EPA/600/8-88/016
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR ALUMINUM
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
B
T-
-o
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with aluminum
and compounds. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
Chemical Abstracts, TOXLINE and the CHENFATE/DATALOG data bases. The basic
literature searched supporting this document 1s current up to Hay, 1986.
Secondary sources of Information have also been relied upon In the prepara-
tion of this report and represent large-scale health assessment efforts that
entail extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1984. Drinking Water Criteria Document for Aluminum.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Drinking Water, Washington, DC. External Review
Draft.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants In ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$o)
exposures.
111
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The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980a) for a discussion of this concept]. The
RfO 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1983).
For compounds for which there Is sufficient evidence of carclnogenlcHy
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, If appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
In a short-term balance study using healthy humans, 125 mg aluminum/day
added to the diet was homeostatlcally controlled with no adverse effects
being noted (Greger and Baler, 1983a). Up to 200 mg/day In the diets of
humans may be associated with reduced phosphorus absorption from the gastro-
intestinal tract, but not with Impaired body function (Campbell et al.,
1957; Greger and Baler, 1983b).
No RfD values were calculated for aluminum. A CS of 10 for aluminum was
based on pulmonary and thoracic effects leading to death in a chronic study
1n rats exposed by Inhalation to aluminum oxide (Klosterkotter, 1960).
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation ,
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral ,
3.3.2. Inhalation ,
3.4. TOXICANT INTERACTIONS ,
CARCINOGENICITY ,
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. HEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDS)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDcr)
Page
. . 1
... 7
. . . 7
. . . 8
. . . 9
. . . 9
. . . 9
n
. . . 12
. . . 12
. . . 13
. . . 14
. . . 14
. . . 15
. . . 15
, . . 16
, . . 16
. . . 16
. . . 16
, . . 16
, . . 16
, . . 17
. . 17
. . 18
. . 19
. . 20
. . 20
. . 20
. . 21
vll
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE 21
6.2.1. Oral (RfD0) 21
6.2.2. Inhalation (RfOj) 22
7. REFERENCES 25
APPENDIX: Summary Table for Aluminum 33
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LIST OF ABBREVIATIONS
AOP Adenoslne dlphosphate
AMP Adenoslne monophosphate
ATP Adenoslne trlphosphate
CAS Chemical Abstract Service
CS Composite score
DMSO Dimethyl sulfoxlde
FEL Frank effect level
HA Health advisory
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$j Subchronlc Inhalation reference dose
RfD$Q Subchronlc oral reference dose
RVd Dose-rating value
RVe Effect-rating value
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties of aluminum and some of Its
compounds are listed In Table 1-1. Aluminum (CAS no. 7429-90-5) Is a
metallic element with an oxidation state of *3 except under extreme condi-
tions when oxidation states of *-2 and «•! have been found (RolUnson, 1978).
Aluminum does not exist naturally In the elemental form (U.S. EPA, 1980b),
but Is found In -300 minerals (e.g., silicates, feldspars, micas and clays)
(U.S. EPA, 1984a).
Aluminum Is soluble In adds and bases, particularly nitric acid, hot
acetic acid, sulfurlc and hydrochloric acids and alkalis. In the environ-
ment, It may exist as stable aluminum salts or as organo-alumlnum compounds
(Oriscoll, 1985; U.S. EPA, 1984a). The half-lives of aluminum and compounds
In air, water and soil could not be located In the available literature. In
the atmosphere, aluminum 1s expected to be present mainly In participate
form as a result of Industrial emissions, fossil fuel burning and natural
emissions Including those from volcanic sources. The ratio of aluminum
emissions from anthropogenic sources to natural sources Is 0.15 (F1shbe1n,
1981). Monitoring data Indicate that aluminum 1s removed from the atmo-
sphere by partlculate settling and washout In precipitation (Landsberger et
al., 1983; Davidson et al., 1985; Ulersema et al., 1984). Particles emitted
from anthropogenic sources tend to be smaller In size and transport over
longer distances than those emitted from natural sources (Mshbeln, 1981).
The level of Al found In natural waters varies geographically. In waters
where pH Is <5, as with Industrial wastes, mine runoff, acidic spring
waters, mires and volcanic areas, the aluminum level can exceed 100 mg/l.
At pH levels >5.5, Al*3 Is nearly Insoluble.
