The Health Effects of Aluminum Exposure
; ; ; ; ;
Background: Aluminum is regularly taken up with the daily diet. It is also used in antiperspirants, as an adjuvant for vaccination, and in desensitization procedures. In this review, we present the scientifically documented harmful effects of aluminum on health and the threshold values associated with them.
Methods: This review is based on publications retrieved by a selective search of the PubMed and SCOPUS databases on the topic of aluminum in connection with neurotoxicity, Alzheimer’s disease, and breast cancer, as well as on the authors’ personal experience in occupational and environmental medicine.
Results: The reference values for the internal aluminum load (<15 µg/L in urine, <5 µg/L in serum) are especially likely to be exceeded in persons with occupational exposure. The biological tolerance value for occupational exposure is 50 µg of aluminum per gram of creatinine in the urine. For aluminum welders and workers in the aluminum industry, declining performance in neuropsychological tests (attention, learning, memory) has been found only with aluminum concentrations exceeding 100 µg/g creatinine in the urine; manifest encephalopathy with dementia was not found. Elevated aluminum content has been found in the brains of persons with Alzheimer’s disease. It remains unclear whether this is a cause or an effect of the disease. There is conflicting evidence on carcinogenicity. The contention that the use of aluminum-containing antiperspirants promotes breast cancer is not supported by consistent scientific data.
Conclusion: The internal aluminum load is measured in terms of the concentration of aluminum in urine and blood. Keeping these concentrations below the tolerance values prevents the development of manifest and subclinical signs of aluminum toxicity. Large-scale epidemiologic studies of the relationship between aluminum-containing antiperspirants and the risk of breast cancer would be desirable.
Aluminum has long been established in medical applications as, e.g., an adjuvant in vaccines and an agent against pathological hyperhidrosis with a low side-effect profile (1, 2). In recent years, however, there has been more focus on the at times highly uncritical public debate about the neurotoxic effect of aluminum and its potential carcinogenic effect. Headlines such as “First evidence that aluminum in deodorants can actually trigger breast cancer” suggest to the reader that there is a proven link. Therefore, the question arises from a scientific perspective as to how high the risk of adverse health effects due to aluminum exposure actually is. There are numerous publications relating to this question (see the review by Willhite et al. ).
Our article examines the question of whether environmental and therapeutic aluminum exposure increases the risk of disease. To this end, Alzheimer’s disease and breast cancer are taken as critical endpoints. Aluminum’s neurotoxic effects in humans and its embryotoxic effects in animal models have been proven (4).
From a preventive medicine perspective, exposure to foreign substances should always be kept as low as reasonably achievable (principle of minimizing). Aluminum, however, is found in the blood and urine of all humans. Particularly in cases where a foreign substance exceeds its reference value (the value of the 95th percentile in the general population), one asks from a medical perspective whether, and from what level, does the substance pose a concrete health hazard.
A selective literature search on aluminum in association with neurotoxicity, Alzheimer’s disease, and breast cancer was carried out in the PubMed and SCOPUS databases; the authors’ experience in occupational and environmental medicine was also included in the analysis.
Environmental, occupational, and treatment-related exposure
Aluminum is the third most abundant element in the earth’s crust and occurs naturally in the environment, foodstuffs, and drinking water.
It is also used in:
- Processed foods
- Materials and articles such as:
– Aluminum-containing food packaging
– Aluminum foils
– Cooking utensils and baking trays
- Cosmetic products (including antiperspirants, sun creams, toothpaste)
- Drugs (antacid agents).
Only around 0.1% of orally ingested aluminum is absorbed from the gastrointestinal tract and is made bioavailable (5).
The tolerable weekly intake (TWI) set by the European Food Safety Authority (EFSA) of 1 mg aluminum/kg body weight (BW) in a 60-kg adult is in some individuals already exhausted or slightly exceeded as a result of estimated daily alimentary aluminum exposure of 1.6–13 mg (0.2–1.5 mg/kg BW/week) (5) (Table 1). Relative exposure in children is higher at up to 2.3 mg/kg BW/week. TWI levels are designed to be precautionary and long-term values for the general population. Exceeding these values does not mean that there is an acute health hazard. Moreover, aluminum exposure depends greatly on the route of exposure. Exposure via the gastrointestinal tract and intact skin is extremely mild in humans. Therefore, the TWI value is suited to only a limited extent to reflecting the organism’s aluminum exposure. Internal exposure, which can be determined from aluminum levels in urine or blood, is a significantly better measure for assessing aluminum-related neurotoxicity.
The literature reports widely differing values for the normal range of aluminum excretion, e.g., <7.5 µg/L plasma and <60 µg/24 h in urine (e1). Background exposure in the general population is put at <5 µg/L serum and <15 µg/L urine (provisional reference values set by the German Federal Environmental Agency [Umweltbundesamt]) (6). Table 1 provides an overview of the current classifications for aluminum. There are currently no studies that permit an evaluation of the different sources of internal exposure.
