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Endpoint:
epidemiological data
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
supporting study
Justification for type of information:
Refer to analogue justification provided in IUCLID section 13.
Cross-referenceopen allclose all
Reason / purpose:
read-across source
Reference
Endpoint:
epidemiological data
Type of information:
other: Epidemiological observational
Adequacy of study:
supporting study
Study period:
1991 - 2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given
Study type:
cohort study (prospective)
Endpoint addressed:
neurotoxicity
Qualifier:
no guideline required
GLP compliance:
no
Type of population:
general
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
HYPOTHESIS TESTED (if cohort or case control study):
The association between local levels of aluminium in drinking water and the risk of developing Alzheimer’s disease (AD)

METHOD OF DATA COLLECTION
- Type: Questionnaire / other:
- Details:
Cognitively normal subjects at baseline provided information on all their residencies during their life, on sources of drinking water at each residence (well vs. municipal) and on a number of potentially confounding factors.
Data on water parameters for the period 1980-2000 were received from water treatment plants supplying the subjects’ residences

STUDY PERIOD:
1991-2002

SETTING:
Canadian Study of Health and Aging: 36 cities and surrounding areas in 5 Canadian regions: British Columbia, the Prairies, Ontario, Quebec and the Atlantic provinces.

STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): A random sample of 15,677 individuals aged 65 years or older
- Participation rate: 10,263 individuals, including 72.1% from the community sample (9,008) and 81.7% of the institutional sample (1,225)
- Selection criteria: Availability of risk factor questionnaires (1,833 subjects excluded based on this criterion) and residential history information (561 subjects excluded); ≥7 years of residential history information during 1980-1991 (157 subjects excluded); no AD at baseline (557 subjects excluded)
- Total number of subjects participating in study: 7,155 subjects; 4,507 of them with successfully assigned Al drinking water concentrations were used in the main analyses.
- Sex/age/race: 65 years or older; both genders
- Smoker/nonsmoker: smokers and non-smokers
- Total number of subjects at end of study: 2,847


COMPARISON POPULATION
- Type: State registry / Regional registry / National registry / Control or reference group / Other comparison group:
- Details:
A category of 0-46.4 µg/L aluminium concentration in drinking water was used as a reference in the categorical analysis.


HEALTH EFFECTS STUDIED
- Disease(s): Alzheimer’s disease (AD), possible or probable
- ICD No.: ICD-10
- Year of ICD revision: 1993 (see Lindsay et al., Am J Epidemiol. 2002 Sep 1; 156(5):445-53).
- Diagnostic procedure:
Baseline examination: For individuals living in the community, a home interview was conducted, including the Modified Mini-Mental State Examination (3MS) screening test for cognitive impairment. Individuals with a 3MS score below 78/100 were subject to a three-stage medical examination (All participants living in institutions received a clinical examination without the screening interview):
1) The 3MS examination was re-administered by a nurse
2) A physician conducted a standardized physical and neurological examination.
3) A psychometrist administered 15 neuropsychological tests to subjects with 3MS score of 50 or above, i.e. to those whose cognitive status was sufficient for the testing process. The subjects with a 3MS score less than 50 were not given the neuropsychological tests and did not receive a neuropsychological diagnosis.
The physician and neuropsychologist independently made a preliminary diagnosis based on DSM-III-R criteria. The diagnoses were compared at a case consensus conference with participation of the whole clinical team. Those with dementia were classified using NINCDS-ADRDA criteria. AD cases for this study were defined as subjects diagnosed with possible or probable AD.
1996-1997 follow-up examination (CSHA-2): same diagnostic process
2001-2002 follow-up examination (CSHA-3): Same methods as in the previous examinations, but the 3MS cutpoint was changed from <78 to <90. Subjects scoring between 50 and 90 on the 3MS and all subjects who had undergone a previous clinical examination continued to the neuropsychological examination. Subjects classified by the neuropsychologist as cognitively impaired attended the clinical assessment, as well as participants with 3MS scores below 50 and subjects who received a clinical evaluation at CSHA-2.

Only incident cases defined as subjects who were free of dementia at baseline and were diagnosed with probable or possible Alzheimer’s disease at CSHA-2 or CSHA-3 were included in the analysis

- Other health effects:

FOLLOW-UP
Enrollment: 1991-1992 (CSHA-1)
Follow-ups: 1996-1997 (CSHA-2) and 2001-2002 (CSHA-3)
Follow-up started on the day of the first screening interview and ended when the subject either was diagnosed with AD, died, was lost to follow-up or completed the CSHA-3. The date of exit from the study for a subject diagnosed with AD at CSHA-2 or CSHA-3 was set at half-way between the last CSHA follow-up when the subject was free of the disease and the follow-up when he/she was diagnosed with AD.
Duration: maximum 11 years.
Completeness: CSHA-2 participation – 4832 subjects out of 7155 participated: 1578 (22%) died and 745 (10%) refused to participate or could not be contacted.
CSHA-3 participation – 2847 subjects participated: 1120 (23% of those participating in CSHA-2) died and 434 (9%) refused to participate or could not be contacted.
Exposure assessment:
estimated
Details on exposure:
TYPE OF EXPOSURE:
Oral via drinking water

TYPE OF EXPOSURE MEASUREMENT: other:
Measurements of Al in drinking water at the water treatment plants


EXPOSURE PERIOD: 1980-1991


POSTEXPOSURE PERIOD: 1991-2002


DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES:
Al (µg/L) Number of subjects Number of subjects
(model with adjustment (fully adjusted model)
for age and gender only)

0-46.4 1039 798
46.4-103.8 1071 851
103.8-121.5 1478 1189
121.5-443.3 438 356
>443.3 481 390
Statistical methods:
1) Cox proportional hazard regression models.
2) Poisson regression approach (AMFIT Poisson regression) to evaluate if the presence of heavily tied data biased the results
Results:
EXPOSURE
- Other: Average Al concentration over all municipalities: 134.04 µg/l. Range of municipal averages: 4.5µg/l – 749.7 µg/l.
Average Al concentration for incident AD cases – 150.8 µg/l (95% CI: 131.6, 167.0);
for subjects without AD – 135.5 µg/l (95% CI : 128.2, 142.8)
for subjects lost to follow-up – 131.0 µg/l (95% CI: 110.0, 152,1)

CO-EXPOSURES
pH average over all municipalities: 7.41, range of municipal averages: 5.7-8.9
Fluoride: average over all municipalities- 0.55 mg/l; range 0.015 mg/l – 1.13 mg/l
Silica: average across all municipalities – 2.70 mg/l; range 0.29 mg/l – 12.45 mg/l
Iron: average across all municipalities - 48,8 µg/l, the municipal averages ranged from 3.67 µg/l to 272.0 µg/l.
Al was positively correlated with fluoride, pH and silica and negatively correlated with iron


FINDINGS

INCIDENCE / CASES
- Incidence/ Number of cases for each disease / parameter under consideration:
- Other:
490 incident cases of probable or possible AD

STATISTICAL RESULTS
- SMR (Standard mortality ratio):
- RR (Relative risk): HR as an estimate of RR
- OR (Odds ratio):
- Other:

Cox regression, fully adjusted model

Categorical analysis
Al (µg/l) HR (95% CI)
0-46.4 1.00 (Ref.)
46.4-103.8 1.06 (0.72-1.57)
103.8-121.5 1.10 (0.77-1.58)
121.5-443.3 0.94 (0.55-1.61)
>443.3 1.46 (0.96-2.24)

Continuous analysis:
HR associated with an increase in Al concentration of 331.81 µg/l (the difference between the means in the highest and in the lowest quartile of exposure) was 1.28 (95% CI: 1.02-1.60)

Threshold model:
Al concentrations > 100 µg/l vs. < 100 µg/l: HR 1.17 (95% CI: 0.94-1.44)

AMFIT Poisson regression, fully adjusted model, categorical analyses
Al (µg/l) HR (95% CI)
0-46.4 --
46.4-103.8 1.00 (Ref.)
103.8-121.5 1.06 (0.72-1.57)
121.5-443.3 1.12 (0.78-1.61)
>443.3 1.27 (0.86-1.85)
The results were very similar to those obtained with the Cox model.

