Updated Aluminum pharmacokinetics following infant exposures through diet and vaccines

ArticleinVaccine 29(51):9538-43 · November 2011with 1,086 Reads 
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Abstract
Aluminum is a ubiquitous element that is released naturally into the environment via volcanic activity and the breakdown of rocks on the earth's surface. Exposure of the general population to aluminum occurs primarily through the consumption of food, antacids, and buffered analgesics. Exposure to aluminum in the general population can also occur through vaccination, since vaccines often contain aluminum salts (frequently aluminum hydroxide or aluminum phosphate) as adjuvants. Because concerns have been expressed by the public that aluminum in vaccines may pose a risk to infants, we developed an up-to-date analysis of the safety of aluminum adjuvants. Keith et al. [1] previously analyzed the pharmacokinetics of aluminum for infant dietary and vaccine exposures and compared the resulting body burdens to those based on the minimal risk levels (MRLs) established by the Agency for Toxic Substances and Disease Registry. We updated the analysis of Keith et al. [1] with a current pediatric vaccination schedule [2]; baseline aluminum levels at birth; an aluminum retention function that reflects changing glomerular filtration rates in infants; an adjustment for the kinetics of aluminum efflux at the site of injection; contemporaneous MRLs; and the most recent infant body weight data for children 0-60 months of age [3]. Using these updated parameters we found that the body burden of aluminum from vaccines and diet throughout an infant's first year of life is significantly less than the corresponding safe body burden of aluminum modeled using the regulatory MRL. We conclude that episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns.

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  • ... In this paper, we will show that Al is harmful to the CNS, acting in a number of deleterious ways and across multiple levels, to induce biosemiotic entropy [17]. A countervailing view exists [18][19][20], but the assertions of safety are invariably based on weak epidemiological designs, ones that overwhelm significant negative signals with irrelevant noise factors. Such studies that fail to detect significant negative outcomes neither stand up to rigorous scrutiny nor outweigh better designed research, in a vast and growing literature, showing significant negative impacts sustaining the central hypothesis of this paper. ...
    ... Al is used extensively in food processing, for example, in Al-mordanted dye lakes for food coloring, in coatings for pharmaceutical tablets and vitamin capsules, for emulsifying, as a rising agent, to thicken gravies, and in meat-binders, stabilizing agents and texturizers [18]. Even drinking water is a source of Al exposure, although the amount contained in drinking water is typically far below concentrations in common antacids [21]. ...
    ... Among the CNS problems in humans attributed to Al are dialysis associated encephalopathy (DAE) [32,62], autism spectrum disorders [9,63,64], Alzheimer's disease, Parkinson's disease, and related dementias [28,36] including those typical in Down syndrome [18]. Experimental and clinical data show the CNS as the most sensitive organ system negatively impacted by Al. ...
    Article
    Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth’s crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed. (PDF) Aluminum-induced entropy in biological systems: Implications for neurological disease. Journal of Toxicology, 2014, Article ID 491316, 27 pages, 2014. doi:10.1155/2014/491316.. Available from: https://www.researchgate.net/publication/333582751_Aluminum-induced_entropy_in_biological_systems_Implications_for_neurological_disease_Journal_of_Toxicology_2014_Article_ID_491316_27_pages_2014_doi1011552014491316 [accessed Jun 03 2019].
  • ... Several known methods exist for pediatric dosing by weight. In Clark's Rule [28][29][30][31][32][33][34][35][36][37][38][39] of pediatric dose calculations, for example, the adult body weight reference is usually (as published) considered to be 150 bs. (68 kg) with the calculated dose being converted to mg/kg. ...
    ... Mitkus et al. [32]'s calculations were based on the day/week propagated error. Mitkus et al. [32] published their study in 2011 when the PTWI was still at 1 mg/kg, further propagating the day/week error. ...
    ... Mitkus et al. [32]'s calculations were based on the day/week propagated error. Mitkus et al. [32] published their study in 2011 when the PTWI was still at 1 mg/kg, further propagating the day/week error. Thus, current assessments of aluminum accumulation from vaccination and dietary exposures are not correct. ...