The internal exposure levels of those exposed in workplaces where aluminum welding is carried out, during electrolysis in aluminum production, or in the processing industries (e.g., foundries, powder production) can be significantly higher compared with individuals not exposed to aluminum at work, meaning that the reference values derived for the general population may be exceeded in these workers. Longitudinal studies on aluminum welders revealed that the aluminum content in welding fumes correlated with aluminum concentrations in blood and urine (8). The median plasma concentrations of approximately 10–14 µg/L are significantly below the plasma concentration of around 50 µg/L assumed to be the toxicity threshold in dialysis patients (8, e4).
The first subclinical changes detected using neuropsychological tests on a group basis was seen in aluminum welders in longitudinal studies over the 5-year study period at median aluminum concentrations post-shift of 120 µg/L (100 µg/g creatinine in urine) and 13 µg/L plasma (8, 9) compared with production workers not exposed to aluminum.
Workers in aluminum powder production in whom early-stage aluminosis was detected exhibited significantly higher aluminum concentrations at 340.5 µg/g creatinine and 33.5 µg/L plasma compared with controls (135.1 µg/g creatinine and 15.4 µg/L plasma) (10). Neurotoxicity was not investigated.
Aluminum in therapeutic applications
Antiperspirants: Aluminum compounds have been used commercially in antiperspirants since as early on as in 1903. Due to their antiperspirant effect, aluminum salts are used in dermatology at significantly higher concentrations (10–30% aluminum chlorohydrate) than in over-the-counter antiperspirants. The German Dermatological Society (Deutsche Dermatologische Gesellschaft) considers these to be a simple and suitable treatment option for hyperhidrosis with low side effects (2). Alternatives in the treatment of hyperhidrosis include tannin preparations with an astringent action, techniques such as tap water iontophoresis, chemical denervation with botulinum toxin A, systemic therapies with antihidrotic agents or psychotropic drugs, as well as surgical procedures (2).
Although aluminum is absorbed through the skin (11, 12), the penetration rate of aluminum chlorohydrate following the dermal application of antiperspirants is extremely low at around 0.01% (in two subjects ) and up to 0.06% in pre-damaged skin (in vitro ). To date, there are no epidemiological studies on internal exposure due to the use of antiperspirants following underarm shaving or the use of hair removal products.
Vaccination and hyposensitization: Aluminum salts are used as adjuvants in preparations for vaccines and hyposensitization. The adsorption of antigens on poorly soluble aluminum hydroxide augments the immunological effect (e5, e6). An aluminum dose of 0.1–0.8 mg is absorbed upon one-off application of a vaccine approved in Europe (14). Hyposensitization products approved for the German market contain 0.1–1.1 mg aluminum hydroxide per dose. Since these products are usually injected monthly over a 3-year period, aluminum exposure is significantly higher compared with a single vaccination.
Following injection, the aluminum salts become systemically available—the possible risks of this are currently the subject of critical discussion. In 2014, the Paul-Ehrlich Institute classified the “contribution of treatment with aluminum-containing therapeutic allergens to the lifelong accumulation of aluminum in the organism compared with aluminum exposure from other sources as low” and considers it acceptable in view of the therapeutic benefits (1). However, data on blood or urine levels in affected patients, which would enable an assessment of the risk of subclinical neurotoxic effects of aluminum, are lacking.
Table 2 shows examples for the long-known aluminum-related chronic diseases, aluminosis and dialysis encephalopathy syndrome, as well as for chronic disorders currently discussed in connection with aluminum exposure: Alzheimer’s disease and breast cancer.
Neurotoxicity of aluminum
Aluminum (Al3+) exhibits a high affinity to proteins, which it is able to cross-link. In contrast to other ubiquitously occurring metals such as iron, manganese, and zinc, aluminum is not known to perform a physiological function in the human organism (23). Clinically relevant, neurotoxic effects have been described in dialysis patients. Aluminum salts, which were formerly added to the dialysate as a phosphate binder, were identified as the causal agents (15). Patients exhibited elevated aluminum concentrations in plasma and brain tissue (15, 24). Those affected showed disorientation, memory impairments, and, at advanced stages, dementia (15). The cause of these effects lies, firstly, in the slow—compared with other organs—removal of aluminum from the brain (e11) and, secondly, in the multitude of biological processes affected by aluminum in the brain (23).
In addition to inducing oxidative stress and binding to negatively charged membrane structures in neurons, aluminum is able to modify hippocampal calcium signal pathways that are crucial to neuronal plasticity and, hence, to memory (e12). Cholinergic neurons are particularly susceptible to aluminum neurotoxicity, which affect synthesis of the neurotransmitter acetylcholine (e13). Particularly the latter two neurobiological effects are also relevant in the presumed association between aluminum and Alzheimer’s disease (the Alzheimer’s hypothesis) (23). Aluminum-related neurotoxic effects could be partially reversed once aluminum contamination was no longer present in the dialysate (15).
