Structure-Function Correlations in the Mechanism of Action of Key Antiperspirant Agents Containing Al(III) and ZAG Salts.

Aluminum hydrolysis chemistry is an important part of modern society because of the dominance of Al(III) as a highly effective antiperspirant active. However, the century-old chemistry centered on aluminum chloride (ACL) is not comprehensive enough to address all of the in vivo events associated with current commercial antiperspirants and their mechanism of action. The present study aims to address the knowledge gap among extensively studied benchmark ACL, its modified version aluminum chlorohydrate (ACH), and a more complex but less explored group of aluminum zirconium chlorohydrate glycine complexes (ZAG salts) toward understanding the mechanism of action under consumer-relevant conditions. ACH, which is the Al source used in the manufacture of ZAG salts, provides a bridge between ACL and ZAG chemistry. High viscosity and gel formation driven by pH and a specific Al(III) salt upon hydrolysis are considered the criteria for building an in vivo occlusive mass to retard or stop the flow of sweat to the skin surface, thus providing an antiperspirant effect. Rheological studies indicated that ACL and aluminum zirconium tetrachlorohydrex glycine (TETRA) were the most efficacious salt actives. Spectroscopic studies, diffraction studies, and elemental analysis suggested that small metal oxide and hydroxide species with coparticipating glycine as well as various polynuclear and oligomeric species are the key to gel formation. At a given pH, the key ingredients (NaCl, urea, bovine serum albumin, and lactic acid) in artificial sweat were found to have little influence on Al(III) salt hydrolysis. The effects of the sweat components were mostly limited to local complex formation and kinetic modification. The in vitro comparative experiments with various Al(III) and ZAG salt systems offer unprecedented insights into the chemistry of different salt types, thus paving the way for engineering more efficacious antiperspirant systems.

Cutaneous Reactions to Aluminum.

: Cutaneous exposure to aluminum may occur via contact with metal items, medications, and personal care products. Despite the widespread use of aluminum, allergic contact dermatitis is relatively rare. Sensitization is often incidentally identified during patch testing with aluminum-based chambers. This article presents several cases along with a literature review summarizing prevalence and clinical manifestations of cutaneous reactions to aluminum, recommendations for patch testing, sources of aluminum, and reproducibility of aluminum allergy over time.

Evaporation-Induced Clogging of an Artificial Sweat Duct.

Metal-based antiperspirants have been in use for centuries; however, there is an increasing consumer demand for a metal-free alternative that works effectively. Here, we develop an artificial sweat duct rig and demonstrate an alternative, metal-free approach to antiperspiration. Instead of clogging sweat ducts with metal salts, we use a hygroscopic material to induce the evaporation of sweat as it approaches the outlet (i.e. pore) of the sweat duct. As a result, the sweat dehydrates almost completely while still being inside of the duct, forming a natural gel-like salt plug that halts the flow. We show that the critical pressure gradient within the duct (∼3 kPa), beneath which clogging occurs, can be rationalized by balancing the mass flow rates of the liquid (Poiseuille's law) and the evaporative vapor (Fick's law).

[Deodorants and antiperspirants]. / Déodorants et antitranspirants.

The terms deodorants and antiperspirants very frequently used interchangeably despite the fact that they employ completely different active substances and mechanisms of action. Antiperspirants are necessarily deodorants due to the lack of substrate to decompose. They nevertheless represent a group of very specific substances that create particular problems due to the presence of aluminium chlorohydrate, or ACH, (Al2(OH)5Cl, 2H2O), aluminium sesquichlorohydrate and aluminium-zirconium complex, which, after hydrolysis, causes intense acidification of the skin, hence the importance of inclusion of emollients and pH regulators in formulations. Moreover, systemic aluminium is thought to be genotoxic and to promote breast cancer, and it is thus at the centre of numerous scientific controversies. Nevertheless, its potential toxicity following topical application is related to its ability to penetrate skin, which is as yet poorly understood but considered very low, a fact that may provide some degree of reassurance regarding its use in cosmetic products. Its role in Alzheimer's disease has not been proven. On the other hand, zirconium salts are considered toxic and are partly regulated in Europe. The problems associated with deodorants are those arising from the presence of antiseptics (triclosan, usnic acid) capable of inducing bacterial resistance, but more particularly, the presence of axillary dermatitis due to the allergenic potential of the fragrances and essential oils used (e.g. isoeugenol, citronellal, lyral, cinnamic aldehyde, etc.).