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Substances dissolved In the water also affect aluminum water solubility.
ComplexIng llgands such as fluoride, phosphate and sulfate, and chelatlng
agents such as ethylenedlamlne tetracetlc add, nltrllotMacetlc acid and
sodium tMpolyphosphate will also Increase the water solubility of aluminum.
The aluminum Ion also complexes with hydroxide under aqueous conditions.
Since aluminum 1s more soluble In water at an addle pH, It Is likely
that It will accumulate 1n aquatic organisms and vegetation under these
conditions. Evidence of photodegradatlon or oxidation of aluminum In water
Is not available (U.S. EPA. 1984a). Strong bonding with humlc substances In
sediments by aluminum Is expected (Raspor et al., 1984).
The fate of aluminum In soil will vary depending upon soil character-
istics, such as soil type, pH and Ion species present (Drlscoll, 1985).
Aluminum can be Immobilized by strong binding with humlc substances (Raspor
et al., 1984; Drlscoll, 1985) and can be mobilized by complexIng with
HCOl organic and other acidic counteranlons (Drlscoll, 1985).
o
0114h -6- 11/04/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Greger and Baler (1983a) conducted a balance study with eight healthy
men. Four of the subjects were given a control diet containing 4.6 mg
aluminum/day for 20 days, while the other four subjects received a test diet
of 125 mg aluminum/day as aluminum lactate. The diets were exchanged for an
additional 20 days with each subject acting as his own control. Fecal,
urine and serum aluminum determinations Indicated that some absorption with
rapid elimination occurred at 125 mg/day. Other studies with different
aluminum compounds (e.g., aluminum carbonate, aluminum hydroxide) showed
that doses >1000 mg aluminum/day resulted 1n significant gastrointestinal
absorption and retention of aluminum (Recker et al., 1977; Gorsky et al.,
1979; Clarkson et al., 1972; Cam et al., 1976). Although the data Indicate
that homeostatlc regulation of aluminum 1s effective at doses of <125 mg
aluminum/day, studies that Investigated the absorption of oral doses of
aluminum between 125 and 1000 mg/day are not available (U.S. EPA, 1984a).
Gastrointestinal absorption of aluminum varies not only with the concentra-
tion of aluminum but also with type of aluminum compound and pH (Savory et
al., 1983).
Krlgman et al. (1985) concluded that aluminum Is absorbed from the human
gastrointestinal tract regardless of the form 1n which H occurs. They
Indicated that the proportion of Ingested aluminum absorbed Is small and
estimate that -35 mg/day Is Ingested. In a review of the pathogenesls of
the nervous disorder, dialysis encephalopathy, AMeff (1985) stated that
"significant absorption of oral aluminum can occur In patients with chronic
renal failure," Implying that absorption may be enhanced 1n these patients
and that they may be a group with Increased risk to the toxldty of aluminum.
0114h -7- 02/11/87
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2.2. INHALATION
Studies with humans have shown that aluminum accumulates In the lungs
with age (Upton and Shafer, 1964; Alfrey, 1980) and that aluminum levels In
the lungs were relatively high compared with other tissues. Including the
trachea, gastrointestinal tract and visceral organs (Teraoka, 1981).
Although thts Information suggests that pulmonary absorption of aluminum
dusts may have occurred, this cannot be concluded definitely because serum
aluminum levels and other pertinent endpolnts were not assessed. Particle
size and solubility of aluminum partlculate and compounds may determine
their fate In the lungs (U.S. EPA, 1984a).
0114h -8- 11/04/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Aluminum Interacts with phosphorus In the gastrointestinal
tract to form Insoluble aluminum phosphate, which Is readily excreted (U.S.
EPA, 1984a). Prolonged aluminum Intake from antacids (aluminum hydroxide)
can lead to phosphorus depletion with hypercaldurla, bone resorptlon and
osteomalada 1n humans.
As discussed 1n Section 2.1., humans treated with aluminum added to the
diet at 125 mg/day (1.8 mg/kg/day) homestatlcally eliminate the absorbed
excess without evidence of 111 effects.