Changes in neuropsychological tests (e.g., in relation to concentration, learning, and memory) were observed following occupational exposure of workers in whom concentrations of approximately 100 µg aluminum/g creatinine and approximately 13 µg/L plasma were measured; the neurotoxic effect of aluminum is considered causal here (8, 9, 25, 26) (Table 3). However, even following aluminum exposure above this threshold, no cases of manifest encephalopathy involving disorientation, impaired memory, and dementia have been reported (8–9, 10, 26, 27, e14). Only a single case report dating back to 1962 is available on one worker in whom rapidly progressive encephalopathy was observed and potentially linked to the patient’s concomitant aluminum fibrosis of the lung (28).
Is there a link between aluminum
and Alzheimer’s disease?
In the course of the search for the causes of the frequently seen Alzheimer’s dementia, the described dementia syndrome following aluminum poisoning was also proposed as an explanation. Dialysis patients exhibited impaired speech, apraxia, and, in the further course, dementia syndrome as well as partly focal, partly generalized seizures (15). Specific EEG changes in the form of alternating spikes (2–3 c/s) and slow waves have proved to be characteristic and diagnostically significant (e15). Neuropathological investigations revealed minimal changes (mild hydrocephalus, only slight neuronal cell loss in the cortex, hippocampus, or Purkinje cells); mild vascular changes or aluminum detected in tissue have occasionally been reported (15), without evident changes typical of Alzheimer’s disease being identified (amyloid plaques and neurofibrillary tangles).
By contrast, in Alzheimer’s patiens the characteristic changes typical of aluminum encephalopathy were not observed. It was shown in several studies that an elevated aluminum content could be detected in the brains of Alzheimer’s patients, frequently in the endothelial cells of the walls of small and very small arteries, often associated with cerebral amyloid angiopathy (CAA) (e16), as well as in the central region of senile plaques (29).
The onset of Alzheimer’s pathology (both neurofibrillary tangles and amyloid plaques) was observed in animal models following intracranial/intraventricular administration of aluminum compounds (e17–e19). On the other hand, intraperitoneal or oral administration mostly produced no significant pathologies (e20, e21).
Wang et al. (16) found an increased risk for Alzheimer’s disease in their meta-analysis of individuals chronically exposed to aluminum in drinking water. In contrast, several studies found no association between aluminum exposure and Alzheimer’s disease after significantly higher occupational aluminum exposure (16–18) (Table 2).
From a critical perspective, the following can be concluded on aluminum exposure and Alzheimer’s disease:
- Aluminum can cause (in the case of extreme exposure) specific encephalopathy with a dementia syndrome.
- This aluminum encephalopathy is a distinct disease entity and is not the same as Alzheimer-type dementia.
- Elevated aluminum concentrations can be detected in the brains of Alzheimer’s patients. However, it is unclear whether aluminum is the cause of the change, or whether a secondary, independent change (apposition) takes place due to the Alzheimer’s pathology.
- Epidemiological studies provide only very uncertain indications of an association between aluminum exposure and Alzheimer’s disease.
Is there an association between aluminum and breast cancer?
For some time, there has been a discussion on whether the use of aluminum-containing antiperspirants can cause breast cancer (30). Although tumors are more frequently diagnosed in the upper outer quadrants of the breast, i.e., in close spatial proximity to where the substances are used, this is also an area with more glandular tissue (31–37). Nevertheless, an increase in this localization has been observed in recent decades (38). However, analysis of 746 consecutive breast tissue specimens showed that the percentage of diagnoses of normal, benign, or malignant tissue changes was comparable between quadrants (39).
Elevated levels of aluminum were also observed in the nipple aspirate fluid from female patients with breast cancer (e22), and likewise in an analysis of malignantly changed breast tissue (e23), whereby concentrations were higher in the outer compared with the inner quadrants (e24). However, aluminum does not appear to be the trigger of the tumors, but instead is stored to a greater degree in tumor tissue, much like other minerals. For example, feeding rats with a carcinogenic, non-aluminum-containing substance (2,7-dimethylbenz[a]anthracene) caused mammary gland tumors in which significantly elevated levels of aluminum were measured (40). Furthermore, besides aluminum, significantly elevated concentrations of other minerals (e.g., Cd and Ni, as well as Br, Ca, Cl, Co, Cs, Fe, K, Mn, Na, Rb, and Zn) were observed in human breast tumor tissue specimens (e25–e27).
