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Diss Factsheets

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Effects of Acute Exposure to Aluminium on Cognition in Humans
Author:
Molloy, D.W. et al.
Year:
2007
Bibliographic source:
Journal of Toxicology and Environmental Health, Part A 70(23):2011-2019

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
neurotoxicity
Principles of method if other than guideline:
Assessment of internal exposure level as well as cognitive function by means of neuropsychological tests after subacute oral exposure.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Aluminium hydroxide
EC Number:
244-492-7
EC Name:
Aluminium hydroxide
Cas Number:
21645-51-2
IUPAC Name:
aluminum trihydroxide
Details on test material:
- Name of test material (as cited in study report): Aluminium hydroxide (Wyeth Amphojel - aluminium hydroxide gel USP)
- Analytical purity: no data

Method

Type of population:
general
Subjects:
Participants included patients with Alzheimer’s disease and other dementias, age-matched normal volunteers selected from the patients’ caregivers and younger normal volunteers. All subjects were aged ≥ 18 years; they were able to ingest the administered aluminium and citrate drinks and to read and write in English; they had no gastric motility disorder and iron deficiency, and were not taking sucralfate. Cognitively impaired subjects had a diagnosis of possible or probable Alzheimer’s disease or a related disorder, with scores between 26 to 10 in the Standarized Mini-Mental State Examination (SMMSE).
Prior to the start of the study, 57 participants had signed informed consent to participate (42 females, 15 males). A total of 19 participants withdrew prior to or during the study procedures. Thus, 38 subjects completed the whole study protocol: 5 Alzheimer’s disease patients, 10 age-matched controls, 3 patients with other dementias and 20 young normal controls.
Ethical approval:
confirmed and informed consent free of coercion received
Remarks:
Subjects or surrogate decision makers (in the case of Alzheimer's disease patients) provided written consent.
Route of exposure:
oral
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
Ingestion of Aluminium and Citrate
Subjects were given an aluminium-containing antacid together with a drink of containing citrate and citrus juice in order to enhance absorption. The participants were required to take only a light breakfast and avoid citrus juices in order to avoid confounding aluminium absorption in the control group. The antacid administered was Wyeth Amphojel – aluminium hydroxide gel USP (64 mg aluminium hydroxide/mL, corresponding to 22.2 mg aluminium/mL). The citrate solution contained 100 g sodium citrate dihydrate and 60 g citric acid per litre. This solution contained ca. 130 mg citrate/mL. The citrate solution was mixed with Snapple Brand lemonade and distilled water, thus masking the bitter taste.A placebo drink was prepared in such a way that it matched the antacid solution in colour, consistency, and taste (2.5 g/100 mL of calcium carbonate, methylcellulose + symple syrup as vehicle and peppermint oil).
Total volumes were kept constant for each dose. The amount of water and placebo was varied in order to preserve the blinding. In Table 1, the compositions of study preparations are presented.