Aluminum Effects in Infants and Children.

Aluminum has no known biological function; however, it is a contaminant present in most foods and medications. Aluminum is excreted by the renal system, and patients with renal diseases should avoid aluminum-containing medications. Studies demonstrating long-term toxicity from the aluminum content in parenteral nutrition components led the US Food and Drug Administration to implement rules for these solutions. Large-volume ingredients were required to reduce the aluminum concentration, and small-volume components were required to be labeled with the aluminum concentration. Despite these rules, the total aluminum concentration from some components continues to be above the recommended final concentration. The concerns about toxicity from the aluminum present in infant formulas and antiperspirants have not been substantiated but require more research. Aluminum is one of the most effective adjuvants used in vaccines, and a large number of studies have documented minimal adverse effects from this use. Long-term, high-concentration exposure to aluminum has been linked in meta-analyses with the development of Alzheimer disease.

Developing a new device for continuously recording, in vivo, the excretion rate of sweat (perspiration) in humans.

BACKGROUND: Some methodologies used for evaluating sweat production and antiperspirants are of a stationary aspect, that is, most often performed under warm (38°C) but resting conditions in a rather short period of time. The aim is to develop an electronic sensor apt at continuously recording sweat excretion, in vivo, during physical exercises, exposure to differently heated environments, or any other stimuli that may provoke sweat excretion. MATERIAL AND METHODS: A sensor (20 cm2 ) is wrapped under a double-layered textile pad. Fixed onto the armpits, these two arrays of electrodes are connected to electronic system through an analog multiplexer. A microcontroller is used to permanently record changes in the conductance between two electrodes during exposure of subjects to different sweat-inducing conditions or to assess the efficacy of applied aluminum hydrochloride (ACH)-based roll-ons at two concentrations (5% and 15%). RESULTS: In vitro calibration, using a NaCl 0.5% solution, allows changes in mV to be related with progressively increased volumes. In vivo, results show that casual physical exercise leads to sweat excretions much higher than in warm environment (37 or 45°C). Only, an exposure to a 50°C environment induced comparable sweat excretion. In this condition, sweat excretions were found similar in both armpits and both genders. Decreased sweat excretions were recorded following applications of ACH, with a dose effect. CONCLUSION: Developing phases of this new approach indicate that usual method or guidelines used to determine sweat excretions in vivo do not reflect true energy expenditure processes. As a consequence, they probably over-estimate the efficacy of antiperspirant agents or formulae.

Particle Size Distribution Analysis of OTC Aerosol or Powder Drug Products With Potential for Inadvertent Inhalation Exposure to Consumers.

The potential for inadvertent inhalation of over-the-counter (OTC) aerosol/powder drug products for topical application requires understanding of the characteristic size distributions of the airborne particles or droplets generated when these products are used as per the directions on the product label. Particle/droplet size is an important factor in determining the depth of particle penetration into the respiratory system after inhalation. Because particles penetrating beyond the larynx into the lung may lead to adverse respiratory effects, OTC aerosol or powder drug product particle size distribution is important to characterize. In this study, laser diffraction was used to analyze the particle size distribution of 32 currently marketed OTC drug products as emitted after actuation or air dispersion from their final package. Among the products surveyed were sunscreens, antiperspirants, topical analgesics, skin protectants, and acne products. The results may be useful to the U.S. Food and Drug Administration in its mission to protect as well as promote public health.

A paper platform for colorimetric determination of aluminum hydrochloride in antiperspirant samples.