It appears that dietary Intake at levels up to -200 mg aluminum/day,
although associated with decreased gastrointestinal uptake of phosphate, Is
not sufficient to Interfere with bodily function (Campbell et al., 1957;
Greger and Baler, 1983b). Intake of aluminum compounds In the form of
antacids 1n amounts of >1 g aluminum/day may cause significant Interaction
with phosphorus 1n healthy Individuals (Insogna et al., 1980; U.S. EPA,
1984a).
Persons with severe reduction of renal function are commonly given
aluminum hydroxide orally 1n large amounts (~3 g aluminum/day) to prevent
hyperphosphatemla (U.S. EPA, 1984a). This large aluminum load may lead to
Increased aluminum levels 1n the bone and possibly the brain, which can
result 1n osteomalada and dialysis encephalopathy. An Increased risk for
encephalopathy has been determined when serum levels of aluminum are >100
yg/mt as compared with normal levels of -5 yg/l (U.S. EPA, 1984a).
High brain aluminum levels have also been associated with encephalopathy 1n
the elderly and In Alzheimer's patients, but 1t has not been established 1f
aluminum acts as a direct causative agent (U.S. EPA, 1984a).
0114H -9- 02/11/87
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Aluminum chloride was administered orally (apparently by gavage in
water) to unspecified numbers of male rats and male guinea pigs at doses of
0, 6, 17 and 50 mg alumlnum/kg/day and to male rabbits at doses of 0, 3, 9
and 27 mg aluminum/kg/day for 20-30 days (Krasovsk11 et al., 1979). Assays
apparently conducted 3 hours after cessation of treatment showed decreased
activity of serum alkaline phosphatase at >17 mg/kg/day 1n the rats and
guinea pigs, and >9 mg/kg/day In the rabbits. Serum levels of ATP, AOP and
AMP were significantly decreased In the rats and guinea pigs at >17 mg/kg
and In the rabbits at 27 mg/kg. Rats were also similarly exposed to 0.0025,
0.25 or 2.5 mg aluminum/kg/day (as aluminum chloride) for 6-12 months
(Krasovskll et al., 1979). Effects Included decreased serum alkaline phos-
phatase and depressed motor reflexes at 2.5 mg/kg; alkaline phosphatase was
also decreased at 0.25 mg/kg, but only during the first month of exposure.
Treatment-related effects on blood erythrocytes B-l1poprote1ns or unspeci-
fied transamlnase activity were not observed. Additional Information
regarding the design or results of the Krasovskll et al. (1979) experiments
was not reported.
Gross and hlstologlcal examinations of the liver, lungs, spleen,
kidneys, brain, heart and testes of groups of seven male Sprague-Dawley rats
exposed to 0, 5, 50 or 500 mg aluminum/1 (as aluminum chloride) In the
drinking water for 30, 60 or 90 days were unremarkable (Olxon et al., 1979).
Groups of eight male Fischer or eight female Sprague-Oawley rats were
subjected to behavioral tests that assessed coordination, locomotor activity
and learning at different points throughout a 12-week period In which 0.2%
aluminum (as aluminum chloride) was administered In the diet (CommissarIs et
al., 1982). Significantly depressed locomotor activity occurred In the
OlMh -10- 11/04/86
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females; the males only showed a trend 1n this effect. If 1t Is assumed
that rats consume the equivalent of 5X of their weight In food per day, the
dally dosage was 100 mg alumlnum/kg/day.
Dietary administration of 0.1% aluminum (as aluminum chloride) for 11
months depressed locomotor activity and learning (acquisition of avoidance
behavior) 1n Sprague-Dawley rats (Commissar 1s et al., 1982). This exposure
corresponds to SO mg/kg/day If It assumed that rats consume the equivalent
of 5% of their weight 1n food per day.
3.1.2. Inhalation. Gross et al. (1973) exposed groups of 14-30 guinea
pigs, rats and hamsters to five metallic aluminum powders (pyro, atomized
and flaked) at air concentrations of 15, 30, 50 or 100 mg/m3, 6 hours/day,
5 days/week for 6 months. Alveolar protelnosls occurred 1n all three
species after 2 months of exposure but other adverse pulmonary effects,
Including flbrosls, did not develop.