    Article
    Full-text available
    FDA regulations require safety testing of constituent ingredients in drugs (21 CFR 610.15). With the exception of extraneous proteins, no component safety testing is required for vaccines or vaccine schedules. The dosing of aluminum in vaccines is based on the production of antibody titers, not safety science. Here we estimate a Pediatric Dose Limit that considers body weight. We identify several serious historical missteps in past analyses of provisional safe levels of aluminum in vaccines, and provide updates relevant to infant aluminum exposure in the pediatric schedule considering pediatric body weight. When aluminum doses are estimated from Federal Regulatory Code given body weight, exposure from the current vaccine schedule are found to exceed our estimate of a weight-corrected Pediatric Dose Limit. Our calculations show that the levels of aluminum suggested by the currently used limits place infants at risk of acute, repeated, and possibly chronic exposures of toxic levels of aluminum in modern vaccine schedules. Individual adult exposures are on par with Provisional Tolerable Weekly Intake “limits”, but some individuals may be aluminum intolerant due to genetics or previous exposures. Vaccination in neonates and low birth-weight infants must be re-assessed; other implications for the use of aluminum-containing vaccines, and additional limitations in our understanding of neurotoxicity and safety levelsof aluminum in biologics are discussed. Project page: http://ipaknowledge.org/Pediatric-Dosing-of-Aluminum.php
  • ... Le stesse agenzie sarebbero state ben consigliate di ordinare studi tossico-cinetici complementari al fine di evitare la propagazione di informazioni azzardate sulla rapida eliminazione degli adiuvanti a base di allumino [54], specialmente dopo che essi sono diventati consapevoli di studi successivi che mostrano la fagocitosi, la persistenza intracellulare, la migrazione a distanza e la neurotossicità degli adiuvanti a base di alluminio [21,50,69,70]. [73,74] Due studi hanno messo a confronto l'impatto teorico negli infanti dell'alluminio assunto con la dieta e dell'alluminio di derivazioni vaccinica [73,74]. Il principio dei due studi è simile: questi sono calcoli teorici basati sull'assunzione e l'escrezione dell'alluminio dalla nascita fino a 12 mesi di età. ...
    ... Le stesse agenzie sarebbero state ben consigliate di ordinare studi tossico-cinetici complementari al fine di evitare la propagazione di informazioni azzardate sulla rapida eliminazione degli adiuvanti a base di allumino [54], specialmente dopo che essi sono diventati consapevoli di studi successivi che mostrano la fagocitosi, la persistenza intracellulare, la migrazione a distanza e la neurotossicità degli adiuvanti a base di alluminio [21,50,69,70]. [73,74] Due studi hanno messo a confronto l'impatto teorico negli infanti dell'alluminio assunto con la dieta e dell'alluminio di derivazioni vaccinica [73,74]. Il principio dei due studi è simile: questi sono calcoli teorici basati sull'assunzione e l'escrezione dell'alluminio dalla nascita fino a 12 mesi di età. ...
    ... Le limitazioni e le imperfezioni metodologiche del modello di Keith et al. [74] hanno giustificato il seguente studio di Mitkus et al. [73]. Mitkus • Mancata presa in considerazione dell'immaturità della filtrazione glomerulare nell'infante che potrebbe influire negativamente sulla rimozione dell'alluminio [73]; dovrebbe essere notato che la questione del la barriera emato-encefalica non è stata presa in considerazione anche se lo sviluppo del sistema nervoso è notoriamente sensibile alle esposizioni tossiche [80]. ...
  • ... According to Priest, it does not allow to predict the aluminium concentrationtime profile, e.g. in plasma. The long-term retention of aluminium for a single subject was further described by a three-component exponential function (Priest, 2004), and reinterpreted as an empirical 3-compartment model by Mitkus et al. (2011). To a variable extent the models are able to predict retention in the body and plasma concentration. ...
    ... Currently, such an assessment would be limited by a number of uncertainties, e.g., regarding tissue distribution (e.g., resulting from potential differences in receptor expression), differences in bone or brain uptake between children and adults (due to growth), etc. In the past, some authors tried to predict the bioburden in infants by vaccination in comparison with exposure from other sources, like breast milk or instant formulas (Keith et al., 2002;Mitkus et al., 2011). Their simulations focussed solely on the retention of aluminium in the body. ...