OTHER OBSERVATIONS:
Cox regression, categorical analysis, fully adjusted model
The overall association assessed by the Wald λ² test was not significant (P=0.4088). No significant increase or decrease in HR in any of the Al categories for pairwise combinations of Al with any other water parameter or for a model including all 5 water parameters together; HRs were reduced in these analyses compared to those listed above.
Adjustment for ApoE status (892 subjects) makes the HR in the top Al category statistically significant: 1.86 (95% CI: 1.05-3.27)
Cox regression, continuous analysis, fully adjusted model
When any of the water parameters are included in the model, the HR is not significant. .
HR adjusted for ApoE status (892 subjects) was 1.44 (95% CI 1.08-1.92)
No evidence of interaction between any of the water parameter variables in either the categorical or continuous model.
Sensitivity analyses (see “Methods”)
1) Accounting for undiagnosed AD for deceased subjects did not appreciably change HRs in either categorical or continuous analyses.
2) Including CIND with the study outcome resulted in a slight change in the HRs but they remained statistically insignificant. The HR in the continuous analysis became non-significant: 0.99 (95% CI: 0.82-1.19)
3) Two-stage regression: RR of 1.22 (95% CI: 0.92-1.63) per 331.81 µg/l increase in Al concentration
Confounding factors:
Fluoride, silica, iron, pH in the drinking water

Gender, age, education, history of stroke, blood pressure

ApoE allele status was determined in a sub-sample of subjects who underwent a clinical examination (892 subjects who also had Al data)

Information on a number of potentially confounding factors was collected at baseline. A variable was retained in the statistical model only if its inclusion changed the HR of at least one exposure quartile by more than 10%.
Strengths and weaknesses:
Strengths:
Large prospective study of a well-defined cohort; detailed information on other potential risk factors for AD including ApoE genotype; availability of information on other water parameters, well-defined health outcome.
Limitations:
The authors point out the following:
- Variations in the information collected from different water treatment plants due to differences in measurement techniques, accuracy and precision, which may lead to exposure misclassification;
- Unavailability of data for some treatment plants for some years resulted in extrapolations in the exposure estimation, which could introduce errors in exposure estimates
- Only total Al in drinking water was available with no speciation
- Values of water parameters at water treatment plants may be different from those at the residential taps due to their changes throughout the distribution system.
- Individual characteristics of exposure (e.g. amount of water consumed) were not available
- Etiologically relevant period of exposure is not well known.

Sensitivity analyses:

1) To assess the effect on risk estimates of failure to account for undiagnosed AD for subjects who died between the CSHA follow-ups: the 82 deceased subjects who were reported by proxy respondents as having been diagnosed with AD before they died were classified as having the outcome of interest.

2) Cognitive impairment not dementia (CIND) often progresses to AD. An analysis was conducted classifying subjects who were diagnosed with CIND at CSHA-2 and did not develop AD by CSHA-3 and subjects diagnosed with CIND at CSHA-3 as having the outcome of interest.

A two-stage regression analysis allowing the baseline hazard function of the standard Cox model to vary at random among the municipalities was conducted to explore the possible effects of spatial auto-correlation (due to assignment of municipal-level data to individuals)

Conclusions:
The results of this study, though suggestive of a higher risk of AD at higher Al levels in drinking water, are equivocal in that inconsistent results were obtained from different analytical approaches. Aluminium in drinking water represents only a small fraction of total oral aluminium exposure, dietary and pharmacological sources being considerably higher and variable. The validity of the exposure measure is unclear.
Executive summary:

This prospective cohort study of potential effects of aluminium in drinking water on the risk of Alzheimer’s disease was based on a sample of 7,155 subjects from the Canadian Study of Health and Aging. The subjects were recruited in 1991-1992, and the incident cases of Alzheimer’s disease (n=490) were ascertained at follow-up examinations in 1996-1997 and in 2001-2002. Exposure assessment was based on residential history information collected from the subjects and data on aluminium concentrations and on several other water parameters (fluoride, silica, iron, pH) from the water treatment plants supplying the subjects’ residencies. A number of potentially confounding variables were explored, and only those changing the hazard ratio of at least one exposure category by more than 10% were retained in the final model. Thus, the analyses were adjusted for gender, age, education, history of stroke and blood pressure. ApoE allele status was determined in a sub-sample of subjects (N=892), and a secondary analysis was conducted with adjustment for this factor. A significant association between the risk of Alzheimer’s disease and Al was found in the analysis applying the continuous standard Cox proportional hazard model, but not in the analysis using the categorical Cox proportional hazard model. After adjusting for autocorrelation in a two stage model no significant association was observed. No interaction between any of the water parameter variables in either the categorical or continuous analysis was observed. The results from this study are equivocal concerning an association between aluminium intake and an increase in the risk of Alzheimer disease.

Reason / purpose:
read-across source
Reference
Endpoint:
epidemiological data
Type of information:
other: Epidemiological observational
Adequacy of study:
supporting study
Study period:
4 years
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given
Study type:
longitudinal study
Endpoint addressed:
not applicable
Qualifier:
no guideline required
GLP compliance:
no
Type of population:
occupational
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
HYPOTHESIS TESTED (if cohort or case control study):
The aim of the study was to examine “the long-term changes of neurobehavioral performance in Al welders in relation to Al exposure and neurobehavioral performance changes of a non-exposed control group.”

METHOD OF DATA COLLECTION
- Type: Interview / Questionnaire / other: Neurobehavioral/cognitive tests
- Details:

STUDY PERIOD:
4 years; years not specified.

SETTING:
Occupational: train and truck construction industry from different regions of Germany (Al welders and assembly workers)


STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): Employees of five companies of the train and truck construction industry from different regions of Germany (Al welders and assembly workers)
- Selection criteria: Absence of neurological diseases related to injuries or relevant metabolic illnesses, sufficient knowledge of German language, at least 2 years of Al exposure (welding) and no current or former exposure to other potential neurotoxic substances (solvents, metals)
- Participation rate: No information
- Total number of subjects participating in study: 81 (44 welders and 37 controls)
- Sex/age/race: male, mean age ~43 years (43.3±7.4 years for welders and 42.9±5.7 years for controls at the last examination)
- Smoker/nonsmoker: no information
- Total number of subjects at end of study: 32 (20 exposed and 12 controls)
- Matching criteria:
- Other: The diminution of the size of the study group and the control group between the first and the last examination was caused by close down of one of the 5 firms and lay-offs in the others related to economic problems.

COMPARISON POPULATION
- Type: Control or reference group:

- Details: Assembly workers from the same companies with no known neurotoxic exposure at work. The control group was comparable to the study group in terms of age, gender (male), education, “physical work environment and social environment”, and work in a weekly rotated three-shift system.
.
HEALTH EFFECTS STUDIED
- Disease(s):
- ICD No.:
- Year of ICD revision:
- Diagnostic procedure:

- Other health effects: changes in neurobehavioral performance
Neurobehavioral methods
1) A German version of the Swedish Q16 Questionnaire for recording psychological and neuropsychological symptoms
2) Standard Progressive Matrices test of logic thinking (only at the 1st examination
3) Verbal intelligence (WST) (only at the 2nd examination)
4) Wechsler Adult Intelligence Scale (WAIS, German – HAWIE)
- recall of digits forward and backward ( for short term memory or working memory)
- block design (for visuospatial thinking and general intelligence)
5) Psychomotor performance (Computer-aided tests from the Motor Performance Series, MLS)
- steadiness
- line tracing
-aiming
- tapping
6) Simple reaction time (computer-aided test)
7) European Neurobehavioral Evaluation System (EURO-NES) (computer-aided tests)
- symbol-digit substitution (for working memory)
- digit span (for short-term memory)
- switching attention: block, arrow, mixed ( for attention processes)

FOLLOW-UP
Examination after 2 years -59 subjects (33 from the exposed and 26 from the control group).
Examination after 4 years: 32 subjects (20 from the exposed and 12 from the control group)
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE:
Inhalation

TYPE OF EXPOSURE MEASUREMENT: Area air sampling / Personal sampling / Biomonitoring (urine) / Biomonitoring blood / other:

EXPOSURE LEVELS:
Relatively high exposure levels: mean pre-shift concentrations of Al in urine 185.9, 184.5 and 158.9 µg/l at the first, second and third examinations, respectively
EXPOSURE PERIOD:
At least 2 years at the time of initial examination (inclusion criteria). At the time of last examination (4th year), the average duration of work in Al welding was 14.8 ± 4.1 years.