In a more recent study, long-term exposure to aluminum chloride transformed breast epithelial cells in vitro in such a way (e.g., by increased DNA synthesis and DNA double-strand breaks) that the cells formed tumors and metastasized in an animal experiment (e28), which can be considered evidence of cell transformation.
A retrospective study showed an earlier age of disease onset in breast cancer patients that had used aluminum-containing antiperspirants combined with underarm shaving (19), whereas case–control studies (20, 21) failed to identify a link between the use of antiperspirants and the risk of breast cancer. Likewise, a systematic analysis of the published literature revealed no increased risk of breast cancer due to antiperspirant use (22).
In summary, there are currently no consistent data from epidemiological studies relating to an association between aluminum exposure and breast cancer risk; the majority of studies available to date found no association in this regard (Table 2). Collecting data on the use of aluminum-containing antiperspirants and breast cancer risk as part of a study with a longer observation period and high case numbers, like the German “National Cohort” (Nationale Kohorte), could yield more information. In addition, further mechanistic studies are needed.
The assessment of measured values in terms of their relevance to health is an important task in medicine. The neurotoxicity proven in humans and animals is the critical adverse effect of aluminum. This includes specific encephalopathy with a dementia syndrome, which, however, is not identical to the pathophysiology of Alzheimer-type dementia. A carcinogenic effect of aluminum has not been proven to date. It is possible to assess whether critical internal exposure levels are present from aluminum concentrations in blood and urine. Occupational health investigations are helpful here, since they describe experience gained in highly exposed groups. The available occupational health studies show, as a whole, that adverse neurotoxic changes are unlikely in the case of urinary excretion of <50 µg aluminum/g creatinine, even following long-term exposure.
Conflict of interest statement
The authors are active for the Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area of the German Research Foundation.
Manuscript received on 8 December 2016, revised version accepted on
21 January 2017
Translated from the original German by Christine Schaefer-Tsorpatzidis
Institut und Poliklinik für Arbeits-, Sozial- und Umweltmedizin
91054 Erlangen, Germany
For eReferences please refer to:
Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine. University of Erlangen-Nuremberg: Dr. rer. nat. Klotz, Dr. med. Weistenhöfer, Prof. Dr. med. Drexler
Departments of Pathology at Städtische Kliniken München GmbH & Technische Universität München: PD Dr. med. Neff
Department of Food Chemistry and Toxicology, Institute for Applied Biosciences, Karlsruhe Institute of Technology (KIT): Prof. Dr. rer. nat. Hartwig
Leibniz Research Centre for Working Environment and Human Factors at Technische Universität Dortmund: PD Dr. rer. nat. van Thriel
|1.||Paul-Ehrlich-Institut: Sicherheitsbewertung von Aluminium in Therapieallergenen. www.pei.de/DE/arzneimittelsicherheit-vigilanz/archiv-sicherheitsinformationen (last accessed on 21 July 2017).|
|2.||Deutsche Dermatologische Gesellschaft: Definition und Therapie der primären Hyperhidrose. S1-Leitlinie vom 15.1.2012. AWMF-Register Nr. 013/059. www.awmf.org/leitlinien (last accessed on 21 July 2017).|
|3.||Willhite CC, Karyakina NA, Yokel RA, et al.: Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts. Crit Rev Toxicol 2014; 44: 1–80 CrossRef MEDLINE PubMed Central|
|4.||BfR (Bundesinistitut für Risikobewertung): Aluminiumhaltige Antitranspiranzien tragen zur Aufnahme von Aluminium bei. Stellungnahme. Nr. 007/2014 des Bundesinstituts für Risikobewertung vom 26. Februar 2014. www.bfr.bund.de (last accessed on 21 July 2017).|
|5.||EFSA (European Food Safety Authority): Safety of aluminium from dietary intake, scientific opinion of the panel on food additives, flavourings, processing aids and food contact materials (AFC). EFSA Journal 2008: 1–34.|