Groups of 35 Fischer rats/sex and 35 Hartley guinea pigs/sex were
exposed to 0.25, 2.5 or 25 mg/m3 aluminum chlorohydrate, 6 hours/day, 5
days/week for 6 and 12 months (Cavender et al., 1978). After 6 months,
alveolar macrophages were Increased at all three exposure levels; decreased
body weight, Increased lung-to-body weight ratios and multlfocal granulo-
matous pneumonia also occurred at 25 mg/m3. Granulomas occurred In the
lungs of 2.5 mg/m3 animals (both species) after 12 months of exposure. It
should be noted that the actual structure of aluminum chlorohydrate Is not
known, but 1s considered to be a complex of basic aluminum chloride and
propylene glycol.
Information regarding effects of exposure to soluble salts of aluminum
(e.g., chloride and sulfate) could not be located. It appears, however,
OlHh -11- 06/03/87
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that for soluble salts of aluminum, effects may be acute In nature and
associated with the corresponding add formed by hydrolysis of the aluminum
compound. Reflecting this, the TIV for soluble aluminum salts of 2 mg/m3
Is based on the TLV for hydrochloric acid assuming 1 mol of aluminum
chloride yields 3 mol of HC1 on hydrolysis and assuming similar toxic
potencies for the acids formed by hydrolysis of different aluminum salts.
3.2. CHRONIC
3.2.1. Oral. Aluminum chloride was administered to groups of 10 mice 1n
drinking water at an average dose of 0 or 19.3 mg alumlnum/kg/day In a
3-generatlon study (Ondrelcka et al., 1966). The parental generation was
treated for 180-390 days and unspecified numbers of weanlings were similarly
treated from 4 weeks of age. Decreased body weight In the second and third
generations was the only effect of treatment. Erythrocyte counts, hemo-
globin levels and histology of the liver, spleen and kidneys In mice from
the first and third generation were similar to controls. The significance
of the decreased weight gain Is difficult to assess, however, since food
consumption was not reported; decreased food Intake was observed with
aluminum exposure 1n other studies Included 1n the same report.
Schroeder and MUchener (1975a) administered 5 ppm aluminum (as aluminum
potassium sulfate) 1n the drinking water of 52 Long-Evans rats/sex for life.
Exposed rats did not differ from controls with respect to body weight,
survival, selected serum chemistries (glucose, cholesterol, uric add)
selected urlnalysls parameters (protein, glucose, pH) or tissue histology
(heart, lung, kidney, liver or spleen).
Groups of 54 weanling Swiss mice/sex were exposed to 0 or 5 mg aluml-
num/i (as aluminum potassium sulfate) In the drinking water for life
(Schroeder and MUchener, 1975b). If It Is assumed that mice consume water
equivalent to 17% of their weight per day, the dosage Is 0.85 mg/kg day.
0114H -12- 11/04/86
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Treatment had no effect on body weight, survival, edema, blanching of the
Incisor teeth, or tissues as Indicated by gross and limited hlstologlcal
("some sections" were made of the heart, lung, liver, kidney and spleen)
examinations.
3.2.2. Inhalation. Pulmonary flbrosls has been associated with occupa-
tional exposure to aluminum powder (metallic aluminum covered with a complex
oxide/hydroxide coating) or alumina (Al_0») dust 1n a number of reports
(U.S. EPA, 1984a); however, U.S. EPA (1984a) demonstrated that these reports
are Inconclusive because confounding factors such as concurrent exposure to
other chemicals (e.g., alloying agents, chemicals used 1n the production of
fireworks, Inks and paints or silica), cigarette smoking (which contributed
directly to the lung burden of aluminum and silicon) or previous workplace
exposures were not always evaluated. ACGIH (1986) and U.S. EPA (1984a)
report that there Is no evidence of flbrogenlc activity of aluminum or
alumina at exposure levels currently recommended by the ACGIH (10 mg/m3
for dust, 5 mg/m3 for powder) and suggest that they be classified as Inert
(nuisance) partlculates. Past exposures associated with flbrotlc lung
changes occurred at extremely high concentrations In poorly or uncontrolled
occupational environments; Insufficient monitoring data preclude estimation
of typical TWA concentrations of aluminum.
Aluminum powders have been administered to humans 1n known exposures In
the treatment of slllcosls. Stoklnger (1981) reviewed data 1n which >42
million aluminum treatments (-150,000 man-years) had been given over a
27-year period ending 1n 1971. Inhalation of ~350 mg/m3 of resplrable
alumina powder for 10 minutes/day did not result In lung damage or other 111
effects; this exposure reportedly Is equivalent to an 8-hour TWA concentra-
tion of 7 mg/m3 (U.S. EPA, 1984a). The data from this study were used as
the basis for the TLV (Stoklnger, 1981; ACGIH, 1986). .