Randomized Crossover Trial
Subjects were given aluminium study preparation and placebo according to a crossover design, in which each subject served as his/ her own control in order to minimise the wide variability in absorption among individuals. Between the two 3-d test sessions, there was a 3-week washout period. Subjects were randomly designated to the Active-Placebo or Placebo-Active test order protocols.
Due to the wide variability in individual absorption, the Amphojel and citrate dose was adjusted for each individual in order to yield serum aluminium levels within the range of 50-150 µg/L. Amphojel + citrate doses were given over 3 consecutive days. The starting dose was 15 mL Amphojel on the first day. The doses on days 2 and 3 were adjusted according to serum analyses perfomerd at the end of days 1 and 2, respectively. The maximum dose was 60 ml Amphojel + citrate (Table 2).
Examinations:
Neuropsychological test battery
A neuropsychological test battery (NTB) was performed on day 1 at baseline and on day 3 both at baseline (time zero) and 90 min following ingestion of the study preparation.
The NTB included: Rey Auditory Verbal Learning Task (Word list learning), Digit Symbol Substitution, Trail-Making, Serial Digit Learning, Digit Vigilance, Word Fluency, and Simple Reaction Time and Complex Reaction Time.
The simple reaction time was assessed as the time (in milliseconds) between the presentation of a visual signal (consisting of a 4-cm black square appearing in the centre of a white computer screen) and the patient's response to the signal (hitting the space bar on the keyboard). The visual signal appeared with random delay after the start of each trial (total: 10 trials).
The complex reaction time was assessed as the time (in milliseconds) between the random presentation of a coloured signal (consisting of a 4-cm green or red square appearing in the centre of a white computer screen), and the patient’s response to the signal (pushing either the right arrow for green or the left arrow for red). This test was repeated 10 times. The number of correct responses as well as the delay to each response were recorded.
More challenging versions were administered on the trail-making and reaction-time tests among normal controls in order to avoid ceiling effects. On trail making, younger normal subjects traced 1, A, 2, B, etc. and others traced 1, 2, 3, etc. On complex reaction time, younger normal subjects pressed the left or right arrow keys as described above. All others pressed any key when a black square appeared.

Aluminium level
Blood samples were taken for measurements of serum aluminium levels both at baseline and 90 min following ingestion on each of the 3 days. The protocol was repeated with subjects crossed over to the opposite preparation after a 3-week wash-out period.
The aluminium concentration in serum was determined with a Perkin-Elmer 703 atomic absorption spectrometer with an HGA 500 furnace, AS-1 autosampler, and Intensitron hollow cathode lamp.

Apolipoprotein genotype
A blood sample was taken on day 1 to analyse for apolipoprotein E (APOE) status in order to determine whether the presence of the genotype was related to either changes in aluminum absorption or neuropsychological performance.
DNA from the peripheral lymphocytes was used for the APOE genotyping in an automated procedure. Briefly, a 208 bp DNA segment from exon 4 of the Apo gene was amplified from genomic DNA by fluorescent-based polymerase chain reaction. The amplified fragments were digested with appropriate restriction endonucleases. The resulting pattern of fragments was visualized on a 6% sequencing gel, which were electronically analysed using an internal fluorescent standard for each lane.

Results and discussion

Clinical signs:
No clinical signs observed.
Results of examinations:
Serum aluminium levels for each time point are given in Table 3. The mean aluminium absorption was similar by group. The highest mean aluminium concentration in serum was measured on day 3, 90 min after administration.
A significant difference was found in the test for order effects regarding digit vigilante scores (t=2.7, p=.01) (Table 4). Those subjects which were randomised to active in the first phase had higher baseline scores than subjects randomised to placebo. No other order effects were observed.
No significant differences were found in NTB scores between active and placebo for any of the individual tests (Table 5) or for any of the groups examined (Table 6).
The results from 54 subjects, for which samples were available for APOE genotyping, are given in Table 7. Two copies of the APOE epsilon-4 allele were present in seven (13%) subjects; one copy of the APOE epsilon-4 allele was present in 19 (35%) subjects; two copies of the epsilon-3 allele were present in 25 (46%) subjects; and one copy of the epsilon-2 allele was present in 3 (6%) subjects. The authors stated that there was no significant relationship between APOE allele and serum aluminium levels or changes in cognitive scores.

Any other information on results incl. tables

Table 3. RCT: Serum aluminium levels by study group—active treatment phase.

