated d a ily dos ages for m i ce exposed to 1000 m g Al/kg diet are as follows : 200 m g /kg-day during pr egnancy and 420 m g /kgday during lactation; doses for the m i ce exposed to 500 m g Al /kg diet are assum e d to be approxim a tely half of that of m i ce fe d 1000 m g Al/kg, or 100 m g /kg-day in pregnant m i ce and

210 m g /kg-day in lactating m i ce (Golub et al ., 1994). At weaning, dam s and pups were

inocula t ed with a ta il v e in in jection of Listeria monocytogenes and m o nitor e d f o r morta lity f o r 10 days. In a separate experim e nt, fem a le m i ce, 6 weeks of age, were exposed to the sam e dietary Al levels for 6 weeks and then inoculated with L. monocytogenes . Estim ated Al dosages were 5, 98 or 195 m g Al/kg bw-day for th e 25, 500 or 1000 mg Al/kg dietary levels, respectively, based on a defau lt food factor of 0.195 kg diet/kg bw-day assum i ng a reference "subchronic" food intake and body weight for fem a le B6C3F1 m i ce over the period from weaning to 90 days (U.S. EPA, 1988). Inocul ation resulted in signifi cantly greater (p<0.025) mortality in dam s expos ed to 500 or 1000 m g Al/ kg diet com p ared to controls. There were no

differences in m o rtality between the groups of i noculated pups or betwee n groups of inoculated

adult m i ce exposed to Al for 6 weeks. The LO AEL for pregnant m i ce was 100 m g Al/kg bw-day and the NOAEL for adult, non-pregnant m i ce wa s 195 m g Al/kg bw-day. Although the exposure duration in this study was only 7 weeks, it is in clu d ed in Table 1 because it provides th e only dose-response data on th e effects of Al on resis t ance to patho g ens.

Carcinogenicity studies

Schroeder and Mitchener (1975a) exposed 52 Long-Evans rats/sex/group to 0 or 5 ppm Al as potassium alum inum sulfate in drinking water for life. Based on default values for drinking water consum ption 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 m g /kg-day, for m a les and

fe m a les, respectively. S t udy endpoints incl uded body and heart weight; serum glucose, cholesterol and uric acid; and ur inary protein, glucose and pH. A ll anim als were necro p sied a t
the tim e of natural death, and histo l o g ical exam inations were carried out on heart, lung, kidney, liver, spleen and gross tumors, for approxim a te ly 50% of the anim als in the group. The only

rem a rkable finding was a significant increase (p <0.005) in gross tum o r incidence in exposed

m a le rats [13/25 (52%) com p ared to 4/26 (15%) in controls], although the tum o r sites were not reported. Six of the tumors in the exposed m a le s (46% of total) were considered m a lignant

com p ared to two m a lignant tum o rs (50% of to tal) in the m a le controls. T h ere were no significant differences in tum o r incidences between exposed and control fem a les.

In another study by the sam e investigators, 54 Sw iss m i ce/sex/group were exposed to drinking water containing 0 or 5 ppm Al as alum inum potassium sulfate for life (Sch roeder and Mitchener, 1975b). Based on default values fo r drinking water consum ption and body weight for

B6C3F1 m i ce in a chronic study (U .S. EPA, 1988), these values approxim ate to Al doses of 1.2 mg/kg-day in both m a les and fe m a les. Study endpoints included body weight, gross pathology,

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and som e lim ited histology of the heart, lung, liver , kidney and spleen. The incidences of gross

tum o rs were 15/41 (36.6%) and 11/38 (28.9%) in e xposed and control m a le s, respectively, and 19/41 (46.3%) and 14/47 (29.8%) in exposed and control fem a les, respectively, differences that

did not ach ieve statis tical sign ifican ce by Fisher ’s exact test, although in cidences of multiple

tum o rs and lym phom a leukem i a were considered by the auth ors to be s i g n if icantly in creas e d in

fe m a les (p<0.025 and p<0.05, respectively). Howeve r, a definitive assessm e nt of alum inum carcinogenicity in both this a nd the rat study (Schroeder and M itchener, 1975a) is precluded by

the lim itations of the pathology exam inations and reporting.

In a m o re recent study, the tum o rigenic pot en tial of alum inum potassium sulfate was

assessed in B6C3F1 m i ce chronically exposed in the diet (O neda et al., 1994). Sixty

anim als/sex/group were fed a diet containi ng 0, 1.0, 2.5, 5.0 or 10.0% (w/w) for 20 months.

