Aluminum salts final content: appendix B

Ontario

1981-1991

McLachlan et al. (1996)

Case-control study

Cases and controls based on brains donated to Canadian Brain Tissue Bank.

Cases: a1--296 AD based on clinical history of dementia and histopathology criteria (neuritic plaques and NFTs in specific brain regions); a2--89 AD as above coexisting with other neuropathologic process.
Controls: c1--125 with no brain histopathology; c2--170 with other neurodegenerative diseases.

Not weighted for residential history:
al vs c1 + c2:
Al≥100 vs <100 µg/L, OR = 1.7 (95% CI 1.2-2.6)
Al≥125 vs <125 µg/L, OR = 3.6 (95% CI 1.4-9.9)
Al≥150 vs <150 µg/L, OR = 4.4 (95% CI 0.98-20)
Al≥175 vs <175 µg/L, OR = 7.6 (95% CI 0.98-61)
a1 + a2 vs c1 + c2:
Al≥100 vs <100 µg/L, OR = 1.7 (95% CI 1.2-2.5)

Weighted for 10-year residential history:
a1 vs c1 + c2:
Al≥100 vs <100 µg/L, OR = 2.6 (95% CI 1.2-5.7)
a1 + a2 vs c1 + c2:
Al≥100 vs <100 µg/L, OR = 2.5 (95% CI 1.2-5.3)
a1 vs c2:
Al≥100 vs <100 µg/L, OR = 2.5 (95% CI 1.1-5.6)

No control for age, sex, education, occupation, etc.

Exposure weighted for 10-year residential history for 119 cases and 51 controls.

AD clinical diagnostic criteria not stated.

Ontario

1984-1991

Forbes et al. (1995b)
Forbes and McLachlan (1996)

Cross-sectional study

AD or presenile dementia based on death certificate data (ICD-9 331.0 and ICD-9 290.1) from LSA cohort.

Forbes et al. (1995b): ≈3000 death certificates reporting dementia (AD and presenile dementia).

Forbes and McLachlan (1996): 1,041 death certificates reporting AD (≥85 years of age).

Forbes et al. (1995b):
For individuals of ≥75 years of age with AD:

For Al alone:
Al≤67 µg/L, RR = 1.00
Al=68-200 µg/L, RR = 0.91 (95% CI 0.82-1.01)
Al≤336 µg/L, RR = 3.15 (95%CI 1.85-5.36)

Adjustment for pH:
Al≤67 µg/L, pH<7.85, RR = 1.00
Al = 68-200 µg/L, pH = 7.85-7.95, RR = 0.91 (95% CI 0.82-1.00)
Al≥336 µg/L, pH≥7.95, RR = 3.27 (95% CI 1.92-5.57)

Adjustment for F:
Al≤67 µg/L, RR = 1.00
Al = 68-200 µg/L, F<300 µg/L, RR = 0.95 (95% CI 0.84-1.06)
Al≥336 µg/L, F≥860 µg/L, RR = 3.10 (95% CI 1.81-5.27)

Adjustment for Al/F interaction term:
Al≤67 µg/L, F<300 µg/L, RR = 1.00
Al = 68-200 µg/L, RR = 1.11 (95% CI 0.92-1.33)
Al≥336 µg/L, RR = 3.88 (95%CI 2.22-6.77)
Al≤67 µg/L, F≥860 µg/L, RR = 1.00
Al = 68-200 µg/L, RR = 0.85 (95% CI 0.74-0.98)
Al≥336 µg/L, RR = 0.98 (95%CI 0.14-6.97)

Adjustment for Si:
Al≤67 µg/L, RR = 1.00
Al = 68-200 µg/L, Si<1.5 mg/L, RR = 0.90 (95% CI 0.81-1.00)
Al≥336 µg/L, Si≥1.5 mg/L, RR = 3.14 (95%CI 1.84-5.34)