    ... Once absorbed, renal elimination of soluble Al3þ (citrate) from plasma is expected to occur rapidly, mainly via filtration by the kidneys. Values of 0.41 (Mitkus et al., 2011) and 0.6 per h (Priest, 2004) for the elimination rate constant from the total plasma compartment (ke) have been estimated. These are in line with short half lifes for renal excretion of about 1e4 h. ...
    As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously re-evaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment.
  • ... • At the end of the study, the authors insist on the absence of terminal phase in the curve of plasma concentrations, that is to say of terminal phase of blood absorption of 26 Al. Examination of the same curves by the Mitkus et al. [73] indicated that, in fact, the passage of 26 Al into the blood had initiated the terminal phase for Al phosphate and was already very close to zero for Al hydroxide on the 28th day of the study (Fig. 1A). For Al hydroxide, the plasma levels of 26 Al were very low since the 100th hour and absorption in blood further decreased from the 400th to the 700th hour, indicating an extremely low Al plasma passage after the initial peak observed from 0 to 48 h. ...
    ... Al vaccine administered to infants [73,74] Two studies compared the theoretical impact of dietary Al and vaccine-derived Al in infants [73,74]. The principle of the two studies is similar: these are theoretical calculations based on the intake and excretion of aluminum from birth to 12 months. ...
    ... Al vaccine administered to infants [73,74] Two studies compared the theoretical impact of dietary Al and vaccine-derived Al in infants [73,74]. The principle of the two studies is similar: these are theoretical calculations based on the intake and excretion of aluminum from birth to 12 months. ...
    Article
    Full-text available
    We reviewed the three toxicokinetic reference studies commonly used to suggest that aluminum (Al)-based adjuvants are innocuous. A single experimental study was carried out using isotopic 26Al (Flarend et al., Vaccine, 1997). This study used aluminum salts resembling those used in vaccines but ignored adjuvant uptake by cells that was not fully documented at the time. It was conducted over a short period of time (28days) and used only two rabbits per adjuvant. At the endpoint, Al elimination in the urine accounted for 6% for Al hydroxide and 22% for Al phosphate, both results being incompatible with rapid elimination of vaccine-derived Al in urine. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to an oral "minimal risk level" (MRL) extrapolated from animal studies. Keith et al. (Vaccine, 2002) used a high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (Vaccine, 2011) only considered solubilized Al, with erroneous calculations of absorption duration. Systemic Al particle diffusion and neuro-inflammatory potential were omitted. The MRL they used was both inappropriate (oral Al vs. injected adjuvant) and still too high (1mg/kg/d) regarding recent animal studies. Both paucity and serious weaknesses of reference studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including both neonatal and adult exposures, to ensure their safety and restore population confidence in Al-containing vaccines.
  • ... In this paper, we will show that Al is harmful to the CNS, acting in a number of deleterious ways and across multiple levels, to induce biosemiotic entropy [17]. A countervailing view exists [18][19][20], but the assertions of safety are invariably based on weak epidemiological designs, ones that overwhelm significant negative signals with irrelevant noise factors. Such studies that fail to detect significant negative outcomes neither stand up to rigorous scrutiny nor outweigh better designed research, in a vast and growing literature, showing significant negative impacts sustaining the central hypothesis of this paper. ...
    ... Al is used extensively in food processing, for example, in Al-mordanted dye lakes for food coloring, in coatings for pharmaceutical tablets and vitamin capsules, for emulsifying, as a rising agent, to thicken gravies, and in meat-binders, stabilizing agents and texturizers [18]. Even drinking water is a source of Al exposure, although the amount contained in drinking water is typically far below concentrations in common antacids [21]. ...
    ... Among the CNS problems in humans attributed to Al are dialysis associated encephalopathy (DAE) [32,62], autism spectrum disorders [9,63,64], Alzheimer's disease, Parkinson's disease, and related dementias [28,36] including those typical in Down syndrome [18]. Experimental and clinical data show the CNS as the most sensitive organ system negatively impacted by Al. ...
    Article
    Full-text available
    Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth’s crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.