These concentrations of alum inum potassium su lfate (as the dodecahydrate) are equivalent to 0, 569, 1422, 2844 and 5687 ppm Al. Using food factors calculated with an algorithm relating food

consum ption to body weight (U.S. EPA, 1988) a nd body weight data estim a ted from growth curves reported by the investigat ors, the dosages of alum inum are estim ated to be 0, 95, 237, 483

or 1024 m g Al/kg-day in m a les and 0, 97, 242, 512 or 1110 mg Al/kg-day in fem a les. Clinical signs, food consum ption, and body weight were evaluated weekly. Hem a tology, clinical

chem istry or urine endpoints were not assess ed. Necropsies that included organ weight

m easure m ents and com p rehensive histological ex am inations (including brain) were perform e d

on all anim a l s, including those that died during the course of the study. S u rvival rates were higher than control values in all treated m a le and fe m a le groups, ranging f r om 86.7-95.0%

com p ared to 73.3% in males and 86.7-91.7% compar ed to 78.3% in females. No changes in food consumption were observed, but body weight ga in was increased in both sexes at 95-97 and

237-242 m g Al/kg-day (weights were 10-23% higher th an controls at end of study), was sim ilar

to controls in both sexes at 483-512 mg Al/kg-day, and decreased in both sexes at 1024-1110 m g Al/kg-day (11-16% low e r than controls at e nd of study). There were no exposure-related

increased incidences of tum o rs, other proliferativ e lesions or non-neoplastic lesions. In fact, the incidence of spontaneous hepatocellular carcin om as was significantly de creased in males at 1024 mg Al/kg-day (5.5% compared to 20.5% in controls, p<0.01).

Inhalation E xposure

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 m g /m 3 alum inum chlorhydrate [Al 2 (OH) 5 Cl ≥ x(H 2 O)] for 6 hours/day, 5 days/week for 6 m onths (Steinhagen et al., 1978). Analysis of the alum inum chlorhydrate by the investigators showed it to co ntain 24.5% Al, indicating that the anim als were exposed to 0, 0.061, 0.61 and 6.1 m g Al/m 3 . Body weights were m easured weekly for the first 8 weeks and biweekly th ereafter. At th e end of the exposure period, 10 an im als (5/sex) of each species were sacrificed for organ weight m eas urem ents (heart, lung, liver, kidney, spleen and brain) and histological exam ina tion of the lungs, liver and kidn ey. In addition, com p rehensive histological exam inations were perform e d on anim als in the control and 6.1 m g AL/ m 3 groups. The rem a inder of the anim als was us ed for he m a t o logy evaluation (RBC, WBC, he m a tocrit and

hem oglobin) and Al m e a s urem ents in blood and tissues. Apparent eff ects of Al included

multif ocal g r anulom atous pneum onia in both spe c i es a t ≥ 0.61 mg Al/ m 3 , significantly increas ed absolute and relative lung weights in both specie s, and decreased body weight gain in rats and

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m i ni m a l lung edem a in guinea pigs at 6.1 m g Al /m 3 . The granulom atous reaction was characterized by foci of gian t vacuoled particle-containing macrophages in the lungs and

m acrophages that did not appear to contain vacuol es or other evidence of phagocytized m a terial in the peribronchial lymph nodes. There was a si gnificant dose-rela ted accum u lation of Al in the lungs of both species at ≥ 0.061 m g Al/m 3 . However, a NOAEL of 0.061 mg/ m 3 could be

identified for the onset of com pound -induced histopathological effects.

In other studies, groups of 14-30 guinea pigs , rats and ham s ters were exposed to fine

m e tallic Al powders (py r o, atom ized and flak ed) at concen trations of 15, 30, 50 or 100 m g powder/m 3 air for 6 hours/day, 5 days/week for 6 m onths (Gross et al., 1973). Alveolar proteinosis occurred in exposed anim als of all three species after 2 m onths of exposure, but fibrosis or other pulm onary changes did not de velop. Sim ilarly, groups of 23 or 46 rats and 48

ham s ters were exposed to undeterm ined concentrat ions of Al fum e s or Al powder (20% Al, 80% Al(OH) 3 ) for m o rning hours only or morning and afte rnoon for up to 20 months (Christie et al., 1963). Effe cts were similar for both for m s of Al in both species, including initial increased

alveolar m acrophage proliferation followed by nodul ar hyalinized areas, with developm ent of

pneum onia but no fibrosis.