0114h -13- 02/11/87
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Exposure to 2.18 rag/m3 aluminum fibers, 6 hours/day, 5 days/week for
up to 86 weeks produced slight Increases In alveolar macrophages and some
Irritation of the nasal passages In a group of 50 Alderly Park rats (Plgott
et al., 1981). Lung edema, pneumonia and pleurisy were observed In 107/145
rats that died from exposure to 33 g/m3 aluminum oxide (Al 0.), 5
fc O
hours/day for up to 285/402 days (Klosterkotter, 1960).
The responses observed 1n the above animal studies are typically
elicited by nuisance participate exposure.
3.3. TERATOGEN1CITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Groups of 31 male Sprague-Dawley rats were administered 0,
5. 50 or 500 mg aluminum/I (as aluminum chloride) 1n the drinking water
(Dlxon et al., 1979). Seven rats from each group were sacrificed after 30,
60 and 90 days for plasma lutenlzlng hormone and follicle-stimulating
hormone determinations, and hlstologlcal examination of the testes. The
remaining 10 males from each group were mated after 90 days of treatment; a
different female was paired with each male every 7 days for a total of 70
days. Treatment-related effects on reproductive capacity as Indicated by
the above evaluation were not observed. Endpolnts In the reproduction study
Included pregnancy rate, Implantation sites, corpora lutea, resorptlon sites
and live and dead Implants.
Decreased spermatozoa counts and sperm motllHy reportedly occurred In
rats that were exposed to 2.5 mg alumlnum/kg/day (as aluminum chloride) by
gavage but not at lower doses (0.0025 or 0.25 mj/kg/day) for 6 months
(Krasovskll et al., 1979). Hlstologlcal and hlstochemlcal alterations In
the testes were also observed at the 2.5 mg/kg/day dose. As Indicated In
Section 3.1.1., aspects of this report are Inadequate.
0114h -14- 11/04/86
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Anderson et al. (1985) exposed sperm-positive Holtzman rats to plain tap
water (four rats) or to a Maalox TC-tap water mixture at a 1:4 ratio (six
rats) beginning on day 2 of gestation until weaning to test the effects of
high Ingested levels of aluminum on reproductive performance. Water Intake
was not measured and .aluir, num Intake was not estimated. At parturition, one
control and one treated Hter were cross-fostered to evaluate the effects
of high levels of Ingest J aluminum on maternal care. One aluminum-exposed
Utter was aborted, but 11 control dams delivered normally. Body weights
were reduced (p<0.05, Ne nan-Kenls test) In aluminum-exposed rats at birth
and at time points up tc 70 days postpartum (p<0.01) In Utters maintained
with dams exposed until weaning. Body weights of pups from treated dams
recovered 1f the pups wen cross-fostered by an untreated dam.
3.3.2. Inhalation. Per Inent data could not be located In the available
literature.
3.4. TOXICANT INTERACTi: NS
As Indicated In Sect')n 2.1., aluminum Interacts with phosphorus In the
gastrointestinal tract o form Insoluble aluminum phosphate, which 1s
readily excreted (U.S. E: \, 1984a). Fluoride has also been shown to react
with aluminum 1n the gast. :>Intestinal tract (U.S. EPA, 1984a).
OlHh -15- 11/04/86
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4. CARCINOGENICITY
4.1. HUNAN DATA
4.1.1. Oral. Pertinent data could not be located In the available
literature.
4.1.2. Inhalation. Occupational exposure -to aluminum has not been
associated with pulmonary or systemic neoplastlc alterations In humans (U.S.
EPA, 1984a; ACGIH, 1986; Stoklnger, 1981).
4.2. 8IOASSAYS
4.2.1. Oral. Schroeder and HHchener (1975a) administered drinking water
containing 5 mg/i aluminum (as aluminum potassium sulfate) to groups of 52
Long-Evans weanling rats/sex for life. Effects on body weight or longevity
were not observed, but 13 males and 14 females died at age 20 months from
nontreatment-related pneumonia. Gross and limited (heart, lung, kidney,
liver, spleen, tumors) hlstologlcal examinations were conducted.