  • ... As very high doses of aluminium can be toxic, safe aluminium compounds concentrations limits were clearly defined as 2 mg/kg per day. It should be emphasized, that exposure to aluminium content in vaccines is substantially lower than exposure originating from a diet (16), despite the fact that aluminium compounds in vaccines do not pass through the gastrointestinal tract, which is a significant barrier (17). ...
    ... Safety of vaccines used according to the immunization program was confirmed by pharmacokinetic studies conducted by the US Food and Drug Administration (FDA), where the estimated risk for infants was found extremely low (17). These results finally updated the results of previously performed studies on aluminium toxicokinetics (27) where half-life of elimination of aluminium from the body was estimated approximately as 24 hours. ...
    Article
    Full-text available
    Since decades aluminium formulations such as aluminium hydroxide and aluminium phosphate are widely used as adjuvants in vaccines for human use. They increase immune response induced by the vaccine antigens by mechanisms eg. a depot effect at the injection site, activation of the complement and stimulation of the macrophages. Many studies, both case control ones and those performed in vivo on animal models, confirmed the safety of aluminium adjuvants even in vaccinated infants and children. Although some of the aluminium-adjuvanted vaccines have certain limitations such as no Th1 reactivity and low stability at temperatures below 2ºC, its easy use, safety profile and low manufacturing costs confirm its suitability.
  • ... In sharp contrast to the quick elimination of soluble Al injected intravenously [93], intramuscular injection of isotopic Al hydroxide is associated with much slower elimination of Al in urine, accounting for 6% of the injected dose 28 days after injection in rabbits [94]. Based on data of this unique experimental toxicokinetic study, the duration for complete translocation of solubilized Al ions from the injected site to blood was calculated to be 5.5 months for Al hydroxide [95]. Consistently, experimental MMF invariably shrinks over time [91]. ...
    ... In addition, theo retical models based on Flarend's pre-conceptions and short-term results are flawed [7]. For example, Mitkus et al. [95] proposed a model to assess the risk of Al vaccines in infants, by reference to an oral minimal risk level (MRL) extrapolated from animal studies. They only considered solubilized Al, with erroneous calculations of absorption duration. ...
    Article
    Full-text available
    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial and poorly undersood disabling disease. We present epidemiological, clinical and experimental evidence that ME/CFS constitutes a major type of adverse effect of vaccines, especially those containing poorly degradable particulate aluminum adjuvants. Evidence has emerged very slowly due to the multiplicity, lack of specificity, delayed onset, and frequent medical underestimation of ME/CFS symptoms. It was supported by an epidemiological study comparing vaccinated vs unvaccinated militaries that remained undeployed during Gulf War II. Affected patients suffer from cognitive dysfunction affecting attention, memory and inter-hemispheric connexions, well correlated to brain perfusion defects and associated with a stereotyped and distinctive pattern of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically yields macrophagic myofasciitis (MMF), a histological biomarker assessing longstanding persistency of aluminum agglomerates within innate immune cells at site of previous immunization. MMF is seemingly linked to altered mineral particle detoxification by the xeno/autophagy machinery. Comparing toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have turned old dogma upside down. Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity. Clinical observations and experiments in sheep, a large animal like humans, confirmed both systemic diffusion and neurotoxic effects of aluminum adjuvants. Post-immunization ME/CFS represents the core manifestation of “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA).
  • ... Examples of these additional nonantigen vaccine ingredients include formaldehyde, antibiotics, aluminum, squalene, and monosodium l-glutamate. Although evidence from animal studies, pharmacokinetic modeling, observational studies, and clinical investigations support the safety of ingredients in currently licensed vaccines [2][3][4][5], some parents cite vaccine ingredients as a safety concern. These concerns may be contributing to increased rates of undervaccination and adoption of alternative immunizations schedules across the United States [6][7][8][9][10]. ...
    ... Aluminum is the third most abundant element on earth, after oxygen and silicon. Food, antacids, buffered analgesics, infant formula and breast milk are common sources of aluminum exposure in the general population [1,4,[24][25][26]. In vaccines, aluminum salts (aluminum hydroxide, aluminum phosphate) have been used as adjuvants for more than 70 years [27,28]. ...