Exposure to 2.18 m g Al fibers/m 3 for 6 hours/day, 5 days/week for up to 86 weeks produced slightly increased alveolar m acrophages a nd som e 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 developm ent of granulom atous nodules also developed in m a le ha m s ters that were exposed to 8 m g Al/ m 3 of Alchlor (a propylene glycol com p lex of alum inum -chloride-hydroxide) for 6 hours/day, 5 days/week for 20 or 30 exposures. The alterations persis ted at the longest post

treatm ent observation (6 weeks) and consiste ntly developed at the bifurcation of the bronchioloalveolar ducts, which is a li kely site of particulate deposition.

DERI VATI O N OF A PROVISIONAL CHRO NIC RfD

FOR ALUMINUM

This survey of the toxicologi cal effects of Al in rodents suggests that neurotoxicological and develop m ental (including neuro d evelopm ental) endpoin t s are am ong the m o st sensitiv e indicators of Al toxicity. Howeve r, as vehicles for the developm ent of toxicity values such as a provisional chronic RfD, the latte r 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 m i ce and rats exposed during various stages of developm ent 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. Thes e deficits include im pa ired operant learning, changes in g r ip streng th, altere d s t artle response and im paired motor coord i nation. In addition,

several studies have shown that oral Al can produce histopathological ch anges 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 m onths, the change s including the appearance of vacuolation of the cell body an d cell p r oces ses of astrocytes in the b r ain and swelling of as tro c ytic p r oces ses. In addition, m o re localized vacuolizat ion of neurons in the brain al so was observed. These changes

2610-23-2006

were observed in rats exposed to elevated Al in the diet and are dis tin c t f r o m the NFD that ha s been observed in rats, rabbits and m onkeys m a in tained on elevated dietary Al in combination with reduced dietary calcium (Garruto et al., 198 9; Kihira et al., 1994; Mitani, 1992; Yano et al., 1989; Yoshida et al., 1990) or in ra bbits adm i nistered intracisternal or intraventricular injections of Al (Kowa ll et al., 1989; W a kaya ma et al., 1993) . Interpretation of the low-calcium studies is

com p licated by the observation that NFD was obs erved in anim als m a intained on low-calcium

diets without excess Al and was e nhanced by the addition of excess Al to these die t s (Garruto et al., 1989; Kihira et al., 1994). Furtherm ore, Al has been shown to inhibit the gastrointestinal absorption o f calcium (Orihuela et al.

, 1996), an effect that m a y exacerb a te the calcium deprivation induced by low calcium diets. Thus

, it is no t c l ea r whether ca lcium depriv ation

enhances th e neurotox icity of Al or Al exacerb a tes the adv e rse effects of calcium deprivation.

Donald et al. (1989) and Go lub et al. (1995) are co-princ ipal studies that identify a

LOAEL of 100 m g Al/kg-day for m i nim a l neurotox icity in the offspring of m i ce exposed to dietary alum inum lactate (soluble alum inum ) duri ng gestation and lactatio n. The neurotoxicity

associa t ed w ith th is LOAEL is consis tent with LOAELs from other developm ental and

subchronic neurobehavioral studi es in m i ce and rats which used higher dietary dosages of

alum inum lactate or alum inum chloride (G olub et al., 1989, 1992a,b; Be rnuzzi et al., 1989; Muller et al., 1990). Of the above, G o lub et al., (1995) is the only study in which a histopatholo g ical exam ination of the brain a nd s p inal co rd was conducted and no abnorm a lities were reported. The Florence et al. (1 994) study indicates that histopat hological abnorm a lities of the CNS can occur in rats exposed subchronically to 84 m g /kg-day; although this is lower than

the LOAEL for neurobehavioral e ffects, it was not chosen as the principal study because the functional significance of the histopa thological lesions are uncertain.

A num b er of studies were identified that, at face v a lue, appeared to ind i cate LOAELs at

lower doses than the 100 m g Al/kg-day value se lected herein, for exam ple, Paternain et al. (1988) and Colom i na et al. ( 1992). However, in these as in m a ny of the studies under consideration, insufficient inform ation on dietary Al (Al content and/or f eed type) was reported

to perm it a r e liab l e es tim ation of the overall dose level to which the an im als were sub j ected.