Adjustment for Al/Si interaction term:
Al≤67 µg/L, Si<1.5 mg/L, RR = 1.00
Al = 68-200 µg/L, RR = 1.00 (95% CI 0.89-1.13)
Al≥336 µg/L, RR = 4.04 (95%CI 2.32-7.03)
Al≤67 µg/L, Si≥1.5 mg/L, RR = 1.00
Al = 68-200 µg/L, RR = 0.67 (95% CI 0.55-0.82)
Al≥336 µg/L, RR = 0.88 (95%CI 0.12-6.29)

Similar analyses with individuals with AD and presenile dementia, with presenile dementia alone, and with AD individuals of all ages were presented. The RRs were smaller.

Forbes and McLachlan (1996):
For individuals ≥85 years of age:
For Al alone:
Al = 68-250 µg/L vs ≤67 µg/L, RR = 0.85, p<0.05
Al>250 µg/L vs ≤67 µg/L, RR = 4.76, p<0.05

Adjustment for water source:
Al = 68-250 µg/L vs ≤67 µg/L, RR = 0.88, p>0.05
Al>250 µg/L vs ≤67 µg/L, RR = 4.93, p<0.05

Adjustment for water source, Si:
Al = 68-250 µg/L vs =67 µg/L, RR = 0.91, p>0.05
Al>250 µg/L vs =67 µg/L, RR = 5.07, p<0.05

Adjustment for water source, Si, Fe:
Al = 68-250 µg/L vs ≤67 µg/L, RR = 0.89, p>0.05
Al>250 µg/L vs. ≤67 µg/L, RR = 6.27, p<0.05

Adjustment for water source, Si, Fe, pH:
Al = 68-250 µg/L vs ≤67 µg/L, RR = 0.91, p>0.05
Al>250 µg/L vs ≤67 µg/L, RR = 7.38, p<0.05

Adjustment for water source, Si, Fe, pH, F:
Al = 68-250 µg/L vs ≤67 µg/L, RR = 0.90, p>0.05
Al>250 µg/L vs. ≤67 µg/L, RR= 7.56, p < 0.05

Adjustment for water source, Si, Fe, pH, F, turbidity:
Al = 68-250 µg/L vs ≤67 µg/L, RR = 0.89, p>0.05
Al>250 µg/L vs ≤67 µg/L, RR = 9.95, p<0.05

No control for sex, education, occupation, etc.

Possible inaccuracies in death certificate data due to the different certification practices of local doctors.

No information on duration of exposure.

RR corresponds to rate ratio where the population reference was from Ontario Longitudinal Study of Aging.

Ontario

1990-1991

Forbes et al. (1992)
Forbes et al. (1994)
Forbes and Agwani (1994)
Forbes et al. (1995a)

Cross-sectional study

Males with cognitive impairment based on interview/questionnaire with modified mental status test for subjects from the LSA cohort. For deceased persons, the questionnaires were administered to survivors or proxy respondants.

Forbes et al. (1992): 485 males.

Forbes et al. (1994): 290 males for analysis restricted to treated surface drinking water and 485 males for other analysis.

Forbes and Agwani (1994): 530 males.

Forbes et al. (1995a): 494-541 males for each analysis.

Total Al in drinking water based on the data of the Water Quality Surveillance Programme of the Ontario Ministry of the Environment for municipal supplies serving place of residence and residential history.

Medians of Al and F concentrations are the cut-off values.

Forbes et al. (1992):
Based on treated water:
Al≥84.7 µg/L vs Al<84.7 µg/L OR = 1.14 (p>0.05)
Al<84.7 µg/L, F>880 µg/L, OR = 1.00
Al≥84.7 µg/L, F>880 µg/L, OR = 1.69 (p>0.05)
Al<84.7 µg/L, F<880 µg/L, OR = 2.21 (p<0.05)
Al≥84.7 µg/L, F<880 µg/L, OR = 2.72 (p<0.01)
Al<84.7 µg/L, F<880 µg/L, OR = 1.00
Al<84.7 µg/L, F>880 µg/L, OR = 0.45 (p<0.05)
Al≥84.7 µg/L, F<880 µg/L, OR = 1.23 (p>0.05)
Al≥84.7 µg/L, F<880 µg/L, OR = 1.00
other combinations of Al and F, OR≈0.61 (p>0.05)
Al<84.7 µg/L, F>880 µg/L, OR = 1.00
Al≥84.7 µg/L, F>880 µg/L, OR = 1.69 (p>0.05)
other combinations of Al and F, OR = 1.95 (p<0.05)