    Article
    Background: In addition to antigens, vaccines contain small amounts of preservatives, adjuvants, and residual substances from the manufacturing process. Some parents have concerns about the safety of these ingredients, yet no large epidemiological studies have specifically examined associations between health outcomes and vaccine ingredients, other than thimerosal. This study examined the extent to which the Vaccine Safety Datalink (VSD) could be used to study vaccine ingredient safety in children. Methods: Children born 2004-2011 were identified in VSD data. Using immunization records, two cohorts were identified: children who were up-to-date and children who were undervaccinated before age 2 years. A database was also created linking vaccine type and manufacturer with ingredient amounts documented in vaccine package inserts. Thirty-four ingredients in two or more infant vaccines were identified. However, only amounts (in mg) for aluminum were consistently documented and commonly contained in infant vaccines. Analyses compared vaccine aluminum exposure across cohorts and determined the statistical power for studying associations between aluminum exposure and hypothetical vaccine adverse events. Results: Among 408,608 children, mean cumulative vaccine aluminum exposure increased from 1.11 to 4.00mg between ages 92-730 days. Up-to-date children were exposed to 11-26% more aluminum from vaccines than undervaccinated children. Power analyses demonstrated that safety studies of aluminum could detect relative risks ranging from 1.1 to 5.8 for a range of adverse event incidence. Conclusions: The safety of vaccine aluminum exposure can be feasibly studied in the VSD. However, possible biological mechanisms and confounding variables would need to be considered before conducting any studies.
  • ... The only processed food that he had on a regular basis were infant formulas (Aptimal brand). Mitkus et al. 11 estimated the body burden of aluminum during the first 400 days of life for infants on formula diets and for a standard vaccination schedule, and the estimates show that the burden of aluminum from vaccinations exceeds that from dietary sources. 11 The child's aluminum containing vaccinations were: Infanrix DTPa-IPV+Hib (4 doses at 500 μg aluminum per dose), Prevenar13 (3 doses at 125 μg aluminum per dose), NeisVac-C Baxter (1 dose at 500 μg aluminum per dose). ...
    ... Mitkus et al. 11 estimated the body burden of aluminum during the first 400 days of life for infants on formula diets and for a standard vaccination schedule, and the estimates show that the burden of aluminum from vaccinations exceeds that from dietary sources. 11 The child's aluminum containing vaccinations were: Infanrix DTPa-IPV+Hib (4 doses at 500 μg aluminum per dose), Prevenar13 (3 doses at 125 μg aluminum per dose), NeisVac-C Baxter (1 dose at 500 μg aluminum per dose). The child was also vaccinated with Priorix (2 doses) but this vaccine does not contain an aluminum adjuvant. ...
  • ... Deux études ont comparé l'impact théorique de l'aluminium alimentaire et vaccinal chez le nourrisson [71,72]. Le principe des deux études est similaire : il s'agit de calculs théoriques fondés sur l'apport et l'excrétion d'aluminium de la naissance à 12 mois. ...
    ... (Tableau 1) [76]. Ce chiffre est un maximum du fait de l'utilisation possible de divers vaccins multivalents ; • abaissement ultérieur du niveau de sécurité, le MRL par voie orale passant à 1 mg Al/kg/j en 2008 [76] ; • non-prise en compte de l'immaturité de la fonction de filtration glomérulaire chez le nourrisson pouvant influer sur l'élimination de l'aluminium absorbé [71] ; il faut noter que la question de la barrière hémato-encéphalique n'a pas non plus été prise en compte alors que le développement du système nerveux est notoirement sensible aux expositions toxiques [78]. La question de l'immaturité de la barrière hémato-encéphalique (BHE) est une question importante en matière de toxicologie des adjuvants aluminiques. ...