|6.||Umweltbundesamt: Aluminium. Stellungnahme der Kommission „Human-Biomonitoring“ des Umweltbundesamtes. Bundesgesundhbl 1998; 41: 271.|
|7.||Deutsche Forschungsgemeinschaft: MAK- und BAT-Werte-Liste 2017: Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte. Ständige Senatskommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe. Mitteilung 53. Weinheim: Wiley-VCH; 2017.|
|8.||Kiesswetter E, Schaeper M, Buchta M, et al.: Longitudinal study on potential neurotoxic effects of aluminium: I. Assessment of exposure and neurobehavioural performance of Al welders in the train and truck construction industry over 4 years. Int Arch Occup Environ Health 2007; 81: 41–67 CrossRef MEDLINE|
|9.||Buchta M, Kiesswetter E, Schaper M, et al.: Neurotoxicity of exposures to aluminium welding fumes in the truck trailer construction industry. Environ Toxicol Pharmacol 2005; 19: 677–85 CrossRef MEDLINE|
|10.||Kraus T, Schaller KH, Angerer J, Hilgers RD, Letzel S: Aluminosis-detection of an almost forgotten disease with HRCT. J Occup Med Toxicol 2006; 1: 4 CrossRef MEDLINE PubMed Central|
|11.||Flarend R, Bin T, Elmore D, Hem SL: A preliminary study of the dermal absorption of aluminium from antiperspirants using aluminium-26. Food Chem Toxicol 2001; 39: 163–8 CrossRef|
|12.||Guillard O, Fauconneau B, Olichon D, Dedieu G, Deloncle R: Hyperaluminemia in a woman using an aluminum-containing antiperspirant for 4 years. Am J Med 2004; 117: 956–9 CrossRef MEDLINE|
|13.||Pineau A, Guillard O, Favreau F, Marrauld A, Fauconneau B: In vitro study of percutaneous absorption of aluminum from antiperspirants through human skin in the Franz diffusion cell. J Inorg Biochem 2012; 110: 21–6 CrossRef MEDLINE|
|14.||Weisser K, Heymans L, Keller-Stanislawski B: Paul-Ehrlich Institut: Sicherheitsbewertung von Aluminium in Impflösungen. Bulletin zur Arzneimittelsicherheit 2015; 03: 7–11.|
|15.||Parkinson IS, Ward MK, Kerr DN: Dialysis encephalopathy, bone disease and anaemia: the aluminum intoxication syndrome during regular haemodialysis. J Clin Pathol 1981; 34: 1285–94 CrossRef|
|16.||Wang Z, Wei X, Yang J, et al.: Chronic exposure to aluminum and risk of Alzheimer‘s disease: a meta-analysis. Neurosci Lett 2016; 610: 200–6 MEDLINE|
|17.||Virk SA, Eslick GD: Occupational exposure to aluminum and Alzheimer disease: a meta-analysis. J Occup Environ Med 2015; 57: 893–6 CrossRef MEDLINE|
|18.||Salib E, Hillier V: A case-control study of Alzheimer‘s disease and aluminium occupation. Br J Psychiatry 1996; 168: 244–9 MEDLINE|
|19.||McGrath KG: An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving. Eur J Cancer Prev 2003; 12: 479–85 CrossRef|
|20.||Mirick DK, Davis S, Thomas DB: Antiperspirant use and the risk of breast cancer. J Natl Cancer Inst 2002; 94: 1578–80 CrossRef|
|21.||Fakri S, Al-Azzawi A, Al-Tawil N: Antiperspirant use as a risk factor for breast cancer in Iraq. East Mediterr Health J 2006; 12: 478–82 MEDLINE|
|22.||Namer M, Luporsi E, Gligorov J, Lokiec F, Spielmann M: The use of deodorants/antiperspirants does not constitute a risk factor for breast cancer. Bull Cancer 2008; 95: 871–80 MEDLINE|
|23.||Kawahara M, Kato-Negishi M: Link between aluminum and the pathogenesis of Alzheimer‘s disease: the integration of the aluminum and amyloid cascade hypotheses. Int J Alzheimers Dis 2011: 276393 CrossRef|
|24.||Alfrey AC, Legendre GR, Kaehny WD: Dialysis encephalopathy syndrome – possible aluminum intoxication. New Engl J Med 1976; 294: 184–8 CrossRef MEDLINE|
|25.||Buchta M, Kiesswetter E, Otto A, et al.: Longitudinal study examining the neurotoxicity of occupational exposure to aluminium-containing welding fumes. Int Arch Occup Environ Health 2003; 76: 539–48 CrossRef MEDLINE|
|26.||Riihimäki V, Hänninen H, Akila R, et al.: Body burden of aluminum in relation to central nervous system function among metal inert-gas welders. Scand J Work Environ Health 2000; 26: 118–30 CrossRef MEDLINE|
|27.||Drexler H, Hartwig A (eds.): Addendum zu Aluminium. Biologische Arbeitsstoff-Toleranz-Werte (BAT-Werte), Expositionsäquivalente für krebserzeugende Arbeitsstoffe (EKA), Biologische Leitwerte (BLW) und Biologische Arbeitsstoff-Referenzwerte (BAR). 16. Lieferung. Weinheim: Wiley-VCH 2009.|