A simple, fast, low-cost, portable, and eco-friendly method using a spot test on a paper platform, together with diffuse reflectance spectroscopy, was developed and validated for the quantification of aluminum hydrochloride, a potential neurotoxic agent, in antiperspirant samples. The determination of aluminum hydrochloride was performed at a wavelength of 615 nm, by measuring consumption of the purple colorimetric reagent Alizarin S, due to reaction with aluminum. The linear range was from 10.0 to 125.0 mg L-1 and could be described by the equation: AR = 0.4479 - 0.002543 CAl (R = 0.999). The limits of detection (LOD) and quantification (LOQ) were 3.06 and 10.2 mg L-1, respectively. The method was specific, accurate, and repeatable, with relative standard deviation (RSD) <5.0%. The recovery was between 92.2 and 103.4%. The method was successfully used for the determination of aluminum hydrochloride in commercial antiperspirant samples, revealing concentrations below the maximum permitted by current legislation.

Assessment of Dermal Absorption of Aluminum from a Representative Antiperspirant Formulation Using a 26 Al Microtracer Approach.

A clinical pharmacokinetic study was performed in 12 healthy women to evaluate systemic exposure to aluminum following topical application of a representative antiperspirant formulation under real-life use conditions. A simple roll-on formulation containing an extremely rare isotope of aluminum (26 Al) chlorohydrate (ACH) was prepared to commercial specifications. A 26 Al radio-microtracer was used to distinguish dosed aluminum from natural background, using accelerated mass spectroscopy. The 26 Al citrate was administered intravenously (i.v.) to estimate fraction absorbed (Fabs ) following topical delivery. In blood samples after i.v. administration, 26 Al was readily detected (mean area under the curve (AUC) = 1,273 ± 466 hours×fg/mL). Conversely, all blood samples following topical application were below the lower limit of quantitation (LLOQ; 0.12 fg/mL), except two samples (0.13 and 0.14 fg/mL); a maximal AUC was based on LLOQs. The aluminum was above the LLOQ (61 ag/mL) in 31% of urine samples. From the urinary excretion data, a conservative estimated range for dermal Fabs of 0.002-0.06% was calculated, with a mean estimate of 0.0094%.

A methodology for the assessment of inhalation exposure to aluminium from antiperspirant sprays.

Inhalative exposure can occur accidentally when using cosmetic spray products. Usually, a tiered approach is applied for exposure assessment, starting with rather conservative, simplistic calculation models that may be improved with measured data and more refined modelling. Here we report on an advanced methodology to mimic in-use conditions for antiperspirant spray products to provide a more accurate estimate of the amount of aluminium possibly inhaled and taken up systemically, thus contributing to the overall body burden. Four typical products were sprayed onto a skin surrogate in defined rooms. For aluminium, size-related aerosol release fractions, i.e. inhalable, thoracic and respirable, were determined by a mass balance method taking droplet maturation into account. These data were included into a simple two-box exposure model, allowing calculation of the inhaled aluminium dose over 12 min. Systemic exposure doses were calculated for exposure of the deep lung and the upper respiratory tract using the Multiple Path Particle Deposition Model (MPPD) model. The total systemically available dose of aluminium was in all cases found to be less than 0.5 µg per application. With this study it could be demonstrated that refinement of the input data of the two-box exposure model with measured data of released airborne aluminium is a valuable approach to analyse the contribution of antiperspirant spray inhalation to total aluminium exposure as part of the overall risk assessment. We suggest the methodology which can also be applied to other exposure modelling approaches for spray products, and further is adapted to other similar use scenarios.

Breast Cancer and Deodorants/Antiperspirants: a Systematic Review.

BACKGROUND: Over the last decade, the possible association between underarm deodorants/ antiperspirants use and breast cancer risk has raised important interest in the scientific community. The objective of our systematic review is to estimate the pooled risk of deodorants/antiperspirants use for breast cancer. METHODS: All observational studies that evaluated the association between breast cancer risk and deodorants/antiperspirants use were reviewed. We have only identified two case-control studies, carried out between 2002 and 2006. RESULTS: The first study was conducted in USA and investigated the possible relationship between use of products applied for underarm perspiration and the risk for breast cancer in women aged 20-74 years. This population-based case-control study gathered information by in-person interview. The second study was conducted in Iraq and investigated the possible relationship between use of antiperspirants and the risk for breast cancer in women attending a teaching hospital. This study also gathered information by in-person interview. There was no risk of antiperspirants use in the pooled risk (odds ratio 0.40, 95% confidence interval 0.35-0.46). CONCLUSION: Our comprehensive search has identified an insufficient number of studies to conduct a quantitative review and obtain reliable results. Further prospective studies are strongly needed.

