Aluminium

Carcinogenicity

Description of key information

The current weight of evidence does not support an association between inhalation exposure to aluminium metal/aluminium oxide and cancers in the respiratory organs. The weight of evidence also does not support a systemic carcinogenic effect from exposure to aluminium metal and aluminium oxide.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the weight of evidence approach for carcinogenicity no classification is required for aluminium metal according to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria.

Additional information

Systemic Effect

Human studies

Systemic carcinogenic effects from exposure specifically to aluminium have not been investigated in epidemiological studies.One study (Friesen et al., 2009; chapter 7.10.2) that investigated associations between alumina dust exposure and cancer incidence did not find evidence of an increase in risk of any cancer. The study was based on relatively few cases observed during a short follow-up period, and only crude adjustment for smoking was done. Although aluminium production has been classified by IARC as Group 1 (Carcinogenic to humans), the ATSDR (2008) states that “It is important to emphasize that the potential risk of cancer in the aluminium production industry is probably due to the presence of known carcinogens (e.g., PAHs) in the workplace and is not due to aluminium or its compounds.” The evidence from epidemiological studies does not support a carcinogenic effect.  

 

Animal studies

Available animal studies do not provide evidence supporting a systemic carcinogenic effect of the target compounds. 

 

Human studies

Local (Respiratory organs)

Local carcinogenic effects from exposure specifically to aluminium have not been investigated in epidemiological studies.

 

One study that examined associations between exposure to alumina dust and cancer incidence (Friesen et al., 2009; chapter 7.10.2) provides no evidence of an increase in the risk of cancers in the respiratory organs. The study was based on relatively few cases observed during a short follow-up period, and only crude adjustment for smoking was done. The available evidence from epidemiological studies does not support a carcinogenic effect.

Additional human study 

Pan et al. (2011) investigated residential proximity to Al smelters in Canada and risk of female breast cancer in a population-based case-control study using data collected by the National Enhanced Cancer Surveillance System (NECSS). The study was based on individual data collected from 21,020 Canadians with one of 19 types of cancers and 5039 population controls aged 20 to 76 years collected between 1994 and 1997 in 8 of the 10 Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan). The protocol was approved by the respective ethics review board of each province and the analyses were based on 2343 incident cases of breast cancer (863 premenopausal and 1480 postmenopausal) and 2467 female controls from all eight provinces. Breast cancer cases were identified by the population-based provincial cancer registries and all cases were verified by pathology reports. Breast cancer was defined as C50 according to the International Classification of Diseases for Oncology, Second Edition. Questionnaires were sent to 3013 cases and 2982 cases were contacted. Completed questionnaires were received from 2362 cases, representing 78.4% of cases. Questionnaires were also mailed to 3847 women without diagnosis of cancer and these women were selected as potential controls using a random sample stratified by age group. In total, 2492 women completed and returned the questionnaire (representing 64.8% of the ascertained controls). The provincial registries collected data by self-administered questionnaires designed to retrieve data on cancer risk and included information on education, average family income over the last 5 years, marital status, ethnic group, height, weight, physical activity, alcohol consumption, diet and vitamin and mineral supplements for the past 20 years. Questionnaires also gathered smoking history, menstrual and reproductive history (including menopausal status), a lifetime residential history and employment history, the distance between a residence and an industrial source and number of years of proximity. Assessment included food consumption frequency and pattern and portion size for each of 69 foods consumed 2 years before interview. Distance to an industrial source was estimated using the locations and years of production for Al smelters and 9 other major industry types: copper smelters and refineries, lead smelters, nickel smelters and refineries, zinc smelters and refineries, petroleum refineries, paper mills, pulp mills, steel mills, and thermal power plants. The risk of breast cancer associated with residential proximity to Al industrial facilities was estimated based on odds ratios and corresponding 95% confidence intervals using unconditional logistic regression with the software package SAS (version 9; SAS Institute, Inc, Cary, NC). Variables of interest were distance and years of residence near an industrial facility. The variable “distance” was categorized as more than 3.2 km (>2 miles), 0.8 to 3.2 km (0.5 to 2 miles), and more than 0.8 km (0.5 mile). The change-in-point estimate approach was used to assess potential confounding factors: age, educational level, family income, alcohol consumption, smoking, body mass index, total calorie intake, recreational physical activity level, menopausal status, and number of live births. The final multivariate models were adjusted for age (years, continuous), province of residence, education (years, continuous), number of live births (none, 1, 2, 3, and ≥4), age at menarche (years, continuous), alcohol consumption (servings per week, continuous), pack-years of smoking (continuous), total caloric intake (kilocalories per week, continuous), and employment in the specific industry under consideration (yes and no). For postmenopausal women, the models were also adjusted for body mass index and recreational physical activity. To evaluate the trends for all models of categorized data, the different categories were treated as a single ordinal variable.