Similar analyses with raw water concentrations were presented but no significant association was reported.

Forbes et al. (1994):
Restricted to treated surface drinking water (N = 290):
Al≥84.7 vs <84.7 µg/L, OR = 1.53 (95% CI 0.94-2.51)
Al<84.7 µg/L, F≥880 µg/L, OR = 1.00
Al≥84.7 µg/L, F≥880 µg/L, OR = 2.13 (95% CI 1.09-4.12)
Al<84.7 µg/L, F<880 µg/L, OR = 2.75 (95% CI 1.20-6.27)
Al≥84.7 µg/L, F<880 µg/L, OR = 3.98 (95% CI 1.72-9.19)

Forbes et al. (1994):
Increased ORs when analysis restricted to subjects residing >5 years at current address.
Analyses based on all treated drinking water (N = 485):

pH<7.85 (N = 68)
Al≥84.7 vs <84.7 µg/L, OR = 0.76 (95% CI 0.28-2.06)
Al≥84.7 vs <84.7 µg/L with F<880 µg/L, OR = 0.91 (95% CI 0.30-2.74)

pH = 7.85-8.05 (N = 54)
Al≥84.7 vs <84.7 µg/L, OR = 0.68 (95% CI 0.21-2.19)
Al≥84.7 vs <84.7 µg/L with F<880 µg/L, OR = 0.67 (95% CI 0.07-6.41)

pH>8.05 (N = 363)
Al≥84.7 vs <84.7 µg/L, OR = 1.30 (95% CI 0.85-2.04)
Al≥84.7 vs <84.7 µg/L with F<880 µg/L, OR = 1.36 (95% CI 0.55-3.39)
Al≥84.7 vs <84.7 µg/L, F≥880 vs <880 µg/L, OR = 0.87 (95% CI 0.50-1.52)
Al<84.7 µg/L, F≥880 vs <880 µg/L, OR = 0.47 (95% CI 0.23-0.97)

Logistic regression adjusted for F, pH, water source, age, education, health, income and number of moves:

Al≥84.7 vs <84.7 µg/L, OR = 1.72 (95% CI 1.08-2.75)

Forbes and Agwani (1994):
Logistic regression adjusted for F, pH, turbidity, dissolved organic carbon and water source:

Al≥84.7 vs <84.7 µg/L, OR = 1.97 (95% CI 1.21-3.22)

Logistic regression adjusted for F, pH, turbidity, dissolved organic carbon, water source and detailed source:

Al≥84.7 vs <84.7 µg/L, OR = 2.27 (95% CI 1.27-4.07)

Forbes et al. (1995a):
Logistic regression adjusted for F, pH, turbidity, dissolved organic carbon, Si, Fe, water source, education, health status, income and number of moves (N = 530):

Without age term:
Al≥84.7 vs <84.7 µg/L, OR = 2.19 (95% CI 1.29-3.71)

With age term:
Al≥84.7 vs <84.7 µg/L, OR = 2.19 (95% CI 1.29-3.71)
With age term and Al/Si interaction term:
Al≥84.7 vs <84.7 µg/L, OR = 2.35 (95% CI 1.32-4.18)

Logistic regression adjusted for F, pH, Si, water source and Al/Si interaction (N = 541):
Al≥84.7 vs <84.7 µg/L, OR = 1.98 (95% CI 1.20-3.26)

Analysis for Si (N = 494):
Al≥84.7 vs <84.7 µg/L, OR = 1.47 (95% CI 0.99-2.20)
Al<84.7 µg/L, Si≥790 vs <790 µg/L, OR = 2.20 (95% CI 1.02-4.74)
Al≥84.7 µg/L, Si≥790 vs <790 µg/L, OR = 0.89 (95% CI 0.54-1.47)

Forbes et al. (1992), Forbes et al. (1994), Forbes and Agwani, (1994), Forbes et al. (1995a):
Exposure not weighted for residential history.
Cognitive impairments generally slight.