POSTEXPOSURE PERIOD: 0
Statistical methods:
Exposure:
- Correlation and regression analyses to investigate interdependence, reliability and stability (during 2- and 4-year intervals) of exposure measures;
- ANOVA for repeated measurements to determine whether Al biomonitoring data are sensitive to exposure changes (pre- and post- shift differences)
Neurobehavioral data
- The data for subjects who participated in all the three examinations were analyzed with multivariate models of covariance (MANCOVA) for repeated measurements. The MANCOVA models included a grouping factor (welders vs. control), a repetition factor (examination, 3 levels,) an interaction term (examination x exposure), and covariates age, education index, CDT as a marker of alcohol abuse. The interaction term “examination x exposure” indicates whether changes in neurobehavioral performances across examinations were different in exposed and control subjects.
- Stepwise regression was applied to test the association between exposure and neurobehavioral measures
- MANCOVA models were used to examine the effects of potential indicators of premorbid intelligence
Results:
EXPOSURE
- Number of measurements:
- Average concentrations:
- Arithmetic mean:
Al welders
- total dust (mg/m³): 7.3, 5.8 8.6 at the 1st, 2nd and 3rd examinations, respectively
- Al in urine pre-shift (µg/l): 185.9, 184.5, 158.9
- Al in urine post-shift (µg/l):210.0, 191.5, 155.7
- Al in urine pre-shift (µg/g creatinine): 110.7, 120.0, 81.5
- Al in urine post-shift (µg/g creatinine): 135.5, 153.0, 113.5
- Al plasma pre-shift (µg/l): 12.5, 13.8, 13.9
- Al plasma post-shift (µg/l): 14.8, 18.6, 17.8
Control group
- Al in urine pre-shift (µg/l): 14.5, 11.5, 11.4
- Al in urine pre-shift (µg/g creatinine): 9.0, 9.6, 10.0
- Al plasma pre-shift (µg/l):4.1, 2.8, 4.5

- Geometric mean:
- Median:
Al welders
- total dust (mg/m³):5.7, 4.5, 6.8 at the 1st, 2nd and 3rd examinations, respectively
- Al in urine pre-shift (µg/l): 136.6, 163.9, 97.7
- Al in urine post-shift (µg/l): 130.0, 145.5, 93.7
- Al in urine pre-shift (µg/g creatinine): 92.1, 90.1, 58.8
- Al in urine post-shift (µg/g creatinine): 97.0, 143.9, 64.5
- Al plasma pre-shift (µg/l): 9.6, 11.1, 10.8
- Al plasma post-shift (µg/l): 11.6, 14.3, 13.2
Control group
- Al in urine pre-shift (µg/l): 5.8, 6.0, 8.3
- Al in urine pre-shift (µg/g creatinine): 4.0, 4.5, 8.5
- Al plasma pre-shift (µg/l):3.5, 2.8, 4.5

- 95-Percentile:
- Standard deviation:
Al welders
- total dust (mg/m³): 6.8, 4.1, 7.7
- Al in urine pre-shift (µg/l): 144.2, 146.7, 174.2
- Al in urine post-shift (µg/l): 217.3, 154.6, 147.4
- Al in urine pre-shift (µg/g creatinine):75.9, 97.0, 74.4
- Al in urine post-shift (µg/g creatinine):103.8, 124.2, 126.1
- Al plasma pre-shift (µg/l): 7.5, 9.3, 8.8
- Al plasma post-shift (µg/l): 9.7, 13.3, 11.6
Control group
- Al in urine pre-shift (µg/l): 29.7, 18.0, 9.3
- Al in urine pre-shift (µg/g creatinine): 15.6, 17.0, 8.4
- Al plasma pre-shift (µg/l): 2.3, 1.1, 0.8

FINDINGS


INCIDENCE / CASES
- Incidence/ Number of cases for each disease / parameter under consideration:
- Other:


STATISTICAL RESULTS
- SMR (Standard mortality ratio):
- RR (Relative risk):
- OR (Odds ratio):
- Other:
- Neuropsychological symptoms: few symptoms in both groups (welders and control), no significant group difference (p=0.08), no significant interaction “examination x exposure”(p=0.45)
- Standard Progressive Matrices test: No significant group differences (P=0.299)
- Verbal intelligence test (WST) – Lower average score for welders (95.3) compared to controls (98.7), no significant group difference when age and CDT were included in the model (p=0.263).
- WAIS block design: significantly lower scores for welders than controls (P=0.033). However, no divergence but a tendency for convergence of the scores in the two groups over time (interaction term non-significant. P=0.51).
- WAIS recall of digits: no significant group difference, non-significant interaction term (P=0.661)
- Trial making test: no significant group difference (P=0.09). Highly significant interaction term (P<0.001), but the trend over time is converging, not diverging.
- Psychomotor performance. No significant group difference in the four subsets (steadiness, line tracing, aiming and tapping). Interaction term insignificant for all the four subsets (P=0.746 for steadiness, P=0.772 for line tracing, P=0.671 for aiming and P=0.452 for tapping)
- Simple reaction time: no significant group difference (P=0.894), non-significant interaction term (P=0.107)
- EURO-NES: no significant group difference (P=0.38) and non-significant interaction term (P=0.417) in the joint analysis of the tests (symbol-digit substitution and digit span)

OTHER OBSERVATIONS:
Significant temporal stability of individual biomonitoring data.
Moderate stability of dust data for 2-year intervals and no stability for 4 years.
High inter-correlation of biomonitoring parameters averaged across the three examinations and a moderate (but significant) correlation with dust measures
Deviation of the trend of biomonitoring means from the trend of dust means.
The authors conclude that their findings indicate suitability of biomonitoring measures for representation of inter-individual exposure differences in the long term. The best measure of differences between individuals, groups and exposure conditions is Al in urine related to creatinine. Total dust in air is of limited validity as a measure of exposure to Al.
Confounding factors:
- Age
- Premorbid intelligence (assessed by the level of performance in verbal intelligence tests which is believed unaffected by exposures and thus can serve as a mean of assessing intellectual levels before a potential neurotoxic damage)
- Education
- Alcohol abuse (assessed by level of carbohydrate-deficient
Strengths and weaknesses:
Strength:
- Longitudinal study design (4 years) in contrast to cross-sectional design of other studies of similar endpoints
- Relatively ”pure” occupational exposure to Al (inclusion criterion - no current or former exposures to other potentially neurotoxic substances)
- Long-term Al exposure (15 years on the average at the last examination)
- Repeated measurements of total dust in air as an indicator of external exposure and biomonitoring parameters (Al in urine, Al in urine related to creatinine and Al in plasma); examination of interdependence, reliability and stability of these exposure measures
- High Al exposure compared to previous studies
- Assessment of a variety of domains of central nervous system function
- Appropriate statistical approach: multivariate analyses including simultaneously interrelated neuropsychological parameters, examining not only group differences (exposed vs. control) but also time trends in these parameters and potential differences in time trends between the two groups
- Adjustment for potential confounders: age, education, ”pre-morbid” intellectual level, objective indicator of alcohol consumption

Limitations
- Small sample size and resulting limited statistical power (partly compensated by the longitudinal design with repeated measurements)
- Possible selection resulted from considerable loss of study subjects during the course of the study. Since these losses were related to economic reasons, they are unlikely to introduce considerable bias.
- Control group includes workers of a different profession (though from the same companies and comparable to the exposed workers in terms of education, physical work load and shift work)
Conclusions:
No effect of relatively high and long-term occupational exposure to Al on neurobehavioral performance was shown during 4 years of observation in Al welders.
Executive summary:

The authors conducted a 4-year longitudinal study with the purpose 1) to characterize various Al exposure measures (total dust in air and biomonitoring data) in terms of representation of individual long-term exposure to Al and 2) to examine long-term trends in neurobehavioral performance of Al welders in relation to Al exposure and in comparison with performance trends in the control group of assembly workers. The authors used neurobehavioral methods relevant for assessing intellectual domains suggested in previous studies as being affected by Al. The findings of this study, based on repeated pre- and post-shift measurements, suggest that biomonitoring parameters (Al in plasma, Al in urine and Al in urine related to creatinine) are reliable, stable, inter-correlated and suitable for representation of inter-individual exposure differences in the long term. Al in urine related to creatinine is the best to characterize distinctions between individuals, between groups or exposure conditions. Total dust in air is of limited validity as a measure of exposure to Al. Analysis applying regression and multivariate covariance-analytical methods detected neither correlation between biomonitoring and neurobehavioral performance variables, nor significant differences between the exposed and the control group in the performance trends during the 4-year study period. The authors note that their findings are relevant only to the 4-year period from the 10th to the 15th year (on the average) of the welder’s working life and caution against extrapolating their findings beyond this period. The strengths of this study include relatively high and “pure” Al exposures, longitudinal study design, repeated exposure measurements, appropriate statistical methods, the use of an indicator of “pre-morbid” intelligence and an objective indicator of alcohol abuse (carbohydrate-deficient transferring in plasma) as covariates in the models. Limitations include small number of subjects and comparison of welders with workers of a different profession. However, the control workers were from the same companies and comparable to the welders in terms of education, physical work load and shift work. Limitations related to small sample size are partly compensated by multiple measurements over time.

Reason / purpose:
read-across source
Reference
Endpoint:
epidemiological data
Type of information:
other: Epidemiological observational
Adequacy of study:
supporting study
Study period:
4 years (calendar year not specified)
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given
Study type:
longitudinal study
Endpoint addressed:
neurotoxicity
Qualifier:
no guideline required
GLP compliance:
no
Type of population:
occupational
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
HYPOTHESIS TESTED (if cohort or case control study):
The aims of the study were: “(a) to test reliability and validity of biomonitoring data, (b) to test the 4-year trends of different neurobehavioral parameters comparing Al welders with referents considering relevant confounders, and (c) studying the structural relationships between neurobehavioral measures, exposure, and measures of general intellectual ability (potential a priori differences”.

METHOD OF DATA COLLECTION
- Type: Interview / Questionnaire / other: Neurobehavioral/cognitive tests
- Details:


STUDY PERIOD:
4 years

SETTING:
Employees of automobile industry in Germany (welders and assembly workers)

STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): No information
- Participation rate: No information
- Selection criteria: Absence of neurological diseases related to injuries or relevant metabolic illnesses, sufficient knowledge of German language, at least 2 years of Al exposure (welding) and no current or former exposure to other potential neurotoxic substances (solvents, metals)
- Total number of subjects participating in study: Initial examination: 148 subjects (98 exposed and 50 controls). The repeated-measurement analyses was based on 142 subjects (92 -exposed group and 50 – control group) who participated in all 3 examinations
- Sex/age/race: males, average age at the end of the 4-year observation 39.17.2 years for welders and 38.47.9 years for controls.
- Smoker/nonsmoker: No information
- Total number of subjects at end of study: 142 (92 -exposed group and 50 – control group)
- Matching criteria:
- Other:

COMPARISON POPULATION
- Type: Control or reference group:
- Details:
Assembly workers in automobile industry with no known neurotoxic exposure at work. The control group was comparable to the study group with regard to gender (male), age, education, physical work load and social environment

HEALTH EFFECTS STUDIED
- Other health effects: changes in neurobehavioral performance
Neurobehavioral methods (same as in Kiesswetter et al., 2007)
1) A German version of the Swedish Q16 Questionnaire for recording psychological and neuropsychological symptoms
2) Cognitive abilities
- Vocabulary Test (WST)
- Standard Progressive Matrices
- Block Design (Wechsler’s Adult Intelligence Scale, WAIS, German – HAWIE)
- Trail Making Test
3) Psychomotor performance
- Four computerized tests (‘steadiness’, line tracing`, ‘aiming’, ‘tapping’)
4) Short term memory, working memory
- Digit span; forward, backward (DS, recall of digits, HAWIE)
- Digit span; forward, backward (European Neurobehavioral Evaluation System, EURO-NES)
- Symbol–digit substitution (EURO-NES)
5) Attention
- Simple reaction time
- Switching attention (EURO-NES)

FOLLOW-UP
Initial examination: 148 subjects (98 exposed and 50 controls)
Examination after 2 years – 147 subjects (97 exposed and 50 controls)
Examination after 4 years – 142 subjects (92 exposed and 50 controls)
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE:
Inhalation

TYPE OF EXPOSURE MEASUREMENT: Personal sampling / Biomonitoring (urine) / Biomonitoring blood:


EXPOSURE LEVELS:
Relatively low exposure levels (the mean Al concentration in urine below 80 µg/l)

EXPOSURE PERIOD:
At least 2 years at the time of initial examination (inclusion criteria). At the last examination (4th year), average duration of work in Al welding was 8.8±1.7 years.
Statistical methods:
Exposure:
- Correlation and regression analyses to investigate interdependence, reliability and stability (during 2- and 4-year intervals) of exposure measures;
- ANOVA for repeated measurements to determine whether Al biomonitoring data are sensitive to exposure changes (pre- and post- shift differences)
Neurobehavioral data
- The data for subjects who participated in all the three examinations were analyzed with multivariate models of covariance analysis (MANCOVA) for repeated measurements. The MANCOVA models included a grouping factor (welders vs. control), a repetition factor (examination, 3 levels,) an interaction term (examination x exposure), and covariates age, education index, CDT as a marker of alcohol abuse. The interaction term “examination x exposure” indicates whether changes in neurobehavioral performances across examinations were different in exposed and control subjects.
- Stepwise regression was applied to test the association between exposure and neurobehavioral measures
- MANCOVA models were used to examine the effects of potential indicators of “premorbid” intelligence
Results:
EXPOSURE
- Number of measurements:
- Average concentrations:
- Arithmetic mean:
Al welders
- total dust (mg/m³):0.8, 0.5, 0.7 at the 1st, 2nd and 3rd examinations, respectively
- Al in urine pre-shift (µg/l): 77.4, 71.4, 37.5
- Al in urine post-shift (µg/l):53.0, 48.6, 22.8
- Al in urine pre-shift (µg/g creatinine): 43.0, 43.2, 22.8
- Al in urine post-shift (µg/g creatinine):42.9, 41.4, 21.3
- Al plasma pre-shift (µg/l): 9.3, 4.7, 4.6
- Al plasma post-shift (µg/l): 9.1, 4.7, 4.8
Control group
- Al in urine pre-shift (µg/l):11.2, 12.9, 12.7
- Al in urine pre-shift (µg/g creatinine):7.3, 16.0, 7.8
- Al plasma pre-shift (µg/l):5.9, 2.4, 4.2

- Geometric mean:
- Median:
Al welders
- total dust (mg/m³):0.5, 0.4, 0.7 at the 1st, 2nd and 3rd examinations, respectively
- Al in urine pre-shift (µg/l): 71.8, 58.3, 21.7
- Al in urine post-shift (µg/l): 47.6, 39.8, 16.1
- Al in urine pre-shift (µg/g creatinine): 38.4, 35.0, 12.6
- Al in urine post-shift (µg/g creatinine): 37.9, 33.6, 15.4
- Al plasma pre-shift (µg/l): 10.3, 4.3, 4.3
- Al plasma post-shift (µg/l): 8.3, 4.1, 4.3
Control group
- Al in urine pre-shift (µg/l):9.0, 7.4, 9.3
- Al in urine pre-shift (µg/g creatinine): 5.2, 6.0, 5.0
- Al plasma pre-shift (µg/l): 4.4, 2.3, 3.8

- 95-Percentile:
- Standard deviation:
Al welders
- total dust (mg/m³): 0.9, 0.3, 0.3
- Al in urine pre-shift (µg/l): 42.7, 51.0, 80.7
- Al in urine post-shift (µg/l): 35.2, 36.1, 27.0
- Al in urine pre-shift (µg/g creatinine): 21.3, 30.7, 64.8
- Al in urine post-shift (µg/g creatinine): 22.7, 31.3, 19.9
- Al plasma pre-shift (µg/l): 3.7, 1.8, 1.7
- Al plasma post-shift (µg/l): 5.2, 2.2, 2.3
Control group
- Al in urine pre-shift (µg/l): 8.5, 16.8, 17.1
- Al in urine pre-shift (µg/g creatinine): 6.4, 55.9, 8.6
- Al plasma pre-shift (µg/l): 4.9, 1.0, 1.9