The Incidence of total gross tumors (all sites) was significantly
(p<0.005) Increased In treated males (13/25 vs. 4/26). -Incidences of
specific types of tumors were not specified, but Incidences of tumors con-
sidered malignant (multiple tumors In the same animal) were 6/25 In the
treated and 2/26 In the controls. The authors considered aluminum to be
Innocuous. Schroeder and MUchener (1975b) also administered aluminum
potassium sulfate In the drinking water (5 mg alumlnum/i) of groups of 54
Swiss mice/sex for life. Treatment had no effect on body weights or
survival. Gross pathological and limited hlstologlcal examinations revealed
an Increased Incidence of lymphoma leukemia 1n the treated females (10/41
vs. 3/47, p<0.025); however, the authors did not consider the compound to be
tumorIgenlc.
0114h -16- 02/11/87
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4.2.2. Inhalation. Groups of 35 rats and guinea pigs/sex were exposed by
Inhalation to 0.25, 2.5 or 25 mg/m3 of aluminum chlorohydrate 6 hours/day,
5 days/week for 6-12 months (Cavender et al., 1978). Lung granulomas
occurred 1n both species following exposure to 25 mg/m3 for 6 months and
2.5 mg/m3 for 12 months.
Granulomatous nodules were also observed In male hamsters that were
exposed 6 hours/day, 5 days/week for 20 or 30 exposures to average aluminum
chlorohydrate concentrations of 52 mg/m3 (Drew et al., 1974). These
alterations persisted up to 6 weeks postexposure but only minor changes (a
few foci of macrophages and heterophlls) occurred after 10 exposures.
Groups of four exposed and four control hamsters were sacrificed after 10,
20 and 30 exposures and 2, 4 and 6 weeks postexposure}. The granulomatous
foci consistently developed at the bifurcation of the bronchloloalveolar
ducts, a probable site of partlculate deposition.
4.3. OTHER RELEVANT DATA
Administration of aluminum or aluminum compound (aluminum hydroxide,
oxide or phosphate) by different routes (Intratracheal, Intraperltoneal,
Intravenous, subcutaneous Implant) In rats, guinea pigs and hamsters did not
elicit treatment-related tumor formation (O'Gara and Brown, 1967; Shublch
and Hartwell, 1969; Wagner et al., 1973; Stenback et al., 1976; Turk and
Parker, 1977).
Elemental aluminum dissolved 1n DMSO was not mutagenlc In Salmonella
typhlmurlum strains TA98, TA1535 and TA1538 (Mllvy and Kay, 1978). Aluminum
chloride (A1C1.) did not produce effects In a ONA damage/repair assay with
Bacullus subtllls strains M45 (rec~) and H17 (rec*) (Nlshloka, 1975),
but did produce chromatId breaks and gaps In mouse bone marrow cells In
vitro (Manna and Das, 1972).
0114h -17- 11/04/86
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4.4. WEIGHT OF EVIDENCE
Aluminum potassium sulfate was administered 1n the drinking water of
rats (Schroeder and MHchener, 1975a) and mice (Schroeder and Kitchener,
19755) at a concentration of 5 mg aluminum/I for life. The Incidence of
total tumors was significantly Increased 1n the male rats but Incidences or
characterization of specific types of tumors were not reported. The Inci-
dence of lymphoma leukemia was significantly Increased In the female mice.
Granulomas developed In the lungs of rats and guinea pigs that Inhaled 2.5
mg/m3 aluminum chlorohydrate, 6 hours/day, 5 days/week for 12 months or 25
mg/m3 for 6 months (Cavender et al., 1978). Exposure to 52 mg/m3 alumi-
num chlorohydrate (20-30 exposures, 6 hours/day, 5 days/week) produced a
similar response In hamsters (Drew et al., 1974). These responses cannot
deflnately be attributed solely to aluminum, however, because the actual
structure of aluminum chlorohydrate Is not known (see Section 3.1.2.). The
available data are Inadequate for evaluating the carclnogenlclty of alumi-
num. Aluminum 1s, therefore, most appropriately categorized In IARC Group 3
and CAG Group C according to the guidelines for evaluating the weight of
evidence of human carcinogenic potential (U.S. EPA, 1986).