Data from 2343 breast cancer cases (863 premenopausal cases and 1480 postmenopausal cases) and 2467 controls (835 premenopausal controls, 1604 postmenopausal controls, and the menopausal status unknown for 28 controls) were available for final analysis. The premenopausal women, compared with controls, were older, had slightly higher family income, started menstruation at an earlier age, and had longer years of menstruation. The postmenopausal women were slightly younger, had higher education, consumed more alcohol and tobacco, had higher body mass index, started menstruation at an earlier age and had fewer live births and longer years of menstruation compared with controls. The results indicated no elevated risk of breast cancer among premenopausal and postmenopausal women living 0.8 to 3.2 km of aluminium smelters.After adjustment for age, province of residence, education, smoking pack years, alcohol consumption, number of live births, age at menarche, total energy intake, and employment in the industry under consideration, the odds ratios were not statistically significant for premenopausal breast cancer women living near aluminium smelters compared to the control group [0.8 to 3.2 km, 8 breast cancer patients and 13 control participants; OR - 0.52 (0.21 - 1.31)] and those living < 0.8 km from smelters [2 breast cancer patients and 1 control participant; OR = 2.08 (0.18-23.72). For postmenopausal breast cancer patients, the adjusted for age, province of residence, education, smoking pack years, alcohol consumption, number of live births, age at menarche, total energy intake, and employment in the industry under consideration, the odds ratios were not statistically significant for women living near aluminium smelters compared to the control [0.8 to 3.2 km, 19 breast cancer patients and 14 control participants; OR = 1.06 (0.50-2.23)] and living less than 0.8 km from aluminium smelters [ 6 breast cancer patients and 6 control participant; OR = 0.97 (0.27 - 3.41). For both pre- and postmenopausal breast cancer patients, the adjusted for age, province of residence, education, smoking pack years, alcohol consumption, body mass index, recreational physical activity, number of live births, age at menarche, menopausal status, total energy intake, and employment in the industry under consideration odds ratios were not statistically significant for women living near aluminium smelters compared to the control [0.8 to 3.2 km, 27 breast cancer patients and 27 control participants; OR = 0.84 (0.48 - 1.49)] and living less than 0.8 km from aluminium smelters [8 breast cancer patients and 7 control participant; OR = 1.10 (0.37-3.25).

Pan et al. (2011) attempted to identify possible associations between breast cancer risk with residential proximity to steel mills, pulp mills, petroleum refineries, and thermal power plants. Among strengths of this population-based study are the relatively large sample size and the length of time that participants had lived near Al smelters and other industrial plants. A number of potential confounders were controlled, including employment in the specific industry under consideration. However, this study has a number of limitations: no information on the particular age of women when they resided near a plant, information was not available for all patients on their family history of breast cancer, benign breast disease or their use of the oral contraceptives or estrogen replacements. No Al exposure measurements or indeed exposure measurements for any other airborne materials were provided for cases and controls inasmuch as mere proximity to a potential source does not necessarily mean that the person had been exposed to materials that may arise from operations at that site. A Reliability Score 3 was assigned.