Aluminium and the human breast.

The human population is exposed to aluminium (Al) from diet, antacids and vaccine adjuvants, but frequent application of Al-based salts to the underarm as antiperspirant adds a high additional exposure directly to the local area of the human breast. Coincidentally the upper outer quadrant of the breast is where there is also a disproportionately high incidence of breast cysts and breast cancer. Al has been measured in human breast tissues/fluids at higher levels than in blood, and experimental evidence suggests that at physiologically relevant concentrations, Al can adversely impact on human breast epithelial cell biology. Gross cystic breast disease is the most common benign disorder of the breast and evidence is presented that Al may be a causative factor in formation of breast cysts. Evidence is also reviewed that Al can enable the development of multiple hallmarks associated with cancer in breast cells, in particular that it can cause genomic instability and inappropriate proliferation in human breast epithelial cells, and can increase migration and invasion of human breast cancer cells. In addition, Al is a metalloestrogen and oestrogen is a risk factor for breast cancer known to influence multiple hallmarks. The microenvironment is established as another determinant of breast cancer development and Al has been shown to cause adverse alterations to the breast microenvironment. If current usage patterns of Al-based antiperspirant salts contribute to causation of breast cysts and breast cancer, then reduction in exposure would offer a strategy for prevention, and regulatory review is now justified.

The toxicity of aluminium in humans.

We are living in the 'aluminium age'. Human exposure to aluminium is inevitable and, perhaps, inestimable. Aluminium's free metal cation, Alaq(3+), is highly biologically reactive and biologically available aluminium is non-essential and essentially toxic. Biologically reactive aluminium is present throughout the human body and while, rarely, it can be acutely toxic, much less is understood about chronic aluminium intoxication. Herein the question is asked as to how to diagnose aluminium toxicity in an individual. While there are as yet, no unequivocal answers to this problem, there are procedures to follow to ascertain the nature of human exposure to aluminium. It is also important to recognise critical factors in exposure regimes and specifically that not all forms of aluminium are toxicologically equivalent and not all routes of exposure are equivalent in their delivery of aluminium to target sites. To ascertain if Alzheimer's disease is a symptom of chronic aluminium intoxication over decades or breast cancer is aggravated by the topical application of an aluminium salt or if autism could result from an immune cascade initiated by an aluminium adjuvant requires that each of these is considered independently and in the light of the most up to date scientific evidence. The aluminium age has taught us that there are no inevitabilities where chronic aluminium toxicity is concerned though there are clear possibilities and these require proving or discounting but not simply ignored.

Shaving effects on percutaneous penetration: clinical implications.

CONTEXT: Human/animal shaving biology. OBJECTIVE: To assess the effect of shaving on percutaneous penetration and skin function. METHODS: We screened 500+publications in Pub Med, Scopus, Cochrane Library and pertinent journals out of which only 17 were deemed relevant. Terms for searches included shaving and skin, percutaneous penetration and shaving, skin absorption and shaving, absorption of dyes and shaving, skin penetration, effects of shaving and absorption, shave and dyes, axillary shaving and stratum corneum, shaving and breast cancer, shaving and infections, etc. RESULT: Shaving appears to have an exaggerated effect on percutaneous absorption; however, some studies do not support this evidence. CONCLUSION: Shaving enhances percutaneous penetration of some chemicals; however this effect is species and chemical specific. Further investigations of chemicals of varying physio-chemical properties are mandated before a generalized theory can be promulgated.

Detection of potentially skin sensitizing hydroperoxides of linalool in fragranced products.