0114h -18- 02/11/87
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5. REGULATORY STANDARDS ANO CRITERIA
The ACGIH (1986) currently recommends 8-hour TWA TLVs of 10, 5, 5, 2 and
2 mg alumlnum/m3 for occupational exposure to aluminum metal dusts, pyro
powders, welding fumes, soluble salts and alkyls, respectively.
0114H -19- 06/03/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfOSQ). As discussed 1n Sections 3.1.1. and 3.1.2., the
mechanism of aluminum toxlclty appears to be Indirect, resulting from the
Interaction of aluminum and phosphate. Excessive exposure to aluminum 1s
associated with phosphate depletion, resulting In bone resorptlon,
osteomalacla and hypercaldurla. Results of the Greger and Baler (1983a,b)
study Indicate that absorption of aluminum occurs 1n healthy humans treated
with 125 mg aluminum/day without retention 1n the body and that effects on
phosphorus absorption 1n the gastrointestinal tract at this dose are very
small and physiologically Insignificant. Although homeostatlc control of
aluminum appears to be effective at 125 mg aluminum/day, the minimal effects
on phosphorus absorption Indicate that this Intake may represent a NOAEL.
In humans, 1ngest1on of 1 g aluminum (14.3 mg/kg/day) Is associated with
significant Interaction with phosphorus 1n healthy Individuals (Insogna et
al., I960). In subchronlc animal tests, 2.5 mg alumlnum/kg/day has been
associated with decreased serum alkaline phosphatase and depressed motor
reflexes 1n rats (Krasovskll et al., 1979) and 100 mg/kg/day with depressed
locomotor activity In rats (Commissar 1s et al., 1982).
6.1.2. Inhalation (RfD^,). Subchronlc data regarding the toxlclty of
aluminum, soluble salts of aluminum, and aluminum alkyls are Insufficient
for derivation of an RfO-, for these compounds.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). The aval'able data were deemed Insufficient for
RfDQ calculation.
Long-term Intake of aluminum compounds (e.g., aluminum hydroxide In
antacids) In amounts of -1 g aluminum/day or more may cause phosphate
depletion, which can eventually lead to osteomalacla (U.S. EPA, 1980b).
OIHh -20- 06/03/87
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Smaller amounts of aluminum will cause decreased uptake of phosphate that Is
not severe enough to elicit adverse effects. Higher dosages (~3 g alumi-
num/day), administered to persons with severe reduction of renal function to
prevent hyperphosphatemla, can lead to accumulation of aluminum 1n the brain
and dialysis encepalopathy. A CS can be calculated for aluminum by regard-
Ing the 1 g aluminum/day Intake as the MED for phosphorus depletion. The
RV. associated with this MED 1s 1. If phosphate depletion potentially
resulting 1n adverse physiological effects 1s assigned an RV of 7, the CS
1s 7.
6.2.2. Inhalation (RfD.). As discussed In Section 3.1.2., there Is no
evidence of flbrogenlc activity or other nonreverslble pulmonary effects of
aluminum powders or alumina dusts at the TLVs (5 mg/m3 for pyro powder, 10
mg/m3 for dust) (ACGIH, 1986). TWA concentrations reflect possible human
NOAELs but cannnot be used to calculate an RfD, for aluminum. It should
be noted that local pulmonary effects of aluminum are presumed to be
Independent of homeostatlc regulation.
Granulomatous pneumonia occurred 1n rats and guinea pigs that were
exposed to 0.25, 2.5 or 25 mg/m3 aluminum chlorohydrate by Inhalation, 6
hours/day, 5 days/week for 6 months (Cavender et al., 1978); granulomas
developed after 12 months exposure to 25 mg/m3. These data are Inappro-
priate for RfDoj calculation because the effects have not been observed 1n
humans at comparable or higher exposures and. furthermore, because the
effects cannot definitely be attributed to aluminum.
Although ACGIH (1986) provides TLV values for fumes, soluble salts and
alkyl compounds of aluminum, since the TLVs are not based on extensive human
data and Inhalation toxlclty data on these forms of aluminum are lacking,
values for these forms of aluminum cannot be derived.
0114h -21- 06/03/87
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Derivation of a CS for Inhaled aluminum 1s complicated by the fact that
specific Information regarding pulmonary effect levels In humans 1s limited.