|28.||Mc Laughlin AI, Kazantzis G, King E, Teare D, Porter RJ, Owen R: Pulmonary fibrosis and encephalopathy associated with the inhalation of aluminium dust. Br J Ind Med 1962; 19: 253–63.|
|29.||Candy JM, Oakley AE, Klinowski J, et al.: Aluminosilicates and senile plaque formation in Alzheimer‘s disease. Lancet 1986; 1: 354–7 CrossRef|
|30.||Darbre PD: Underarm cosmetics and breast cancer. J Appl Toxicol 2003; 23: 89–95 CrossRef MEDLINE|
|31.||Darbre PD: Aluminium, antiperspirants and breast cancer. J Inorg Biochem 2005; 99: 1912–9 CrossRef MEDLINE|
|32.||Hussain MA, Ali S, Tyagi SP, Reza H: Incidence of cancer breast at Aligarh. J Indian Med Assoc 1994; 92: 296–7 MEDLINE|
|33.||Patterson SK, Helvie MA, Joynt LK, Roubidoux MA, Strawderman M: Mammographic appearance of breast cancer in African-American women: report of 100 consecutive cases. Acad Radiol 1998; 5: 2–8 CrossRef|
|34.||Jaiyesimi IA, Buzdar AU, Sahin AA, Ross MA: Carcinoma of the male breast. Ann Intern Med 1992; 117: 771–7 CrossRef|
|35.||Rizk SN, Assimacopoulos CA, Ryan JJ: Male breast cancer: three case reports and review of the literature. S D J Med 1994; 47: 343–6 MEDLINE|
|36.||Azzena A, Zen T, Ferrara A, Brunetti V, Vasile C, Marchetti M: Risk factors for breast cancer. Case-control study results. Eur J Gynaecol Oncol 1994; 15: 386–92 MEDLINE|
|37.||Raju GC, Naraynsingh V: Breast cancer in West Indian women in Trinidad. Trop Geogr Med 1989; 41: 257–60 MEDLINE|
|38.||Darbre PD: Recorded quadrant incidence of female breast cancer in Great Britain suggests a disproportionate increase in the upper outer quadrant of the breast. Anticancer Res 2005; 25: 2543–50 CrossRef|
|39.||Lee AH: Why is carcinoma of the breast more frequent in the upper outer quadrant? A case series based on needle core biopsy diagnoses. Breast 2005; 14: 151–2 CrossRef MEDLINE|
|40.||Ogoshi K, Yanagi S, Moriyama T, Arachi H: Accumulation of aluminum in cancers of the liver, stomach, duodenum and mammary glands of rats. J Trace Elem Electrolytes Health Dis 1994; 8: 27–31 MEDLINE|
|e1.||Rückgauer M: Labor und Diagnose, Indikation und Bewertung von Laborbefunden für die medizinische Diagnostik. 8 edition. Frankfurt/Main: TH-Books Verlagsgesellschaft mbH 2008.|
|e2.||WHO Joint FAO/WHO Expert Committee on Food Additives: Safety evaluation of certain food additives and contaminants. 2012. http://apps.who.int/iris/bitstream/10665/44788/1/WHO_TRS_966_eng.pdf (last accessed on 17 July 2017).|
|e3.||IARC (International Agency For Research On Cancer): Occupational exposures during aluminium production. IARC Monographs on the evaluation of carcinogenic risks to humans. No. 100F. Lyon (FR) 2012. https://monographs.iarc.fr/ENG/Monographs/vol100F/mono100F-22.pdf (last accessed on 21 July 2017).|
|e4.||Mardini J, Lavergne V, Ghannoum M: Aluminum transfer during dialysis: a systematic review. Int Urol Nephrol 2014; 46: 1361–5 CrossRef MEDLINE|
|e5.||Kool M, Fierens K, Lambrecht BN: Alum adjuvant: some of the tricks of the oldest adjuvant. J Med Microbiol 2012; 61: 927–34 CrossRef MEDLINE|
|e6.||Oleszycka E, Lavelle EC: Immunomodulatory properties of the vaccine adjuvant alum. Curr Opin Immunol 2014; 28: 1–5 CrossRef MEDLINE|
|e7.||WHO (World Health Organization): Aluminium. International programme on chemical safety (IPCS), environmental health criteria 194. Genf: WHO1997. www.inchem.org/documents/ehc/ehc/ehc194.htm (last accessed on 21 July 2017).|
|e8.||Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB: Occupational exposures to solvents and aluminium and estimated risk of Alzheimer‘s disease. Occup Environ Med1998; 55: 627–33 CrossRef MEDLINE PubMed Central|
|e9.||Gun RT, Korten AE, Jorm AF, et al.: Occupational risk factors for Alzheimer disease: a case-control study. Alz Dis Assoc Dis 1997; 11: 21–7 CrossRef|
|e10.||Salib E: Risk factors in clinically diagnosed Alzheimer’s disease: a retrospective hospital-based case control study in Warrington. Aging Ment Health 2000; 4: 259–67 CrossRef|
|e11.||Priest ND: The biological behaviour and bioavailability of aluminium in man, with special reference to studies employing aluminium-26 as a tracer: review and study update. J Environ Monitor 2004; 6: 375–403 CrossRef MEDLINE|