On prolonged exposure to air, linalool can form sensitizing hydroperoxides. Positive hydroperoxide patch tests in dermatitis patients have frequently been reported, but their relevance has not been established. Owing to a lack of analytical methods and data, it is unclear from which sources the public might be exposed to sufficient quantities of hydroperoxides for induction of sensitization to occur. To address this knowledge gap, we developed analytical methods and performed stability studies for fine fragrances and deodorants/antiperspirants. In parallel, products recalled from consumers were analysed to investigate exposure to products used in everyday life. Liquid chromatography-mass spectrometry with high mass resolution was found to be optimal for the selective and sensitive detection of the organic hydroperoxide in the complex product matrix. Linalool hydroperoxide was detected in natural linalool, but the amount was not elevated by storage in a perfume formulation exposed to air. No indication of hydroperoxide formation in fine fragrances was found in stability studies. Aged fine fragrances recalled from consumers contained a geometric mean linalool concentration of 1,888 µg/g and, corrected for matrix effects, linalool hydroperoxide at a concentration of around 14 µg/g. In antiperspirants, we detected no oxidation products. In conclusion, very low levels of linalool hydroperoxide in fragranced products may originate from raw materials, but we found no evidence for oxidation during storage of products. The levels detected are orders of magnitude below the levels inducing sensitization in experimental animals, and these results therefore do not substantiate a causal link between potential hydroperoxide formation in cosmetics and positive results of patch tests.

Effects of antiperspirant aluminum percent composition and mode of application on mock microcalcifications in mammography.

OBJECTIVE: Active ingredients in antiperspirants - namely, aluminum-based complexes - can produce radiopaque particles on mammography, mimicking microcalcifications. The present study was designed to investigate whether the appearance of antiperspirant induced radiopaque particles observed on mammograms is dependent on the percentage of aluminum-based complexes in antiperspirants and/or on their mode of application. METHODS: A total of 43 antiperspirants with aluminum-based complex percentages ranging between 16% and 25% were tested. Each antiperspirant was applied to a single use plastic shield and then placed on an ultrasound gel pad, simulating breast tissue. Two experiments were performed, comparing antiperspirants based on (1) their percentage of aluminum-based complexes (20 antiperspirants) and (2) their mode of applications (solid, gel, and roll-on) (26 antiperspirants). Two experienced, blinded radiologists read images produced in consensus and assessed the appearance of radiopaque particles based on their density and shape. RESULTS: In experiment 1, there was no statistically significant association between the percent aluminum composition of invisible solid antiperspirants and the density or shape of the radiopaque particles (p-values>0.05). In experiment 2, there was a statistically significant association between the shape of the radiopaque particles and the mode of application of the antiperspirant (p-value=0.0015). CONCLUSIONS: Our study suggests that the mammographic appearance of the radiopaque antiperspirant particles is not related to their percent composition of aluminum complexes. However, their mode of application appears to influence the shape of radiopaque particles, solid antiperspirants mimicking microcalcifications the most and roll-on antiperspirants the least.

Aluminum concentrations in central and peripheral areas of malignant breast lesions do not differ from those in normal breast tissues.

BACKGROUND: Aluminum is used in a wide range of applications and is a potential environmental hazard. The known genotoxic effects of aluminum might play a role in the development of breast cancer. However, the data currently available on the subject are not sufficient to establish a causal relationship between aluminum exposure and the augmented risk of developing breast cancer. To achieve maximum sensitivity and specificity in the determination of aluminum levels, we have developed a detection protocol using graphite furnace atomic absorption spectrometry (GFAAS). The objective of the present study was to compare the aluminum levels in the central and peripheral areas of breast carcinomas with those in the adjacent normal breast tissues, and to identify patient and/or tumor characteristics associated with these aluminum levels. METHODS: A total of 176 patients with breast cancer were included in the study. Samples from the central and peripheral areas of their tumors were obtained, as well as from the surrounding normal breast tissue. Aluminum quantification was performed using GFAAS. RESULTS: The average (mean ± SD) aluminum concentrations were as follows: central area, 1.88 ± 3.60 mg/kg; peripheral area, 2.10 ± 5.67 mg/kg; and normal area, 1.68 ± 11.1 mg/kg. Overall and two-by-two comparisons of the aluminum concentrations in these areas indicated no significant differences. We detected a positive relationship between aluminum levels in the peripheral areas of the tumors, age and menopausal status of the patients (P = .02). CONCLUSIONS: Using a sensitive quantification technique we detected similar aluminum concentrations in the central and peripheral regions of breast tumors, and in normal tissues. In addition, we did not detect significant differences in aluminum concentrations as related to the location of the breast tumor within the breast, or to other relevant tumor features such as stage, size and steroid receptor status. The next logical step is the assessment of whether the aluminum concentration is related to the key genomic abnormalities associated with breast carcinogenesis.