It Is apparent, however, that exposures exceeding the TLV by many times are
necessary to elicit adverse effects. F1bros1s Is an equivocal effect of
aluminum exposure 1n humans and has not been produced 1n exposed animals.
Lung alterations consistent with Inhalation of nuisance participates (poten-
tially reversible effects), therefore, appear to be the most appropriate
basis for a CS. Since these types of alterations have been produced In
animals at known exposures, animal effect levels (see Section 3.2.2.) can be
used to calculate the CS. Lung edema, pneumonia and pleurisy sufficient to
Induce death occurred In rats exposed to 33 g/m3 of aluminum oxide
(-17.2 g alumlnum/m3), 5 hours/day for up to 285/402 days (Klosterkotter,
1960). Slight Increases 1n alveolar macrophages and some nasal Irritation
were observed 1n rats exposed to 2.18 mg/m3 of aluminum fibers, 5 days/
week for up to 86 weeks (Plgott et al., 1981), but these effects seem mini-
mally adverse. The 17.2 g alumlnum/m3 FEL 1s equivalent to 1.6 g/kg/day
If It Is assumed that the respiratory rate was 0.223 mVday and body
weight was 0.35 kg. Multiplying this dose by the cube root of the ratio of
animal weight to human body weight (assumed 70 kg) gives a human MED of 19.2
g/day for a 70 kg man. The RV. associated with the dose Is 1 since log
MEO 1s >3. The mortality associated with this exposure 1s given an RV of
10. A CS of 10. the product of the RVd and RVe> results. Since the CS
associated with Inhalation exposure to aluminum 1s greater than that asso-
ciated with oral exposure, the Inhalation CS of 10 1s adopted to represent
the toxlclty of aluminum. A CS of 10 corresonds to an RQ of 1000.
01 Hh -22- 06/03/87 ™
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Documentation of the Threshold Limit Values and Biological Exposure Indexes,
5th ed. Cincinnati, OH. p. 22.
Alfrey, A.C. 1980. Aluminum metabolism In uremia. Neurotoxlcology. 1:
43-53. (Cited 1n U.S. EPA, 1984a)
Anderson, B.J., J.A. Williams, S.M. Nash, O.S. Oungan and S.F. Davis. 1985.
Prenatal exposure to aluminum or stress. I. Birth-related and developmental
effects. Bull. Psychon. Soc. 23(1): 87-89.
Arleff, A.I. 1985. Aluminum and the pathogenesls of dialysis encephalo-
pathy. Am. J. Kidney D1s. 6(5): 317-321.
Cam, J.M., V.A. Luck, 3.B. Eastwood and H.E. deWardner. 1976. The effect
of aluminum hydroxide orally on calcium, phosphorus and aluminum metabolism
1n normal subjects. CUn. Sd. Mol. Med. 51: 407-414. (Cited 1n U.S. EPA,
1984a)
Campbell, I., J.H. Cass, 3. Cholak and R.A. Kehoe. 1957. Aluminum In the
environment. Ind. Health. 15: 361-448. (Cited In U.S. EPA, 1984a)
Cavender, F.L., U.H. Stelnhagen and B.Y. Cockrell. 1978. Chronic toxlclty
of aluminum chlorhydrate. CUn. Toxlcol. 12: 606.
0114h -23- 06/03/87
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Clarkson. E.M.. V.A. Luck, W.V. Hynson, et al. 1972. The effect of alumi-
num hydroxide on calcium, phosphorus and aluminum balances; the serum para-
thyroid hormone concentration and the aluminum content of bone In patients
with chronic renal failure. Cl1n. Sc1. 43: 519-531. (Cited In U.S. EPA,
1984a)
Commissar 1s, R.L., J.J. Gordon, S. Sprague, J. Kelser, G.H. Mayor and R.H.
Rech. 1982. Behavioral changes 1n rats after chronic aluminum and para-
thyroid hormone administration. Neurobehavlor. Toxlcol. Teratol. 4:
403-410.
Darragh, K.V. 1978. Aluminum compounds A12(SO.)3 alums. In.: K1rk-
Othmer Encyclopedia of Chemical Technology, Vol. 2, H. Grayson and D.
Eckroth, Ed. John Wiley and Sons, Inc., New York. p. 45.
Davidson, C.I., M.D. Goold. T.P. Mathlson, G.B. Wlersma, K.W. Brown and M.T.
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