Forbes et al. (1992), Forbes and Agwani, (1994):
No control for age, education, occupation, etc.

Forbes et al. (1994), Forbes et al. (1995a):
Selected analyses included control for education, health status at age 62, income at age 45, number of moves and age.

Ontario

1986-1987

Neri and Hewitt (1991)
Neri et al. (1992)

Case-control

Cases: AD and presenile dementia based on ICD criteria from individuals' hospital discharge data.

Controls: other diagnoses (not psychiatric or neurological) matched to cases for age/sex.

≥55 years of age.

Neri and Hewitt (1991): 2232 cases/2232 controls.

Neri et al. (1992): 2258 cases/2258 controls.

Neri and Hewitt (1991); Neri et al. (1992):
Significant dose-response between AD and concentrations =10 µg/L (p<0.05).

Neri and Hewitt (1991):
<10 µg/L, RR = 1.0
10-99 µg/L, RR = 1.13
100-199 µg/L, RR = 1.26
>200 µg/L, RR = 1.46
95% CI or p value are not mentioned

Neri et al. (1992):
<10 µg/L, RR = 1.00
10-99 µg/L, RR = 1.15
100-199 µg/L, RR = 1.45
>200 µg/L, RR = 1.46
95% CI or p value are not mentioned

Quebec (Saguenay-Lac-Saint-Jean)

1994

Gauthier et al. (2000)

Case-control study

Cases: 68 probable and possible AD based on a three-step procedure: (1) MMS examination, (2) DSM-IV criteria, (3) NINCDS-ADRDA and ICD-10.

Controls: 68 free of cognitive impairment, matched with cases for age and sex.

≥70 years of age.

Al in drinking water based on water samples of 54 municipalities collected four times from 1995 to 1996.

Al species (for example, dissolved, monomeric, polymeric) were quantified.

The fourth quartile of the concentration of each Al species was the cut-off value.

For long-term exposure to Al (1945 to onset):
No significant association for any Al species.

For exposure estimated at onset (vs <fourth quartile):
Total (>77.2 µg/L): OR = 2.10 (95% CI 0.83-5.35)
Total dissolved (>38.9 µg/L): OR = 1.93 (95% CI 0.79-4.67)
Monomeric organic (>12.2 µg/L): OR = 2.67 (95% CI 1.04-6.90)
Monomeric inorganic (>8.4 µg/L): OR = 0.71 (95% CI 0.29-1.72)
Al-OH (>8 µg/L): OR = 0.53 (95% CI 0.20-1.42)
Al-F (>0.3 µg/L): OR = 0.67 (95% CI 0.26-1.67)
Al-Si (>0.04 µg/L): OR = 0.67 (95% CI 0.26-1.69)
Polymeric (>14.6 µg/L): OR = 1.98 (95% CI 0.79-4.98)

Examination of the speciation of Al in drinking water.

Control for age, sex, education level, family history, ApoE e4 allele and occupational exposure.

France (southwestern: Gironde and Dordogne)

1988-1989

Jacqmin et al. (1994)
Jacqmin-Gadda et al. (1996)

Cross-sectional study

Cognitive impairment based on the MMS examinations of individuals ≥65 years of age from the PAQUID cohort.

Jacqmin et al. (1994): 3,469 individuals.

Jacqmin-Gadda et al. (1996): 3430 individuals.

Jacqmin et al. (1994):
No significant association with Al without adjustment for pH; association positive for pH≤7.3, association negative for pH≥7.3 (p values not mentioned).