    Article
    Full-text available
    We reviewed the three reference toxicokinetic studies commonly used to suggest innocuity of aluminum (Al)-based adjuvants. A single experimental study was carried out using isotopic ²⁶Al (Flarend et al., 1997). This study ignored adjuvant cell capture. It was conducted over a short period of time (28 days) and used only two rabbits per adjuvant. At the endpoint, Al retention was 78% for aluminum phosphate and 94% for aluminum hydroxide, both results being incompatible with quick elimination of vaccine-derived Al in urines. Tissue distribution analysis omitted three important retention sites: the injected muscle, the draining lymph node and bone. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to the oral Minimal Risk Level (MRL) extrapolated from animal studies. Keith et al., 2002 used a too high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (2011) only considered absorbed Al, with erroneous calculations of absorption duration. They ignored particulate Al captured by immune cells, which play a role in systemic diffusion and the neuro-inflammatory potential of the adjuvant. MRL they used was both inappropriate (oral Al vs injected adjuvant) and far too high (1mg/kg/d) with regard to experimental studies of Al-induced memory and behavioral changes. Both paucity and serious weaknesses of these studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including post-natal and adult exposures, to ensure innocuity and restore population confidence in Al-containing vaccines. Copyright © 2017 Académie Nationale de Pharmacie. All rights reserved.
  • ... Adjuvants licensed for human use are coadministered in all except live vaccines, to enhance immunogenicity [20], and International Journal of Rheumatology 3 mostly consist of aluminium phosphate/hydroxide, oil in water emulsions (squalene), and liposomes [21]. Aluminium in vaccines and diet has been convincingly shown to lack adverse effects in infants in the first year of life [22] but aluminium itself, squalene, and all other currently used adjuvants have been associated with autoimmunity in a recent collection of reports grouping gulf war syndrome, siliconosis, macrophagic myofasciitis, and postvaccination syndrome collectively known as ASIA, autoimmune/inflammatory syndrome. In ASIA, the causative role of adjuvants is based on experimental models for which several immune-mediated mechanisms have been proposed [23]. ...
    Article
    Full-text available
    In the wake of the Portuguese vaccination program 50th anniversary it seems appropriate to review vaccination in patients with systemic lupus erythematosus. Controversial issues as regards the association between autoimmune diseases, infections, and vaccines are discussed as well as vaccine safety and efficacy issues as regards chronic immunosuppressant (IS) drug therapy. After a brief overview of national policies, specific recommendations are made as regards vaccination for adult patients with SLE with a particular focus on current IS therapy and unmet needs.
  • ... As a vaccine component, aluminum has been extensively tested for safety as part of pre-licensure clinical trials. We know from studies examining the aluminum exposure of infants that the cumulative amount of aluminum from vaccines in the first 6 months of life is actually far less than that received from dietary sources, including both breast milk and formula (Keith et al., 2002;Mitkus et al., 2011). Both sources represent far less exposure than that represented by a regulatory minimal risk level (MRL), which is established by the Agency for Toxic Substances and Disease Registry. ...
    Article
    Full-text available
    The World Health Organization has named vaccine hesitancy as one of the top ten threats to global health in 2019. The reasons why people choose not to vaccinate are complex, but lack of confidence in vaccine safety, driven by concerns about adverse events, has been identified as one of the key factors. Healthcare workers, especially those in primary care, remain key influencers on vaccine decisions. It is important, therefore, that they be supported by having easy access to trusted, evidence-based information on vaccines. Although parents and patients have a number of concerns about vaccine safety, among the most common are fears that adjuvants like aluminum, preservatives like mercury, inactivating agents like formaldehyde, manufacturing residuals like human or animal DNA fragments, and simply the sheer number of vaccines might be overwhelming, weakening or perturbing the immune system. As a consequence, some fear that vaccines are causing autism, diabetes, developmental delays, hyperactivity, and attention-deficit disorders, amongst others. In this review we will address several of these topics and highlight the robust body of scientific evidence that refutes common concerns about vaccine safety.
  • ... 4 An infant may receive about four milligrams of aluminum from vaccinations during the first year of his or her life. 5 However, the website omits the fact that infants may also receive about 7 milligrams of aluminum from nursing, as it is found naturally in breast milk. 6 It also fails to mention that adults ingest 7 to 9 mg of aluminum per day. ...
  • ... And the clinical symptoms in patients diagnosed with MMF "are considered to be due to separate, coincidental immune or neurological disorders that are unrelated to the presence of aluminum in vaccines." 54 The Global Advisory Committee on Vaccine Safety, established by WHO, welcomed the FDA's analysis endorsing the safety of aluminum in vaccines. 63 The CDC vigorously defends the presence of aluminum in vaccines as well. ...