FINDINGS


STATISTICAL RESULTS
- SMR (Standard mortality ratio):
- RR (Relative risk):
- OR (Odds ratio):
- Other:
Symptoms (from Q16 questionnaire): few reported symptoms in either group. No significant group difference (P=0.86) or interaction ”examinationexposure” (P=0.24)
Cognitive abilities
- Vocabulary IQ test (WST): no significant group differences (P=0.83) and no significant interaction ”examinationexposure” (P=0.55)
- Standard progressive matrices test (SPM): No significant group difference (P=0.32)
- Block design: No significant group differences (P=0.87) or interaction ”examinationexposure” (P=0.25)
- Trial making test: No significant group differences (P=0.19), similar trends from examination 1 to examination 3
Psychomotor performance
No significant exposure effect (group differences) for any of the four motor tests: P=0.83, 0.66, 0.54 and 0.1 for steadiness, line tracing, aiming and tapping, respectively. No significant interaction ”examinationexposure”: P=0.68, 0.45, 0.73, 0.4 for steadiness, line tracing, aiming and tapping, respectively.
Short term memory, working memory
-Recall of digits (HAWIE): no significant exposure effect (P=0.60) and no significant exposure-examination interaction effect (P=0.18)
- Digit span and symbol-digit substitution (EURO-NES) analyzed together: No significant group difference (P=0.39) and no significant differences in temporal trends between the groups (P=0.63 for the interaction term)
Attention
- Simple reaction time: significant group difference (P=0.015), but this model considers only the strength of the effect and disregards the opposite direction of differences of the two test parameters: the welders were slower than controls in their reactions (decision time), but quicker in motor movements. No significant interaction “examination x exposure” (P=0.86)
- Switching attention: no significant group difference (P=0.47) or interaction effect (P=0.33)

OTHER OBSERVATIONS:
- No considerable differences between pre- and post-shift measurements of Al in urine and Al in plasma in Al welders.
- Significant differences between the exposed and the control in pre-shift measurements of creatinine adjusted Al urine concentrations (P<0.001) and Al plasma concentrations (P<0.001), but this difference for Al plasma concentrations diminishes towards the 3rd examination.
-Low inter-correlation of biomonitoring data between examinations (<0.50). A tendency for temporal stability was observed only for creatinine-adjusted Al in urine. Extremely inconsistent pattern for dust in air data.
- The most consistent pattern of significant inter-correlations to other exposure parameters was observed for creatinine-adjusted Al in urine.
- The only biomonitoring variable meeting all 3 criteria (a significant inter-correlation with other biomonitoring variables, a significant temporal stability, and a significant correlation with external dust exposure) was post-shift creatinine adjusted Al concentration.
The authors concluded that Al biomonitoring measures have lower reliability and sensitivity at low exposure levels and, with the exception of creatinine-adjusted Al concentration in urine, are not well suited to characterize continuous individual exposure differences.
Confounding factors:
- Age
- “Premorbid intelligence (assessed by performance level on verbal intelligence tests which is believed unaffected by exposures)
- Education
- Alcohol abuse (assessed by level of carbohydrate-deficient transferring in plasma, CDT)
Strengths and weaknesses:
Strength:
- Longitudinal study design (4 years) in contrast to cross-sectional design of other studies of similar endpoints
- Relatively “pure” occupational exposure to Al (inclusion criterion - no current or former exposures to other potentially neurotoxic substances)
- Repeated measurements of total dust in air as an indicator of external exposure and biomonitoring parameters (Al in urine, Al in urine related to creatinine and Al in plasma); examination of interdependence, reliability and stability of these exposure measures
- Assessment of a variety of domains of central nervous system function
- Appropriate statistical approach: multivariate analyses including simultaneously interrelated neuropsychological parameters, examining not only group differences (exposed vs. control) but also time trends in these parameters and potential differences in time trends between the two groups
- Adjustment for potential confounders: age, education, ”pre-morbid” intellectual level, objective indicator of alcohol consumption
- Relatively large sample size
Limitations
- Control group includes workers of a different profession (though from the same industry and comparable to the exposed workers in terms of education and physical work load)
Conclusions:
No effect of occupational exposure to Al on neurobehavioral performance was shown in Al welders of automobile industry during 4 years of observation. This finding agrees with the findings of the previous study (Kiesswetter et al., 2007) which applied the same methods and was conducted among welders of train and truck construction industry exposed to higher Al levels for longer periods of time.
Executive summary:

The study is the second of the two parallel longitudinal studies examining potential neurobehavioral effects of Al exposure in welders over 4 years. The authors used the same methods, but the participants of the current study (92 Al welders and 50 non-exposed assembly workers in automobile industry) were, on average, about 5 years younger; the welders’ exposures were lower and of shorter durations compared to the previous study (Kiesswetter et al., 2007). As in the previous study, the aims were to examine inter-correlation, stability and reliability of various Al exposure measures and to examine long-term trends in neurobehavioral performance of Al welders in relation to Al exposure and in comparison with performance trends in the control group. It was shown that biomonitoring measures were less stable, less variable between and within subjects, and less inter-correlated at lower Al exposure levels in this study. However, Al load still differed significantly between the exposed and the control subjects, and Al in urine adjusted for creatinine was the best measure to differentiate between the exposed and the unexposed worker. In line with the previous findings, it was shown that the development of neurobehavioral performances over the 4-year study period in the welders did not differ from that in the control group. The authors note that these results should not be extrapolated beyond the study period. The strengths of the study include “pure” Al exposures, longitudinal study design, repeated exposure measurements, appropriate statistical methods, the use of an indicator of “pre-morbid” intelligence and an objective indicator of alcohol abuse (carbohydrate-deficient transferring in plasma) as covariates in the models, relatively large sample size.

Reason / purpose:
read-across source
Reference
Endpoint:
epidemiological data
Type of information:
other: Epidemiological observational
Adequacy of study:
supporting study
Study period:
Not stated.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given
Study type:
cross sectional study
Endpoint addressed:
respiratory irritation
Qualifier:
no guideline required
Principles of method if other than guideline:
This cross-sectional study included 62 male workers from 8 departments at two plants producing aluminium powder in Germany. The participants completed a standardized questionnaire on occupational history, including exposures to fibrotic agents. They were subjected to a physical examination of the cardiopulmonary system, lung function assessment, conventional X-rays and high resolution computed tomography. Lung function was assessed according to the American Thoracic Society criteria. This included measurements of the vital capacity (VC), forced expiratory volume (FEV1), total resistance (Rtot) and total lung capacity (TLC). Aluminium in urine and plasma was determined by graphite furnace atomic absorption spectrometry. Conventional X-rays were evaluated according to the International Labour Office classification of pneumoconiosis by a radiologist who was unaware of the workers’ exposure status or clinical data. CT scans were evaluated according to a semi-quantitative score system for computed tomography developed by Krauz, Raithel and Hering, 1996 (Int. Arch. Occ. Environ Health 68:249-254). When changes potentially related to aluminium exposure were detected, further diagnostic tests were performed to exclude other interstitial lung diseases. These tests included ergometry, diffusion capacity, blood gas analysis, and immunological parameters. Smoking was quantified by cumulative cigarette smoking in pack-years. Unpaired t-test was used for univariate evaluation of distributional differences between cases of occupational disease and non-cases of the following factors: age, weight, height, body mass index, duration of exposure, plasma Al, urine Al and lung function parameters.
GLP compliance:
no
Type of population:
occupational
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
HYPOTHESIS TESTED (if cohort or case control study):
The aim of the study was “to check whether sensitive tools for the detection of interstitial lung diseases, such as high resolution computed tomography (HR-CT), allow for the early detection of aluminium induced lung disease.” A hypothesis was not explicitly stated.