Logistic regression adjusted for age, sex, education, occupation, calcium, pH:

OR = 5.2 (95% CI 1.1-25.1),with increase of logarithm of the Al concentration (1 mg Al/L)
OR = 0.80 (95% CI 0.65-0.98), with increase of logarithm of the Al concentration (1 mg Al/L) with the pH/Al interaction term
No significant association (p>0.05) when adjusted for education and occupation.

Jacqmin-Gadda et al. (1996):
Logistic regression adjusted for age, sex, education, occupation, calcium, pH, Si:
Only significant association (p<0.05) with Al when the cutpoint was the first quartile of Al (vs median and third quartile):
Al≥3.5 µg/L vs <3.5 µg/L:
OR = 1.65 (95% CI 0.80-3.39) (without Al/Si interaction term)
OR = 3.94 (95% CI 1.39-11.2) (with Al/Si interaction term)

Logistic regression adjusted for personal characteristics and calcium:
Al<3.5 µg/L, pH<7.35, Si<10.4 mg/L, OR = 1.00
Al≥3.5 µg/L:
pH≥7.35, Si≥10.4 mg/L, OR = 0.75 (95% CI 0.59-0.96)
pH≥7.35, Si<10.4 mg/L, OR = 0.89 (95% CI 0.64-1.22)
pH<7.35, Si≥10.4 mg/L, OR = 0.74 (95% CI 0.53-1.02)
pH < 7.35, Si < 10.4 mg/L, OR = 1.30 (95%CI 0.75­-2.24)

Control for age, sex, education levels, principal lifetime occupation and calcium.

Exposure not weighted for residential history.

France (southwestern: Gironde and Dordogne)

1988-1989 to 1997

Rondeau et al. (2000)
Rondeau et al. (2001)

Longitudinal study (follow-up analysis in eight years)

Dementia and AD based on a two-step procedure: (1) DSM-III criteria, (2) for those with positive DSM results or decline of MMS score (>2 points), NINCDS-ADRDA criteria for AD and Hachinski score for vascular dementia.

Re-evaluation of the subjects one, three, five and eight years after the initial visit (the subjects from Dordogne were not re-evaluated after one year).

Initially, 2698 nondemented subjects ≥65 years of age from the PAQUID cohort participated in this study

Total Al in drinking water based on data from treatment plant or distribution system serving place of residence (from two analysis surveys).

Data from distribution system were weighted to take into account the period length of use of each treatment plant over the previous 10 years (1981-1991) and the hourly flow or the relative contribution of the treatment plant.

RR for 253 cases of dementia:
Adjustment for age and sex:
Al≥100 vs <100 µg/L, RR = 2.33 (95% CI 1.42-3.82)
Increase of 100 µg/L Al, RR = 1.36 (95%CI 1.15-1.61)

Adjustment for age, sex, educational level, wine consumption and place of residence:
Al<3.8 µg/L, RR = 1
Al≥3.8 vs <11.0 µg/L, RR = 1.03 (95% CI 0.74-1.43)
Al≥11.0 vs <100 µg/L, RR = 0.98 (95% CI 0.69-1.40)
Al≥100 µg/L, RR = 2.00 (95%CI 1.15-3.50)
Al≥100 vs <100 µg/L, RR = 1.99 (95% CI 1.20-3.28)
Increase of 100 µg/L Al, RR = 1.25 (95%CI 1.05-1.50)

RR for 182 cases of AD:
Adjustment for age and sex:
Al≥100 vs <100 µg/L, RR = 2.20 (95% CI 1.24-3.84)
Increase of 100 µg/L Al, RR = 1.46 (95%CI 1.23-1.74)
Adjustment for age, sex, educational level, wine consumption and place of residence:
Al<3.8 µg/L, RR = 1
Al≥3.8 vs <11.0 µg/L, RR = 1.16 (95% CI 0.78-1.72)
Al≥11.0 vs <100 µg/L, RR = 0.97 (95% CI 0.63-1.49)
Al≥100 µg/L, RR = 2.27 (95%CI 1.19-4.34)
Al≥100 vs <100 µg/L, RR = 2.14 (95% CI 1.21-3.80)
Increase of 100 µg/L Al, RR = 1.35 (95%CI 1.11-1.62)