 

 

Day 1/Baseline at time zero

Day 1/90 min

Day 2/Baseline

Day 2/90 min

Day 3/baseline

Day 3/90 min

Group (n)

Mean

(µg/L)

95% CI

Mean (µg/L)

95% CI

Mean (µg/L)

95% CI

Mean (µg/L)

95% CI

Mean (µg/L)

95% CI

Mean (µg/L)

95% CI

Alzheimer's disease (5)

2.2

(0.4, 4.0)

11

(3.6, 18)

6.7

(0, 17)

289

(0, 765)

33

(24, 42)

149

(34, 264)

Age-matched controls (10)

2.9

(0.5, 5.3)

14

(9.3, 19)

2.6

(0.9, 4.3)

207

(121, 292)

28

(13, 43)

300

(216, 385)

Other dementias (3)

0

na

31

(3.4, 58)

7.3

(0, 16)

327

(0, 1042)

74

(0, 275)

612

(0, 2369)

Young normal controls (20)

1.2

(0.1, 2.2)

18

(13, 23)

4.2

(1.7, 6.7)

114

(65, 162)

26

(20, 32)

286

(101, 471)

Combined (38)

1.7

(0.8, 2.5)

17

(14, 20)

4.4

(2.6, 6.3)

181

(111, 251)

36

(27, 45)

294

(181, 407)

 

 

Table 4. NTB scores – test for treatment order effects.

 

 

Order la

Order 2b

 

Test

Mean differencec

95% CI

Mean differenced

95% CI

Unpaired t (p value)

Word List Learning

-1.4

(-2.9, 0.1)

0.9

(-1.1, 2.8)

-1.9 (0.06)

Digit Symbol Substitution

5.7

(1.6, 9.8)

4.3

(1.2, 7.4)

0.6 (0.6)

Delayed Recall

-0.4

(-1.4, 0.4)

-0.5

(-1.3, 0.4)

0.1 (0.9)

Trail Making

-18.4

(-28.9, -7.9)

-30.1

(-53.3, -8.6)

1.1 (0.3)

Digit Vigilance

8.7

(2.6, 14.7)

-2.4

(-8.6, 3.9)

2.7 (0.01)*

Word Fluency

8.3

(4.4, 12.1)

4.1

(-0.3, 8.5)

1.5 (0.15)

Simple Reaction Time

-61

(-247, 125)

27

(-193, 246)

-0.6 (0.54)

Complex Reaction Time

-103

(-180, -25)

-57

(-112, -2)

-1.0 (0.32)

 

aPhase 1 active, phase 2 placebo.

bPhase 1 placebo, phase 2 active.

cDelta of active phase, dayl/baseline; placebo phase, dayl/baseline.

dDelta of placebo phase, dayl/baseline; active phase, dayl/baseline.

* Statistically significant.

 

 

Table 5. NTB scores: paired comparison of active with placebo.

 

 

Active

Placebo

 

Test

Mean differencea

95% CI

Mean differencea

95% CI

Paired t (p value)

Word List Learningb

-0.9

(-2.0, 0.2)

-1.7

(-3.1, -0.2)

0.19 (0.85)

Digit Symbol Substitutionc

1.3

(-0.9, 3.5)

1.9

(-3.1, -0.2)

-0.67 (0.51)

Delayed Recalld

-0.31

(-1.0, 0.37)

-1.1

(-1.9, -0.3)

1.4 (0.18)

Trail Malringe

-7.9

(-16.9, 1.1)

-2

(-11.2, 7.1)

-0.33 (0.75)

Digit Vigilancef

1.1

(-2.1, 4.3)

2

(-0.7, 4.8)

-1.2 (0.23)

Word Fluencyg

3.0

(0.0, 6.0)

1.9

(-1.0, 4.7)

0.8 (0.4)

Simple Reaction Timeh

-5

(-39, 28)

30

(-10, 70)

-1.2 (0.25)

Complex Reaction Timei

6

(-13, 24)

-41

(-112, 29)

1.3 (0.2)

 

aDelta of d 3/90 min and d 1/baseline scores.

bMean number of words recalled (higher score indicates improvement).

cMean number of symbols substituted (higher score indicates improvement).

dMean number of words recalled after delay (higher score indicates improvement).

eMean number of seconds to complete "trail" (lower score indicates improvement).

fMean number of numbers crossed off (higher score indicates improvement).

gMean number of words produced (higher score indicates improvement).

hMean number of milliseconds to push any button after computer prompt (lower score indicates improvement).

iMean number of milliseconds to push correct button after computer prompt (lower score indicates improvement).