METHOD OF DATA COLLECTION
- Type: Interview / Questionnaire / Record review / Work history / Clinical tests / other

Details:
- Standardized questionnaire on occupational history, including exposures to fibrotic agents.
- Physical examination of the cardiopulmonary system
- Lung function assessment
- Conventional X-rays
- High resolution computed tomography.
- When changes potentially related to aluminium exposure were detected, further diagnostic tests were performed: ergometry, diffusion capacity, blood gas analysis, immunological parameters.

STUDY PERIOD: Unclear.

SETTING: Two plants for aluminium powder production in Germany

STUDY POPULATION
Total population (Total no. of persons in cohort from which the subjects were drawn): 120

Selection criteria: all workers from 8 departments at 2 plants for aluminium powder production who had “high exposure” to aluminium powder”. The definition for high exposure was not provided.

Total number of subjects participating in study: 62

Participation rate: 52% (44.7% in one plant and 63.6% in the other). The authors stated that non-participation was not related to medical reasons.

Sex/age/race: male; age range 22-64 years, median 41 years, mean 41.4 (SD 9.9) years.

Smoker/nonsmoker: 20 non-smokers, 32 current smokers and 10 former smokers

Total number of subjects at end of study: Not longitudinal.

Matching criteria: Not done; it was cross-sectional descriptive.


COMPARISON POPULATION
- Type: State registry / Regional registry / National registry / Control or reference group / Other comparison group:
- Details: No control group was used.

HEALTH EFFECTS STUDIED
- Disease(s): “Aluminium induced lung disease” or “aluminosis”
- ICD No.:
- Year of ICD revision:
- Diagnostic procedures/examinations:
- Physical examination of the cardiopulmonary system
- Conventional X-rays evaluated according to the International Labour Office classification of pneumoconiosis by a radiologist who was unaware of the workers’ exposure status or clinical data. X-rays were performed for the first 28 examined workers and were discontinued because of “the lack of aluminium-related findings in the chest X-rays.”
- High resolution computed tomography. CT scans were evaluated according to a semi-quantitative score system for computed tomography developed by Krauz, Raithel and Hering, 1996 (Int. Arch. Occ. Environ Health 68:249-254).
- Lung function was assessed according to the American Thoracic Society criteria (Am J Respir Crit Care Med 1995, 152: 1107-1136). This included measurements of the vital capacity (VC), forced expiratory volume (FEV1), total resistance (Rtot) and total lung capacity (TLC).
- When changes potentially related to aluminium exposure were detected, further diagnostic tests were performed to exclude other interstitial lung diseases. These tests included ergometry, diffusion capacity, blood gas analysis, and a battery of immunological parameters.

FOLLOW-UP
Not applicable.
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE:
Inhalation

TYPE OF EXPOSURE MEASUREMENT: Biomonitoring (urine) / Biomonitoring blood

EXPOSURE LEVELS:
Adequate environmental monitoring results were not available.

EXPOSURE PERIOD:
Not specified.

POSTEXPOSURE PERIOD:
Unclear.

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES: Not applicable.
Statistical methods:
The unpaired t-test was used for univariate evaluation of differences between cases of occupational disease and non-cases of the following factors: age, weight, height, body mass index, duration of exposure, plasma Al, urine Al and lung function parameters. Differences in distribution of smoking history were analyzed using λ² tests. Multivariate analysis using a logistic regression model was performed to assess associations between the occurrence of aluminosis and factors for which the p value in the univariate analysis was below 0.4. A p-value of 0.05 was considered statistically significant.
Results:
No information was provided on the particle size distribution. It is stated that in workers exposed in stamping workplaces “most aluminium dust is respirable with a diameter smaller than 5 µm.”
Duration of exposure: median 123 months, range 13-360 months
Duration of exposure for 15 workers with parenchymal lung changes detected at high resolution CT (see below) was between 78 and 360 months.

Plasma Al
From the text: Median 12.5 µg/L; range 2.5-84.4 µg/L
Among 15 workers with parenchymal lung changes detected at CT (see below), measurements of Al in plasma were reported as 5.7-256 µg/L(Table in the publication). Historical biomonitoring data was available for 11 of these 15 workers; maximum Al in plasma - 9.8-183 µg/L (median 85 µg/L, arithmetic mean 84.6 µg/L).

Urine Al
From the text: Median 83.3 µg/L; range 3.7-630.0 µg/L
Median 104.3 µg/g creatinine; range 7.9-821 µg/ g creatinine.

In 20 individuals (32.3%) the “biological tolerance value at workplace” of 200 µg/L was exceeded.
There was a significant correlation between aluminium concentrations in plasma and in urine (r=0.83 for urinary Al concentrations expressed in µg/L and r=0.93 for urinary Al concentrations expressed in µg/ g creatinine)
Aluminium concentrations in plasma and urine were dependent on the workplace; both were highest in stampers.

CO-EXPOSURES
Exposure to fibrotic agents in previous occupations was reported by 14 workers (11 were exposed to asbestos and 3 to silica dusts).
Exposure to “other fibrotic agents at the current workplace (e.g. other metals including cobalt, beryllium etc.)” could not explain the study results.
FINDINGS
Self-reported symptoms: chronic cough and phlegm was reported by 15 workers (11 of them smokers); shortness of breath during exercise by 4 workers.
Medical history: 9 workers had a history of pneumonia, pleuritis or tuberculosis.
Chest X-ray: X-rays were performed for the first 28 workers who were examined and were discontinued because of “the lack of aluminium-related findings in the chest X-rays.” In 3 of the 28 workers, “small rounded and irregular opacities” were seen, which were classified by the radiologist as non-specific.
High resolution CT findings: Parenchymal changes of the same pattern were detected in 15 (24.2%) of the workers. These changes were characterized by “small rounded opacities” (maximum diameter of 3 mm) mainly in the upper lobe of the lung. In 4 cases, the opacities were also located in the middle and lower lobes. In 3 cases, there were signs of thickening of the interlobular septae. Nine of the 15 workers had worked as stampers; 10 had urine Al concentrations over 200 µg/L.
4 of 15 (26.7%) workers with parenchymal lung changes (“affected” workers) and 10 of 42 (23.8%) unaffected workers were exposed to fibrotic agents in previous occupations, 5 ‘affected” workers reported symptoms of chronic bronchitis (cough and phlegm) and 4 - shortness of breath during physical exercise. Nine of the 15 “affected” workers were current smokers, 3 were former smokers and 3 non-smokers.
Four affected workers had an exercise-induced decrease in pO2. Eight affected workers had positive results of immunological tests for specific IgE indicating sensitization to environmental antigens, but none of them had symptoms suggestive of any clinical relevance of these positive results. Three workers had “slightly positive” results on tests for auto-antibodies without clinical symptoms of corresponding diseases. Therefore, the authors concluded that “etiologic agents and pathogenetic considerations other than aluminium cannot be supported.”
Parenchymal changes were detected only in participants who were exposed to non-greased or barely-greased aluminium powder (stearin content<0.1%)
STATISTICAL RESULTS
Logistic regression analysis
Parenchymal changes in the lung were significantly correlated with higher (≥200 µg Al/g creatinine ) urine concentration (OR=1.008; 95% Wald Confidence Interval 1.002-1.013) and longer (≥ 120 days) duration of exposure (OR=1.015; 95% CI 1.002-1.029). The reasons for choosing (≥200 µg Al/g creatinine and 120 days as the cut-offs is unclear.
There was no significant effect of age (OR=0.94; 95% CI 0.84-1.07), smoking (OR=1.52; 95% CI 0.17-13.2), VC (OR=0.94; 95% CI 0.87-1.006), FEV1/VC (OR=1.25; 95% CI 0.98-1.59) or resistance (OR=0.007; 95% CI <0.001-632.5). In all these cases, the reference category is not indicated.
Descriptions of categories used in the analyses were lacking in this article.
- Other:
Univariate comparisons:
Workers with changes detected at CT had significantly higher plasma Al concentrations (p=0.01), urine Al concentrations (p=0.007) and a significantly lower VC (p=0.01). There was no difference between workers with and without lung changes in terms of age (p=0.39), duration of exposure (p=0.17), TLC, (p=0.11) Rtot (p=0.14) and FEV1/VC (p=0.07).
There were no differences between the “affected” group and the “unaffected” group in smoking habits and history (λ² test, p=0.5)
Confounding factors:
Exposure to fibrotic agents in previous occupations, smoking history
Strengths and weaknesses:
Strengths: Detailed examination including instrumental methods and laboratory tests to detect early changes in the lung potentially related to aluminium exposure and to rule out other interstitial lung diseases.
Limitations: This is a cross-sectional study among current workers; workers who left before the study initiation were “lost” to the study leading to a possible selection bias. The participation rate was low (even though the authors state that non-participation was unrelated to medical reasons). No information was provided on the “physical examination of the cardiopulmonary system” and on the questionnaire used for collection of data on occupational history, medical history, respiratory symptoms and smoking. It is not clear whether the questionnaire was self-administered or interviewer-administered. This makes it difficult to evaluate the quality of the data. Inclusion of a control group examined in the same way would make the study results more valid. The description of the logistic regression analyses and results required clearer definitions and justification of categories and cut-offs that were employed.
Conclusions:
In 15 of 62 workers exposed to aluminium powder, high resolution CT scans revealed changes in the lungs suggestive of “alveolitis without fibrotic activity”. These early changes could not be detected at regular medical check-ups involving lung function tests and conventional chest X-rays. The results of this study provide additional evidence that lung function tests and chest X-rays may lack the sensitivity necessary to detect possible aluminium-related lung changes. The study findings suggest that exposure to aluminium powder may induce inflammatory changes in the lung and that high resolution CT is a sensitive tool for detecting these early changes in exposed workers.
Executive summary:

Sixty-two male workers from 8 departments at two plants producing aluminium powder inwere participants of this study. The participation rate was 44.7% in one plant and 63.6% in the other (overall 52%). The authors stated that non-participation was not related to medical reasons. The participants completed a standardized questionnaire on occupational history, including exposures to fibrotic agents. They were subjected to a physical examination of the cardiopulmonary system, lung function assessment, conventional X-rays and high resolution computed tomography. Lung function was assessed according to the American Thoracic Society criteria. This included measurements of the vital capacity (VC), forced expiratory volume (FEV1), total resistance (Rtot) and total lung capacity (TLC). Aluminium in urine and plasma was determined by graphite furnace atomic absorption spectrometry. Conventional X-rays were evaluated according to the International Labour Office classification of pneumoconiosis by a radiologist who was unaware of the workers’ exposure status or clinical data. CT scans were evaluated according to a semi-quantitative score system for computed tomography developed by Krauz, Raithel and Hering, 1996 (Int. Arch. Occ. Environ Health 68:249-254). When changes potentially related to aluminium exposure were detected, further diagnostic tests were performed to exclude other interstitial lung diseases. These tests included ergometry, diffusion capacity, blood gas analysis, and immunological parameters. Smoking was quantified by cumulative cigarette smoking in pack-years. There were 20 non-smokers, 32 current smokers and 10 former smokers among the participants.

Chest X-rays were performed for the first 28 examined workers and were discontinued because of “the lack of aluminium-related findings in the chest X-rays.” In 3 of the 28 workers, “small rounded and irregular opacities” were seen, which were classified by the radiologist as non-specific.

At high resolution CT, parenchymal changes were detected in 15 (24.2%) of the workers. These changes were characterized by “small rounded opacities” (maximum diameter of 3 mm) mainly in the upper lobe of the lung. Four of 15 (26.7%) workers with parenchymal lung changes detected at CT (“affected workers”) and 10 of 42 (23.8%) unaffected workers were exposed to fibrotic agents in previous occupations. Parenchymal changes were detected only in study participants who were exposed to non-greased or barely-greased aluminium powder (stearin content <0.1%) and not in all workers who experienced the higher exposures. Eight affected workers had positive results of immunological tests for specific IgE indicating sensitization to environmental antigens, and three workers had “slightly positive” results on tests for auto-antibodies in the absence of clinically-relevant symptoms. The authors concluded that “etiologic agents and pathogenetic considerations other than aluminium cannot be supported.”

Univariate comparisons showed that workers with lung changes detected at CT had significantly higher plasma Al concentrations (p=0.01), urine Al concentrations (p=0.007) and a significantly lower VC (p=0.01) than workers without such changes. There was no difference between workers with and without lung changes in terms of age (p=0.39), duration of exposure (p=0.17), TLC, (p=0.11), Rtot (p=0.14) and FEV1/VC (p=0.07). There were no differences between the “affected” group and the “unaffected” group in smoking habits (test, p=0.5).

Logistic regression analysed showed that parenchymal changes in the lung were significantly correlated with higher (≥ 200 µg Al/g creatinine) urine concentration and longer (≥ 120 days) duration of exposure. There was no significant effect of age, smoking, VC, FEV1/VC or Rtot.

The authors noted that changes in the lungs detected at high resolution CT in 15 of 62 workers exposed to aluminium powder were suggestive of “alveolitis without fibrotic activity”. These early changes could not be detected at regular medical check-ups involving lung function tests and conventional chest X-rays.The study findings suggest that exposure to aluminium powder may induce inflammatory changes in the lung and that high resolution CT is a sensitive tool for detecting these early changes in aluminium-exposed workers.

Reason / purpose:
read-across source
Reference
Endpoint:
epidemiological data
Type of information:
other: Epi observational
Adequacy of study:
supporting study
Study period:
1995-1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given
Study type:
cross sectional study
Endpoint addressed:
not applicable
Qualifier:
no guideline required
GLP compliance:
no
Type of population:
occupational
Ethical approval:
confirmed and informed consent free of coercion received
Details on study design:
HYPOTHESIS TESTED (if cohort or case control study):
The objective was “to determine whether cumulative bauxite exposure is associated with respiratory symptoms or changes in lung function in a group of bauxite miners.” No hypothesis was stated explicitly although the objective was clearly stated.

- Details:
An interviewer-administered questionnaire was used to collect information on demographic characteristics, employment history, respiratory symptoms, smoking and other potential confounders, such as family history of asthma.
Respiratory symptoms were obtained from the British Medical Research Council questionnaire with additional questions on temporal relationship of symptoms to work.
Chronic bronchitis was defined as “cough or sputum on most days for at least 3 months”. Current smokers had smoked at least one cigarette per day for at least 1 year and ex-smokers had not smoked any cigarettes for at least 3 months.
Lung function (forced expiratory volume in 1 s – FEV1 and forced vital capacity – FVC) was assessed with a Spirotech S401 rolling seal spirometer (Graseby Andersen, Smyrna, Ga., USA) according to American Thoracic Society (ATS) recommendations corrected to Body Temperature and Pressure Saturated (American Thoracic Society. Standardization of spirometry 1994 update. Am J Resp Crit Care Med 1992;152:1107-1136)
Height was measured with a portable stadiometer (Harpenden, Wales, UK).
Atopy was assessed by a skin prick test with four common allergens (house-dust mite, grass mix, cat dander, and mould mix). Positive and negative controls were used to standardize the assessment of a positive atopic response. If the mean diameter of any weal was at least 3mm greater than the negative control, the subject was considered atopic.
Employment history included information on work site, operating center, job title and tasks for the whole period since joining the company.
STUDY PERIOD: 1995 –1996

SETTING: Three bauxite mines in Australia


STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): 799
- Inclusion criteria: All employees were invited to participate
- Total number of subjects in the study: 690 employees participated (participation rate 86%).
- Sex: Only male workers (n=651) were included in the analysis because there were few exposed females. Of these individuals, 572 were exposed and 79 were unexposed.
- Smoker/non-smoker: The study sample included smokers and non-smokers

COMPARISON POPULATION
- Type: State registry / Regional registry / National registry / Control or reference group / Other:

- Details: unexposed workers (n=79)


HEALTH EFFECTS STUDIED

- Other health effects:
Respiratory symptoms and lung function
FOLLOW-UP: Not applicable

Exposure assessment:
estimated
Details on exposure:
Estimated and measured exposure assessment:
A complete job dictionary was developed for all current and past job titles, including site, department, operating centre, job title, and for each job title - the tasks performed as part of that job. A full job history was collected from each subject at interview and was classified on the basis of the job dictionary. All available exposure monitoring data on bauxite dust were provided by company hygienists. Significant changes in the work process that could result in a change in exposure were recorded. A task- exposure matrix (TEM) was created consisting of a geometric mean of measured exposure to bauxite for each task for each year. Tasks for which there were no monitoring data were assigned values from similar monitored tasks. Values were also extrapolated to years for which no measurements were available. A value of half the limit of detection was assigned to tasks with no monitoring data, no similar monitored tasks and which the hygienists considered to have very low exposure. The TEM data and the job histories were then combined to calculate individual cumulative lifetime exposures to bauxite dust in mg/m³ years.