    Article
    Full-text available
    Aluminum is a neurotoxin, yet infants and young children are repeatedly injected with aluminum adjuvants from multiple vaccines during critical periods of brain development. Numerous studies provide credible evidence that aluminum adversely affects important biological functions and may contribute to neurodegenerative and autoimmune disorders. It is impossible to predetermine which vaccinated babies will succumb to aluminum poisoning. Aluminum-free health options are needed.
  • ... soluble aluminium and other routes of exposure, may not represent valid approaches. For example, aluminium retention rate observed after intravenous injections of traceable soluble aluminium citrate (Priest, 2004) has been used to set up the reassuring infant retention model of aluminium adjuvants (Mitkus et al., 2011). This model was based on the hypothesis that aluminium adjuvants are solubilized by citrate ions in muscle interstitial fluid (Flarend et al., 1997), without any consideration of quick adjuvant cellular uptake and systemic long term diffusion of adjuvant agglomerates (Khan et al., 2013;Eidi et al., 2015). ...
    Article
    Aluminium (Al) oxyhydroxide (Alhydrogel®), the main adjuvant licensed for human and animal vaccines, consists of primary nanoparticles that spontaneously agglomerate. Concerns about its safety emerged following recognition of its unexpectedly long-lasting biopersistence within immune cells in some individuals, and reports of chronic fatigue syndrome, cognitive dysfunction, myalgia, dysautonomia and autoimmune/inflammatory features temporally linked to multiple Al-containing vaccine administrations. Mouse experiments have documented its capture and slow transportation by monocyte-lineage cells from the injected muscle to lymphoid organs and eventually the brain. The present study aimed at evaluating mouse brain function and Al concentration 180 days after injection of various doses of Alhydrogel® (200, 400 and 800 μg Al/kg of body weight) in the tibialis anterior muscle in adult female CD1 mice. Cognitive and motor performances were assessed by 8 validated tests, microglial activation by Iba-1 immunohistochemistry, and Al level by graphite furnace atomic absorption spectroscopy.
  • ... Extrapolating mouse to human dosage is a challenging issue since a firm scientific basis for allometric conversion is still lacking. To approximate human to mouse dosage for aluminum studies, a conversion factor of ×30 is used by the Agency for Toxic Substances and Disease Registry [21] and by the US Food and Drug Administration [22]. Since ASIA usually occurs after multiple aluminum-containing vaccine administrations (up to 12 injectionsnot restricted to a single vaccine-in our experience [23]) administration Autoimmunity Reviews xxx (2018) xxx-xxx AUTREV-02167; No of Pages 3 of important doses may not be so unrealistic. ...
  • ... As stated in text, dosage was determined following the recommendations of the French drug safety agency AFSSAPS (now called ANSM). Of note, the conversion factor of x12.3 used to approximate human to mouse dosage is far lower than the x30 factor used by the Agency for Toxic Substances and Disease Registry (Keith et al., 2002) and by the US Food and Drug Administration (Mitkus et al., 2011). Furthermore, when Hawkes and Benhamu indicate we say that "Engerix vaccine contains 500 μg of Alhydrogel", Hawkes and Benhamu do not cite us correctly and apparently make no difference between the dose of the whole molecule (Alhydrogel: AlOOH) and the dose of Al. ...
  • ... Aluminum adjuvants are present in vaccines against hepatitis A, hepatitis B, diphtheria-tetanus-pertussis (DTaP), Haemophilus influenzae type b (Hib), human papillomavirus (HPV) and pneumococcus infectious agents (Center for Disease Control, mg of aluminum present as aluminum phosphate (HogenEsch et al., 2018). It is thought that the amount of aluminum found in these vaccines poses a low risk of harm compared to its benefits (Mitkus et al., 2011). In the present study, we used 10-100 µg/mL concentrations which are in the range used by other investigators to assess the in vitro response to ABAs (Ulanova et al., 2001;Mold et al., et al., 2016;Vrieling et al., 2020). ...