|e12.||Nday CM, Drever BD, Salifoglou T, Platt B: Aluminium interferes with hippocampal calcium signaling in a species-specific manner. J Inorg Biochem 2010; 104: 919–27 CrossRef MEDLINE|
|e13.||Jankowska A, Madziar B, Tomaszewicz M, Szutowicz A: Acute and chronic effects of aluminum on acetyl-CoA and acetylcholine metabolism in differentiated and nondifferentiated SN56 cholinergic cells. J Neurosci Res 2000; 62: 615–22 CrossRef|
|e14.||Letzel S, Lang CJG, Schaller KH, et al.: Longitudinal study of neurotoxicity with occupational exposure to aluminum dust. Neurology 2000; 54: 997–1000 CrossRef MEDLINE|
|e15.||Zschocke S, Hansen HC: Klinische Elektroenzephalographie. Heidelberg: Springer 2012.|
|e16.||Bhattacharjee S, Zhao Y, Hill JM, et al.: Selective accumulatin of aluminum in cerebral arteries in Alzheimer‘s disease (AD). J Inorg Biochem 2013; 126: 35–7 CrossRef MEDLINE PubMed Central|
|e17.||Klatzo I, Wisniewski H, Streicher E: Experimental production of neurofibrillary degeneration. I. Light microscopic observations. J Neuropathol Exp Neurol 1965; 24: 187–99 CrossRef MEDLINE|
|e18.||Katsetos CD, Savory J, Herman MM, et al.: Neuronal cytoskeletal lesions induced in the CNS by intraventricular and intravenous aluminium maltol in rabbits. Neuropathol Appl Neurobiol 1990; 16: 511–28 CrossRef MEDLINE|
|e19.||Zhang QL, Jia L, Jiao X, et al.: APP/PS1 transgenic mice treated with aluminum: an update of Alzheimer‘s disease model. Int J Immunopathol Pharmacol 2012; 25: 49–58 CrossRef MEDLINE|
|e20.||Ulusoy HB, Sonmez MF, Kilic E, et al.: Intraperitoneal administration of low dose Aluminium in the rat: how good is It to produce a model for Alzheimer Disease. Arch Ital Biol 2015; 153: 266–78.|
|e21.||Akiyama H, Hosokawa M, Kametani F, et al.: Long-term oral intake of aluminium or zinc does not accelerate Alzheimer pathology in AbetaPP and AbetaPP/tau transgenic mice. Neuropathol 2012; 32: 390–7 CrossRef MEDLINE|
|e22.||Mannello F, Tonti GA, Medda V, Simone P, Darbre PD: Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer-affected patients. J Appl Toxicol 2011; 31: 262–9 CrossRef MEDLINE|
|e23.||Millos J, Costas-Rodriguez M, Lavilla I, Bendicho C: Multiple small volume microwave-assisted digestions using conventional equipment for multielemental analysis of human breast biopsies by inductively coupled plasma optical emission spectrometry. Talanta 2009; 77: 1490–6 CrossRef MEDLINE|
|e24.||Exley C, Charles LM, Barr L, Martin C, Polwart A, Darbre PD: Aluminium in human breast tissue. J Inorg Biochem 2007; 101: 1344–6 CrossRef MEDLINE|
|e25.||Ng KH, Bradley DA, Looi LM: Elevated trace element concentrations in malignant breast tissues. Br J Radiol 1997; 70: 375–82 CrossRef MEDLINE|
|e26.||Romanowicz-Makowska H, Forma E, Brys M, Krajewska WM, Smolarz B: Concentration of cadmium, nickel and aluminium in female breast cancer. Pol J Pathol 2011; 62: 257–61 MEDLINE|
|e27.||Mulay IL, Roy R, Knox BE, Suhr NH, Delaney WE: Trace-metal analysis of cancerous and noncancerous human tissues. J Natl Cancer Inst 1971; 47: 1–13 MEDLINE|
|e28.||Mandriota SJ, Tenan M, Ferrari P, Sappino AP: Aluminium chloride promotes tumorigenesis and metastasis in normal murine mammary gland epithelial cells. Int J Cancer 2016; 19: 30393.|
Aluminum Exposure and Gestational Diabetes Mellitus: Associations and Potential Mediation by n-6 Polyunsaturated Fatty AcidsEnvironmental Science & Technology, 202010.1021/acs.est.9b07180
Neuroprotective Effect of Turmeric Extract in Combination with Its Essential Oil and Enhanced Brain Bioavailability in an Animal ModelBioMed Research International, 202110.1155/2021/6645720
Importance of Mineral Nutrition for Mitigating Aluminum Toxicity in Plants on Acidic Soils: Current Status and OpportunitiesInternational Journal of Molecular Sciences, 201810.3390/ijms19103073
Acta Universitatis Cibiniensis. Series E: Food Technology, 202010.2478/aucft-2020-0005
International Journal of Environmental Research and Public Health, 202010.3390/ijerph17238990
Journal of Gerontology and Geriatrics, 202010.36150/2499-6564-420
Journal of Basic and Clinical Physiology and Pharmacology, 202110.1515/jbcpp-2020-0220