Other developm ental studies w ith alum inum hydroxide and/or citrate in m i ce and rats

identified a NOAE L wh ich are e quivalent (95.5 mg Al/kg-day), or a m i nimu m L OAE L that was greater (133 mg Al/kg-day) than the 100 m g Al/kg-day criti cal LOAEL (Dom ingo et al., 1989;

Gom ez et al., 1991), an overlap potentially rela ted to differences in effective doses due to variations in unreported Al dietary content and f actors aff ecting absorp tion such as chem ical

for m (e.g., the use of less absorbable alum inum hydroxide). In addi tion, the LOAEL of 43.3 m g Al/kg-day for decreased body weight gain in m i ce exposed to alum inum c h loride for 180-390 days (Ondreicka et al., 1966) was thought be inappr opriate f o r risk assessm e nt due to the sm all

sam p le size and to the poor repor ting of study details. Alum inum nitrate caused alterations in levels of brain biogenic am ines and hepatic and hem a tological indices in rats exposed to 21.4 m g Al/kg-day for 6 weeks (Flora et al., 1991). Th is dose is not a LOAEL be cause insufficient

inform ation is availab l e to determ ine if the effects are adverse.

Therefore, the LOAEL of 100 m g Al/kg-day for m i ni m a l neurot oxicity in the offspring of

m i ce (Donald et al., 1989, Golub et al., 1995) is selected as the ba sis for the provisional chronic

2710-23-2006

RfD. The LOAEL is considered m i nim a l because the results of the postweaning neu r obehavio r al test battery indicate that perform a nce deficits m a y be m a rginal. In pa rticular, of the three observed effects (d ecreased forelim b and increas ed hindlim b grip strength s, increased hindlim b foot splay distance), one effect (increased grip strength) has un clea r toxic o logica l sig n if icance and two effects (increased grip strength and foot splay distance) did not pe rsis t af ter 2 weeks of no further exposure.

Application of an uncertainty factor (UF) of 100 (3 for use of a m i ni m a l LOAEL, 10 for interspecies extrapolation and 3 for intrahum an variab ility wh ere th e 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 m g Al/kg-day is approxim a tely 3-fold higher than estim ated

norm a l daily Al intake of approxim a tely 0.2- 0.3 mg/kg-day (Iyengar et al., 1987; Ganrot, 1986;

W ilhel m et al., 1990). Chronic users of m e dicati ons such as antacids, buffered aspirins and

antiu lcerativ es would be expected to ingest m u ch larger am ounts of Al, possibly as high as 10-70 mg/kg-day. However, these s ubjects would not represent the most sensitive population (developing infants), as i ndicated by the anim al data.

Low confidence is p l aced in the co -critical studies, because they only identify a LOAEL

for a sensitive effect and evaluated com p arativel y sm all numbers of anim als. Confidence in the

data base is low because the m o st reliable suppor ting data for neurotox icity of Al in hum ans are of lim ited general relevance (e.g., dialysis encep halopathy is m a nifested in patients with

im paired renal function and excessive Al upt ake from intravenous exposure). In fact, neurotoxicity rem a ins to be assessed in anim al s chronically exposed to Al, and developm ental morphology has not been adequately investigated in two anim al spec ies. These lim itations in the Al data base do not increase uncertainty in the Rf D; therefore, a data base uncertainty f actor was not used. However, reflecting the low confidence in the co-c ritica l stud ie s, there is lo w overall

confidence in the RfD.

DERI VATI O N OF A PROVISIONAL CHRO NIC RfC F O R ALUM INUM

Al seem s to be the m o st likely cause for the gener a lly and con s isten tly rep o rted psychom otor and cognitive effects (particularly si gns of i m paired coordi nation) in Al production workers and welders (Bast-Petter sen et al., 1994; Rifat et al., 1990; Hosovski et al., 1990; W h ite 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. T hus, a degenerative neurological syndrom e (dialysis dem e ntia) has been docum ent e d in hum ans with chronic renal failure, apparently due to an increased exposure to Al from dialysis treatm e nt and/or ingestion of phosphate binding agents which contain Al (Alf rey, 1993). This syndrom e is characterized by gradual loss of m o tor, speech a nd co gnitiv e functions. Neuro t oxic ity, pa rticula r ly neu r om uscular

effects such as decreased m o tor activity, startle responsiveness a nd grip strength, has also been

observed in m i ce following subchronic oral expos ure and in the offspring of m i ce and rats exposed orally during gestation a nd/or lactation. Based on this inform ation, as well as evidence