RR for 105 cases of dementia (among 1,638 individuals):
Adjustment for mineral water consumption, age, sex, education level, wine consumption and place of residence:
Al≥100 vs <100 µg/L, RR = 3.36 (95% CI 1.74-6.49)

Control for age, sex, education, wine consumption and place of residence.

Exposure not weighted for residential history.

France (southwestern: Gironde and Dordogne)

1988-1989

Michel et al. (1991)

Cross-sectional study

Spearman rank correlation between Al concentration and AD was significantly different from zero (p<0.05).

Logistic regression adjusted for age, education and place of residence:

Increase of 10 µg/L, RR = 1.16, p = 0.0014
Increase of 100 µg/L, RR = 4.53 (95% CI 3.36-6.10)

Eight regions of England and Wales

1986-1992

Martyn et al. (1997)

Case-control
study

Cases: 106 with clinical diagnosis of AD or normal computer tomography (CT) scan or cerebral atrophy, with a progressive deterioration of cognition in the absence of other causes for dementia.

Controls: 99 patients with other types of dementia (normal CT), 226 patients with brain cancer and 441 patients with other neurological disorders.

Cases and controls were all males born between 1916 and 1945.

No significant association between AD and drinking water concentrations based on several OR (27 OR were presented and were not significant p>0.05):

Al = 15-44, Al = 45-109 and Al≥110 µg/L in comparison to Al<15 µg/L

When:
Al concentrations were averaged over 10 years before diagnosis
Al concentrations were averaged from age 25 to 10 years before diagnosis
Al concentrations were averaged over 10 years before diagnosis

For the three sets of controls (that is, other dementia, brain cancer, other diagnoses).
No significant association between AD and Al in drinking water when Si<6 mg/L (again based on 27 OR, with ≈40 cases, ≈34 patients with other dementia, ≈60 patients with brain cancer and ≈166 patients with other diagnoses).

Control for age, neuroradiology centre where diagnosis was made and distance of residence from neuroradiology centre.

AD clinical diagnostic criteria not stated.

Northern England

1990-1992

Forster et al. (1995)

Case-control study

Cases: 109 AD-type presenile dementia diagnosed before 65 years of age based on a three-step procedure: (1) hospital case notes (NINCDS-ADRDA and DSM criteria), (2) MMS examination, (3) geriatric mental state examination.

Controls: 109 from general population paired for age and sex with exclusion of potentially dementia.

Al in drinking water 10 years before dementia onset:
Al<50 vs >50 µg/L, OR = 1.2 (95% CI 0.67-2.37)
Al>50 vs <50 µg/L, OR = 0.8 (95% CI 0.42-1.50)
Al>99 vs <99 µg/L, OR = 0.8 (95% CI 0.44-1.49)
Al>149 vs <149 µg/L, OR = 1.0 (95% CI 0.41-2.43)

Same conclusions when the exposure is based on Al in drinking water at birthplace (N = 80 cases/control).

>4 cups tea/day, OR = 1.4 (95% CI 0.81-2.63)
Prolonged antacids used, OR = 1.6 (95%CI 0.77-3.51)

Control for age and sex.

Same conclusions with control for family history of dementia.

No information on presence or absence of Al in antacids.

Northern England
(three districts: North Tyneside, Sunderland and Durham)

1982-1985

Wood et al. (1988)

Cross-sectional study

Control for age and sex.

Primary focus of study was bone mass/hip fracture.

No information on the history of exposure.

Details of mental test scores not provided.

Switzerland (Zurich)

≈1989

Wettstein et al. (1991)

Cross-sectional study