Cantone et al. (2011) investigated relationships between the inhaled Al and other metal (manganese, nickel, zinc, arsenic, lead, iron) particulates and the expression of the cancer-promoting gene histone 3 lysine 4 dimethylation (H3K4me2) and histone 3 lysine 9 acetylation (H3K9ac) activity in peripheral blood leucocytes of 63 steel workers exposed to metal-rich particulate matter (PM). Detailed information on lifestyle, smoking, drug use, medical conditions, body mass index (BMI), education, and residential history was obtained through a self-administered questionnaire. Records from the factory administrative files were used to extract information on occupational history. Metals (aluminum, manganese, nickel, zinc, arsenic, lead, iron) and PM with aerodynamic diameters ≤ 10μm and ≤ 1μm (PM10 and PM1, respectively) were measured in working areas. Concentrations of individual metals in PM10 were measured by inductively coupled plasma mass spectrometry using the total quant method. Personal exposure was calculated as the average level of metals and PM in the work area weighted by the time spent in each area. Cumulative exposure was estimated as the product of the time-weighted levels of metals and PM during the study by the years of employment in the plant. Workers participating in the study were on average 44.0 years old (with a range 27 – 55 years) and 40% (n = 25) were current smokers.The average workplace air level of inhalable Al was 8.50 ± 18.07 mg/m³ with the maximum individual exposure level of the 84.07 mg/m³ and minimum of the 0.4 mg/m³ with a difference in the individual exposure level more than 200 times. No statistically significant associations were observed between the activity of H3K4me2 and H3K9ac and airborne levels of Al either for personal or cumulative exposure. In spite of the study limitations (limited number of participants, lack of control group, possible exposure misclassification and selection biases, lack of complete exposure measurements, limited endpoints studied), the results suggest that long-term exposure to inhalable Al failed to cause changes at the genomic levels of histone modifications in blood leukocytes of the exposed workers. In addition, reported findings provide evidence for low genotoxic potential of inhaled Al particulate. A Reliability Score 3 was assigned.

 

Animal studies

The studies by Gross et al. (1973) (Klimisch Score = 2) and Pigott et al. (1981) do not support a carcinogenic effect for aluminium metal and aluminium oxide.

Gross et al. (1973) exposed rats, guinea pigs and hamsters to three different aluminium powders (British pyro powder, a US-flake powder, and a US-source atomized powder with approximately spherical particles) and also aluminium oxide dust, included as a negative control. The Al2O3 content was 16.6% for the British pyro powder, not stated for theflake powder and 2.9% for the atomized powder. The doses administered by inhalation ranged from 15 to 100 mg/m³, 6 hours per day, 5 days per week for either 6 or 12 months. Thirty rats were exposed to pyro powder at each 15, 30, 50 and 100 mg/m³, 30 rats were exposed to atomized metal powder at each 15, 30, 50 and 100 mg/m³, 30 rats were exposed to flake powder at 15 and 30 mg/m³, and 30 rats were exposed to aluminium oxide dust at 30 and 70 mg/m³. Five rats were sacrificed per time point (6, 8, 12 and 18 months). Thirty hamsters were exposed to pyro powder at 50 and 100 mg/m³, 30 hamsters were exposed to atomized powder at 50 and 100 mg/m³, and 30 hamsters were exposed to aluminium oxide at 70 mg/m³. Between 15 and 25 guinea pigs were exposed to each of the aluminium powders at 15 and 30 mg/m³. Twelve guinea pigs were exposed to aluminium oxide dust at 30 mg/m³. The chambers were approximately 1.2 m³ in volume, moisture was removed using anhydrous calcium chloride and powders were dispersed through the chambers by means of a dust-feed mechanism (Wright). Air flow was limited to 10 litres/min to attain high dust concentrations. 

The dusts, suspended in tap water, were also administered by intratracheal instillation to different groups of animals.Concentrations were used such that 1mL of the suspension contained the required dose. Injections were performed under anaesthetic (ether) using an illuminated laryngeal speculum to facilitate the introduction of the 18-gauge, blunt needle. A tap water “vehicle” control group was included. For intratracheal instillation, 15 rats and 15 hamsters were allocated to each dose for the pyro, atomized and flaked powders. With the exception of the highest dose level, 1 to 5 animals were sacrificed at 6 months and 7 to 10 animals at 12 months post-exposure. At the 100 mg/m³ dose level for the pyro powder, 15 animals were dosed, 4 were sacrificed at 2 months, 4 at 4 months and 7 at 6 months. At the 100 mg/m³ dose level for the atomized powder, 15 animals were dosed, 3 animals were sacrificed at 2 months, 3 animals at 4 months and 2 animals at 6 months.