2810-23-2006

that Al is absorbed by Al production workers an d welders, the hypothesis that the occupational

studies are indicative of a neurot oxic effect of Al a ppears to be justified. However, the only occupational study that has yielded suitable m onitori ng data is that of Hos ovski et al. (1990), in which workers were exposed to presum ed tim e- weighted average (TWA) concentrations of 4.6-

11.5 m g Al/m 3 m a gnitude for an average of 12 years. Using 4.6 m g Al/m 3 as the L OAEL for psychom otor and cognitive im pairm e nt for an 8-hour occupational exposure (Hosovski et al., 1990) and corrections for di scontinuous exposure (10 m 3 /20 m 3 and 5 days/7 days), the

LOAEL HEC is 1.64 m g /m 3 . Applying an uncertainty factor of 300 for intrahum an variability (10), use of a LOAEL (10) and an incom p lete database (3) yields a provisional RfC of

p-RfC = 1.64 mg/m 3 /300 = 5E-3 mg/m 3

.

The lack of inhalation developm ental studies m a y increase uncertainty in the database

because o r al data in anim als indicate that n e urotoxic and m o rphological developm ental effects

m a y occur at lower doses than neurotoxicity in a dults. Additionally, there is uncertainty related to the lack of corroborating data on air concentrat ions associated with neurotoxicity. C onfidence in the critical study is lo w to m e dium because o n ly a LOAEL was identified. Confidence in the

database is m e diu m bec a use (1) there are no co rroborating data on effect levels (NOAELs and

additional L OAELs), (2) no data are available fo r developm ental neurotoxicity by the inhalation route and (3) a well-designed two-generation reproduction study is lacking. Reflecting the low

to m e dium c onfidence in the crit ical study and database, there is low to m e dium confi d ence in the prov isio nal Rf C.

PROVISIONAL CARCINOGENICITY ASS E SSMENT FOR

ALUMINUM

Weight-Of-Evidence Classifica tion

A considerable num ber of epidem iological studi es have exam ined the incidence of excess

tum o r for m a tion in persons occupationally exposed to Al in the for m of dusts or fum e s. In general, a body of inferential ev idence exists for an increase in cancer of the bladder and lung through such occupational exposure to Al, altho ugh conclusions linking these responses to the effects of Al are confounded by attendant co-expos ure to other harm ful em issions such as PAHs and by cigarette sm oking. A 20- m o nth exposure of B6C3F1 m i ce to Al potassium sulfate dodecahydrate in the diet at concentrations up to 10% w/w displayed no indication of compoundrelated carcinogenicity a nd, in general, no indication of advers e toxicological effects of any kind (Oneda et al., 1994). Sim ilarly, the life-tim e e xposure of Swiss m i ce and Long-Evans rats to 5

ppm Al as alum inum potassium sulfate in dri nking water provided no convincing evidence for the carcinogenicity of Al co m pounds (Schroeder and Mitchene r, 1975a,b). Gene reversion experim e nts on Al com p ounds 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, alum inum is classified as inadequate information to assess carcinogenic potential . The basis for this classifica tion is in s u f f i cient evidence in epidem iological/occupational studies, lack of demonstrated carci nogenicity or m u tagenicity in

2910-23-2006

available anim al studies, lack of positive evidence of non-carcinoge nicity and lack of mode of

action data f o r alum inum.

Quantita tiv e Estima tes of Carcinog e nic Ris k

Due to insufficient data, a provisional oral sl ope f actor and inhalation unit risk could not be developed.

REFE RE NCES

ACGIH (Am e rican Conference of Governm e nt al Industrial Hygienists). 1998. 1998 Threshold

Lim it Values for Che m ical Substances and Phys ical Agents and Biologi cal Exposure Indices. ACGIH, Cincinnati, OH.

Agarwal, S.K., L. Ayya sh, C.S. Gourley, J. Levy, K. Faber and C.L. Hughes Jr. 1996. Evaluation of the developm ental neuroendocrine and reproductive toxi cology of alum i n um

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