 

 

Table 6. NTB scores: mean differences by demographic group (active – placebo).

 

 

Younger normal controls (n = 20)

Age-matched controls (n = 10)

Alzheimer's disease (n = 6)

Other dementias (n = 3)

 

Test

Mean

95% CI

Mean

95% CI

Mean

95% CI

Mean

95% CI

F statistic (p value)a

Word List Leamingb

0.4

(-2,2, 3.0)

-1.4

(-5.1, 2.3)

2

(-4.9, 8.9)

1.3

(-10.4, 13.1)

0.52 (0.67)

Digit Symbol Substitutionc

-1.2

(-5.2, 2.8)

-2

(-9.1, 5.1)

-1

(-24.7, 22.7)

6

(-82.9, 95.0)

0.44 (0.73)

Delayed Recalld

0.4

(-0.9, 1.6)

0.9

(-1.1, 2.9)

-0.67

(-4.5, 3.1)

2.3

(-1.5, 6.1)

0.82 (0.50)

Trail Makinge

-1.2

(-10.0, 7.6)

-7.7

(-49.0, 33.6)

1

(-240.3, 242.3)

9.5

(-35.0, 54.0)

0.12 (0.95)

Digit Vigilancef

-0.4

(-5.0, 4.2)

-3.9

(-9.3, 1.5)

-6

(-31.9,19.9)

-3

(-219.0, 213.0)

0.46 (0.71)

Word Flueneyg

1.1

(-4.6, 6.8)

-1.5

(-7.9, 4.9)

4.5

(-0.5, 9.5)

8.3

(3.2, 13.5)

0.83 (0.49)

Simple Reaction Timeh

-9

(-52, 34)

-61

(-173, 51)

-255

(-1167, 658)

79.1

(-539, 697)

1.84 (0.16)

Complex Reaction Timei

80

(-40, 201)

-8

(-40, 23)

n.a.

 

n.a.

 

1.09 (0.29)

 

aComparison of the means for the four study groups.

bMean number of words recalled (higher score indicates improvement).

cMean number of symbols substituted (higher score indicates improvement).

dMean number of words recalled after delay (higher score indicates improvement).

eMean number of seconds to complete "trail" (lower score indicates improvement).

fMean number of numbers crossed off (higher score indicates improvement).

gMean number of words produced (higher score indicates improvement).

hMean number of milliseconds to push any button after computer prompt (lower score indicates improvement).

iMean number of milliseconds to push correct button after computer prompt (lower score indicates improvement) (demented groups did not perform this test).

 

 

Table 7. APOE type by demographic group (n = 54).

 

 

Distribution of APOE types within demographic groups

 

APOE allele

Younger controls % (n)

Age-matched controls % (n)

Alzheimer' s disease % (n)

Other dementias % (n)

APOE dis tribution across entire sample % (n)

Allele type

 

2,3

4.5 (1)

5.9 (1)

10 (1)

0 (0)

5.6 (3)

3,3

50.0 (11)

29.4 (5)

60 (6)

60 (3)

46.3 (25)

3,4

31.8 (7)

52.9 (9)

10 (1)

40 (2)

35.2 (19)

4,4

13.6 (3)

11.8 (2)

20 (2)

0 (0)

13.0 (7)

Allele frequency

 

epsilon-2

0.023

0.029

0.050

0.000

0.028

epsilon-3

0.682

0.588

0.700

0.800

0.667

epsilon-4

0.295

0.382

0.250

0.200

0.306

Applicant's summary and conclusion

Conclusions:
Aluminum ingested as aluminium hydroxide does not induce acute effects on cognition or adverse effects at aluminium levels in serum up to ca. 600 µg/L . The results of this study did not reveal that Alzheimer's disease patients are more vulnerabIe.