Mortality was reported but no data on clinical signs, body weight, or organ weights was provided.Histopathological examinations of the lungs were conducted on sections cut in triplicate from lung tissue stained with either eosin alone to show aluminium particles, hematoxylin-eosin,or PAS/ van Gieson. To show cellular components and stromal support structures, the hematoxylin-eosin stained sections were examined before and after decolorization and impregnation with silver (Gordon and Sweets method).

Intratracheal injection of the aluminium powders caused nodular pulmonary fibrosis in the lungs of the rats only at the highest dose administered (100 mg).A fibrotic response was not observed in hamsters indicating inter-species differences in response. 12 mg of dust administered intratracheally did not lead to collagen production in rats or hamsters. The response of hamster and guinea pigs lungs differed from rats. At higher concentrations (i.e. 100 mg/m³ for hamsters, unclear for guinea pigs), hamster and guinea pig lungs developed metaplastic foci of alveolar epithelium that persisted beyond the resolution of alveolar proteinosis and clearance of the dust particles. 

Progressive fibrosis was not observed in rats on inhalation exposure to the powders indicating that the intratracheal instillation mode of test compound delivery may lead to artifacts not representative of physiologically relevant exposures.There was no dose response evident or a noticeable difference between responses to the different aluminium powders. All three species developed widespread alveolar proteinosis, rats exhibiting the most severe response. However, alveolar walls appeared thin and normal. The proteinosis resolved progressively after cessation of exposure. Small scattered foci of endogenous lipid pneumonitis (granulomatous inflammation) developed associated with cholesterol crystals that were not surrounded by alveolar proteinaceous material. These effects generally occurred in regions not associated with dust particles and left small collagenous scars. The group of rats exposed for 12 months to 15mg/m³ of aluminium powder showed moderate alveolar proteinosis after 6 months of exposure. Granulomatous inflammation was observed at 50 mg/m³ after about 3 months of exposure.

Overall, there was no consistent relationship between dose and severity of response for any of the aluminium powders.The results showed no clear difference in reaction to the different powders. The results from this study do not provide evidence to support a progressive fibrotic response on inhalation exposure to aluminium powder.No alveolar proteinosis or thickening of alveolar walls was observed in rats, hamsters or guinea pigs exposed to Al2O3 dust (66% < 1μm) included in the study as a control. 

The reason for the high and variable rates of mortality in this study is unclear and is a limitation of the study.Several endpoints specified in the 90-day inhalation toxicity guideline (OECD TG 413) were not assessed, particularly body and organ weights. The study design and animal husbandry were not described in sufficient detail. Considering reliability for use in the hazard identification, a Klimisch Score of 2 is appropriate for the lung pathology results and a Score of 3 for the mortality results.

 

Pigott et al. (1981) reported no evidence of fibrosis in a repeated dose inhalation study that administered alumina fibres (Saffil) at levels between 2 and 3 mg/m³ for 86 weeks. The respirable fraction of the particulates was 30 - 40% and the median diameter ca. 3.0 μm). The only pulmonary response observed was the occurrence of pigmented alveolar macrophages. The authors reported qualitatively that a minimal alveolar epithelialization was seen in control animals but that the numbers were slightly higher in rats dosed with aged Saffil.There were no lung tumors in the Saffil treated animals, and no significant group difference in the frequency of extrapulmonary tumors was observed.

One study of ultrafine Al2O3 particles administered by intratracheal instillation to rats was identified.Induction of lung tumours was observed. The results from this study lack relevance to actual human exposures due to the mode of administration and the high doses administered.

Due to the high doses applied and the high dose rate, rat-specific effects due to lung overload are likely. 

The available evidence from animal studies does not support a carcinogenic effect specific to aluminium oxide and aluminium metal in humans.

 

In-vitro studies and Mechanism of Action

The results from in-vitro studies indicate that aluminium oxide has low cytotoxicity. 

Overall, the current weight of evidence does not support an association between inhalation exposure to aluminium metal/aluminium oxide and cancers in the respiratory organs. The weight of evidence also does not support a systemic carcinogenic effect from exposure to aluminium metal and aluminium oxide.