Randomized control trial: evaluating aluminum-based antiperspirant use, axilla skin toxicity, and reported quality of life in women receiving external beam radiotherapy for treatment of Stage 0, I, and II breast cancer.

PURPOSE: Standard skin care instructions regarding the use of antiperspirants during radiotherapy to the breast varies across North America. Women have articulated that when instructed to not use antiperspirant, the potential for body odor is distressing. Historical practices and individual opinions have often guided practice in this field. The present study had 2 purposes. To evaluate whether the use of aluminum-based antiperspirant while receiving external beam radiotherapy for stage 0, I, or II breast cancer will increase axilla skin toxicity and to evaluate whether the use of antiperspirant during external beam radiotherapy improves quality of life. METHODS: A total of 198 participants were randomized to either the experimental group (antiperspirant) or control group (standard care-wash only). The skin reactions in both groups were measured weekly and 2 weeks after treatment using the National Cancer Institute Common Toxicity Criteria Adverse Events, version 3, toxicity grading criteria. Both groups completed the Functional Assessment for Chronic Illness Therapy's questionnaire for the breast population quality of life assessment tool, with additional questions evaluating the effect of underarm antiperspirant use on quality of life before treatment, immediately after treatment, and 2 weeks after treatment during the study. RESULTS: The skin reaction data were analyzed using the generalized estimating equation. No statistically significant difference was seen in the skin reaction between the 2 groups over time. The quality of life data also revealed no statistically significant difference between the 2 groups over time. CONCLUSIONS: Data analysis indicates that using antiperspirant routinely during external beam radiotherapy for Stage 0, I, or II breast cancer does not affect the intensity of the skin reaction or the self-reported quality of life. This evidence supports that in this particular population, there is no purpose to restrict these women from using antiperspirants during their treatment, and the decision to use an antiperspirant or not in this setting should be left to the discretion of the patient.

Patterns of aluminum hydroxychloride deposition onto the skin.

BACKGROUND: Aluminum hydroxychloride (AlCl(3) ) is an antiperspirant. AIM: To revisit the AlCl(3) deposition in vivo and in vitro on glass slides and stratum corneum (SC) harvested by cyanoacrylate skin surface strippings (CSSS). METHODS: Transepidermal water loss (TEWL) was assessed following application of 5% AlCl(3) on the forearms. The AlCl(3) -coated skin, glass slides and CSSS were observed using two ultraviolet light-emitting CCD cameras in order to record changes in specular reflectance related to AlCl(3) deposition. In addition, the corneoxenometry bioassay was performed in order to predict AlCl(3) irritation. RESULTS: AlCl(3) deposited on glass slides looked as linear threads and rings of similar sizes. AlCl(3) deposits on skin were almost restricted inside the microrelief lines and as annular deposits at their crossings where acrosyringia are opening. After daily AlCl(3) applications, deposits extended on the CSSS plateaus. At rest in absence of sweating, TEWL was decreased following AlCl(3) applications. During physical exercise, the TEWL increase was limited on the AlCl(3) areas. CSSS appeared unreactive to AlCl(3) at the corneoxenometry bioassay. CONCLUSION: The similar aspect of AlCl(3) deposits on human SC and on glass slides suggested a physical property of AlCl(3) . Repetitive applications of AlCl(3) increased both the deposit area and the barrier function.