Details on exposure:
TYPE OF EXPOSURE: inhalation

TYPE OF EXPOSURE MEASUREMENT: Area air sampling / Personal sampling / Exposure pads / Biomonitoring (urine) / Biomonitoring blood / other: It is not clear whether area or personal sampling was performed.
EXPOSURE LEVELS:
Quartiles of exposure to bauxite
Q1: <2.5 mg/m³-years (n=137); Q2: 2.5-6.0 mg/m³ years (n=156); Q3: 6.1-10 mg/m³ years (n=124); Q4: >10 mg/m³-years (n=155)

Statistical methods:
Cross-tabulations and the chi-squared statistic were used to test associations of exposure/non-exposure with demographic characteristics and the presence of symptoms.

Generalized linear models were used to estimate prevalence ratios of work related symptoms with adjustment for age (continuous), smoking (never versus ex-smoker versus current smoker) and, in some analyses, pack-years of smoking. The subjects were divided into quartiles of exposure to bauxite dust. The analyses were also conducted including only subjects who had ever worked in production jobs (n=327), excluding those who had only worked in administrative or maintenance jobs.

Mean values of FEV1, FVC and FEV1/FVC were calculated for exposed and unexposed workers. Linear regression was conducted with FEV1, FVC and FEV1/FVC as outcomes and exposure to bauxite as predictor; adjustment was made for age (continuous), smoking (never versus ex-smoker versus current smoker), height (continuous) and autopy (dichotomous).
Results:
SAMPLE CHARACTERISTICS
There were fewer never-smokers (34.3% vs. 46.8%) and fewer subjects with university education (6.6% vs. 32.9%) among exposed compared to unexposed. The proportion of atopic subjects was slightly lower among exposed (46.3%) than among unexposed (50.6%), Mean height was176.3 for exposed and 179.0 for unexposed, mean age -41.1 years for exposed and 39.7 years for unexposed.

EXPOSURE
- Number of measurements:
1,337 inspirable dust samples were collected during the period 1977-1996, and 525 respirable dust samples were collected during the period 1992-1996.
The geometric mean inspirable dust levels were 0.65 mg/m³ (n=479), 0.47 mg/m³ (n=164) and 0.44 mg/m³ (n=120) for mines 1, 2 and 3. The respirable dust levels were 0.14 mg/m³ (n=119), 0.26 mg/m³ (n=111) and 0.20 mg/m³ (n=93) for the three mines, respectively.

Respiratory symptoms
Few subjects reported work-related respiratory symptoms (except rhinitis reported by 33.6% of exposed and 30.4% of unexposed). The proportions of subjects with work-related symptoms did not differ between the exposed and the unexposed; mean levels of exposure were similar for exposed and unexposed.

Multivariate analyses
Prevalence ratios (95% confidence intervals) for respiratory symptoms by quartiles of cumulative exposure to bauxite (reference group-unexposed with adjustment for age and smoking) were provided in the article. The results provided no evidence for an association between exposure and symptoms at any level of exposure. The number of cases of work-related chest tightness was too small for multivariate analysis.
These results provide no evidence of an association between respiratory symptoms and the level of exposure to bauxite dust.
To account for differences between exposed and unexposed subjects (most unexposed subjects worked in the offices and administration and were, on the average, better educated), analyses were conducted including only those who had ever worked in production jobs. These restricted analyses did not substantially change the results.
Lung function
Mean FVC was somewhat lower (5.07 L vs. 5.24 L, p=0.09) and mean FEV1 – significantly lower (4.00 L vs. 4.18 L, p=0.03) in exposed subjects compared to unexposed. FEV1/FVC ratios were similar (79.0% in the exposed and 79.8% in the unexposed, p=0.3)
Regression analysis with adjustment for age, height, smoking and atopy did not show any significant differences in lung function between exposed and unexposed workers. The lowest adjusted FEV1, FVC and FEV1/ FVC were observed in the highest exposure quartile. However, they were not significantly different from those in the unexposed subjects. No clear dose-response was observed.
There was a significant association between FEV1 and duration of employment with the company (but not duration of employment in the current job) regardless of exposure to bauxite. This effect was similar for non-smokers, current or ex-smokers, for atopic and non-atopic subject.
Confounding factors:
Age, smoking, education, atopy, and height were measured as possible confounding factors.
Strengths and weaknesses:
Strengths: rigorous exposure assessment
Limitations: possible selection bias due to the cross-sectional study design; possible residual confounding by smoking
Conclusions:
No effect of cumulative bauxite exposure was observed on respiratory symptoms or lung function in this study.
Executive summary:

Beach et al. (2001) reported results from a cross-sectional survey of current employees from three bauxite mines in, part of the “Healthwise” study programme in the Australian aluminium industry. The survey was conducted during 1995 and 1996. Information on employment, demographic details, respiratory symptoms (Medical Research Council questionnaire), smoking and family history of asthma was collected through interview-administered questionnaires. Chronic bronchitis was defined as “cough or sputum on most days for at least 3 months”. Current smokers had smoked at least one cigarette per day for at least 1 year and ex-smokers had not smoked any cigarettes for at least 3 months. Skin prick tests for four common allergens were performed with positive and negative controls to standardize the assessment of a positive atopic response. Subjects were considered atopic if the mean diameter of any weal was at least 3mm greater than the negative control. Spirometric measurements were conducted according to American Thoracic Society (ATS) criteria corrected to BTPS (Body Temperature and Pressure Saturated). Exposure assessment was based on subject-reported job history and available hygiene data on bauxite dust levels. The exposure index used in the analyses was the cumulative lifetime exposure in mg/m3-years. Geometric mean levels of inhalable bauxite dust were 0.65 (n=479), 0.47 (n=164) and 0.44 (n=120) mg/m3at the three mines. Respirable dust levels were 0.14 (n=119), 0.26 (n=111), and 0.20 (n=93) mg/m3. Peak levels were not reported. Six hundred and ninety of 799 individuals (86%) agreed to participate, 651 men and 39 women. The analyses were restricted to the sample of men due to the low exposures experienced by the majority of the women. Education levels were lower and smoking levels higher in the exposed group. Exposed workers did not report more work-related respiratory symptoms than the unexposed. Although a significant deficit in lung function parameters was evident in the exposed group on univariate analysis, the differences were not significant after adjustment for age, height, smoking and atopy. The multivariate analyses showed a small but statistically significant association between FEV1and duration of employment. Overall, these results suggest exposure to bauxite at the levels in this study is not associated with an adverse effect on respiratory health although given the cross-sectional nature of the study, these results may be based on a selected survivor population.

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Results:
source, RA-A, bauxite, Beach, 2001:
No effect of cumulative bauxite exposure was observed on respiratory symptoms or lung function in this study.
supporting, source, RA-A, 7429-90-5, Kraus, 2006:
In 15 of 62 workers exposed to aluminium powder, high resolution CT scans revealed changes in the lungs suggestive of “alveolitis without fibrotic activity”. The study findings suggest that exposure to aluminium powder may induce inflammatory changes in the lung.
supporting, source, RA-A, 7429-90-5, Kiesswetter, 2007:
No effect of relatively high and long-term occupational exposure to Al on neurobehavioral performance was shown during 4 years of observation in Al welders.
supporting, source, RA-A, 7429-90-5, Kiesswetter, 2009:
No effect of occupational exposure to Al on neurobehavioral performance was shown in Al welders of automobile industry during 4 years of observation.
supporting, source, RA-A, 7429-90-5, Boom, 2008:
The results of this study, though suggestive of a higher risk of AD at higher Al levels in drinking water, are equivocal in that inconsistent results were obtained from different analytical approaches. Aluminium in drinking water represents only a small fraction of total oral aluminium exposure, dietary and pharmacological sources being considerably higher and variable.

Applicant's summary and conclusion