Open Journal of Bacteriology, 201810.17352/ojb.000007
Interdisciplinary Toxicology, 201910.2478/intox-2019-0007
Analysis and Health Risk Assessment of Potentially Toxic Elements in Three Codonopsis Radix Varieties in ChinaBiological Trace Element Research, 202110.1007/s12011-021-02806-y
Open Chemistry, 202110.1515/chem-2021-0197
From Lithographically Patternable to Genetically Patternable Electronic Materials for Miniaturized, Scalable, and Soft Implantable Bioelectronics to Interface with Nervous and Cardiac SystemsACS Applied Electronic Materials, 202110.1021/acsaelm.0c00753
MUSCULOSKELETAL SURGERY, 202110.1007/s12306-021-00729-4
Ameliorative effect of selenium nanoparticles against aluminum chloride-induced hepatorenal toxicity in ratsEnvironmental Science and Pollution Research, 201910.1007/s11356-019-06417-y
Deutsches Ärzteblatt international, 201810.3238/arztebl.2018.0098b
In Utero Exposure to Aluminium and Other Neurotoxic Elements in Urban Coastal South African Women at Delivery: An Emerging ConcernInternational Journal of Environmental Research and Public Health, 202010.3390/ijerph17051724
Investigation about iron(III) incorporation into layered double hydroxides: Compositional and structural properties of Mg2FeyAl(1−y)(OH)6-Cl and Zn2FeyAl(1−y)(OH)6-ClJournal of Alloys and Compounds, 202110.1016/j.jallcom.2021.161184
Environmental Science and Pollution Research, 202110.1007/s11356-021-14700-0
International Journal of Molecular Sciences, 202010.3390/ijms21239332
The physicochemical properties and distribution of aluminum in the environment, the effect on living organisms, the reduction of its toxic effectMedical academic journal, 202110.17816/MAJ64912
Selective removal of aluminum, nickel and chromium ions by polymeric resins and natural zeolite from anodic plating wastewaterInternational Journal of Environmental Health Research, 202110.1080/09603123.2019.1631263
Long-term exposure to low doses of aluminum affects mineral content and microarchitecture of rats alveolar boneEnvironmental Science and Pollution Research, 202110.1007/s11356-021-13937-z
Optimized Use of Ferric Chloride and Sesbania Seed Gum (SSG) as Sustainable Coagulant Aid for Turbidity Reduction in Drinking Water TreatmentSustainability, 202010.3390/su12062273
Turkish Journal of Engineering, 202110.31127/tuje.846455
Deutsches Ärzteblatt international, 201810.3238/arztebl.2018.0098a
Impact of Daily Antiperspirant Use on the Systemic Aluminum Exposure: An Experimental Intervention StudySkin Pharmacology and Physiology, 202010.1159/000502239
Concentration, Source, and Potential Human Health Risk of Heavy Metals in the Commonly Consumed Medicinal PlantsBiological Trace Element Research, 201910.1007/s12011-018-1357-3
INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND NANO-MEDICINE FROM NATURAL RESOURCES FOR BIOMEDICAL RESEARCH: 3rd Annual Scientific Meeting for Biomedical Sciences10.1063/1.5110005
Assessment of Trace Elements Supply in Canned Tuna Fish Commercialized for Human Consumption in BrazilInternational Journal of Environmental Research and Public Health, 202110.3390/ijerph182212002
Synthesis and characterization of hydrophobic glass-ceramic thin film derived from colloidal silica, zirconium(IV) propoxide and methyltrimethoxysilane via sol–gel methodJournal of Sol-Gel Science and Technology, 202110.1007/s10971-021-05482-5
International Journal of Environmental Research and Public Health, 202010.3390/ijerph17228357
Aluminum-Induced Cognitive Impairment and PI3K/Akt/mTOR Signaling Pathway Involvement in Occupational Aluminum WorkersNeurotoxicity Research, 202010.1007/s12640-020-00230-z
European Journal for Philosophy of Science, 202110.1007/s13194-021-00381-6
Monitoring of Aluminum content in food and assessment of dietary exposure of residents in North ChinaFood Additives & Contaminants: Part B, 202110.1080/19393210.2021.1912191
Magnesium Increases the Protective Effect of Citicoline on Aluminum Chloride-induced Cognitive ImpairmentClinical Psychopharmacology and Neuroscience, 202010.9758/cpn.2020.18.2.241
Air Pollution-Related Brain Metal Dyshomeostasis as a Potential Risk Factor for Neurodevelopmental Disorders and Neurodegenerative DiseasesAtmosphere, 202010.3390/atmos11101098