    Article
    Aluminum-based adjuvants (ABAs) are used in human vaccines to enhance the magnitude of protective immune responses elicited against specific pathogens. One hypothesis is that stress signals released by aluminum-exposed necrotic cells play a role in modulating an immune response that contributes to the adjuvant’s effectiveness. We hypothesized that aluminum adjuvant-induced necrosis would be similar irrespective of cellular origin or composition of the adjuvant. To test this hypothesis, human macrophages derived from peripheral monocytic cell line (THP-1) and cells derived from the human brain (primary astrocytes) were evaluated. Three commercially available formulations of ABAs (Alhydrogel, Imject alum, and Adju-Phos) were examined. Alum was also used as a reference. Cell viability, reactive oxygen species formation, and production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) were quantified. Cells were exposed to different concentrations (10-100 µg/mL) of the adjuvants for 24 h or 72 h. The two FDA approved adjuvants (Alhydrogel and Adju-Phos) decreased cell viability in both cell types. At the 72 h time point, the decrease in viability was accompanied with increased ROS formation. The size of the aluminum agglomerates was not relatable to the changes observed. After exposure to ABAs, astrocytes and macrophages presented a distinct profile of cytokine secretion which may relate to the function and unique characteristics of each cell type. These variations indicate that aluminum adjuvants may have differing capability of activating cells of different origin and thus their utility in specific vaccine design should be carefully assessed for optimum efficacy.
  • ... Interestingly, a previous study showed that boiling acidic food such as fruits in aluminum pots could induce chemical corrosion and release of aluminum from the pots into food [27]. Furthermore, Al-containing adjuvants were used in several vaccines routinely injected to infants and young children such as diphtheria-tetanus-acellular pertussis (DTP) vaccine, haemophilus influenza type b vaccine, hepatitis B vaccine, and pneumococcal vaccine [28]. Unfortunately, the toxicity of Al in vaccines is still subject of debate [29]. ...
    Article
    Toxic element exposure increases risk of neurodevelopmental disorders. However, hair element profiles of well-nourished urban resident children were largely unknown. We identified prevalence and the contributing factors of high hair aluminum (Al), arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg) levels in 111 Thai children (aged 3–7 years old). Most participants were well-nourished with high socioeconomic status. Since ROC curve of hair element data showed inadequate sensitivity for cutoff set-up, US reference hair levels were used to categorize high and low level groups. Nevertheless, compared to the current reference at 5 μg/dL, blood lead cutoff at 2.15 μg/dL provided more consistent results with that of hair lead levels. High As and Pb levels were the first and second most prevalent element, while Al was the element found in highest amount in hair. High hair Al (12% prevalence) levels were associated with being male regardless of age or nutritional status. High hair As levels were associated with living in Bangkok (OR = 6.57) regardless of school type. High hair Pb levels were associated with being under 5 years old and living in Bangkok (OR = 3.06). However, no associations were found between blood Pb, hair Cd, Hg, and tested factors. These findings suggested that under 5-year-old boys living in capital city like Bangkok may be at risk of exposure to multiple toxic elements. Future studies in these children are warranted to identify their exposure sources and proper risk management strategies.
  • ... This study explored the ability of a biomaterial that concentrates antigen-specific T H 2 memory T cells, already formed with previous vaccinations, to promote blood perfusion recovery of ischemic tissue. Virtually all persons born in the United States have received childhood vaccinations recommended by the Centers for Disease Control and Prevention, such as those for DTaP (diphtheria, tetanus, and pertussis) and hepatitis B, that contain aluminum, a potent T H 2 adjuvant (22,23). A biomaterial that provides localized release of antigen specific to these T H 2 memory T cells at later times in these patients may transiently recruit and activate these cells to produce cytokines at sites of ischemia and promote vascularization. ...
    Article
    Full-text available
    Ischemic diseases are a leading cause of mortality and can result in autoamputation of lower limbs. We explored the hypothesis that implantation of an antigen-releasing scaffold, in animals previously vaccinated with the same antigen, can concentrate T H 2 T cells and enhance vascularization of ischemic tissue. This approach may be clinically relevant, as all persons receiving childhood vaccines recommended by the Centers for Disease Control and Prevention have vaccines that contain aluminum, a T H 2 adjuvant. To test the hypothesis, mice with hindlimb ischemia, previously vaccinated with ovalbumin (OVA) and aluminum, received OVA-releasing scaffolds. Vaccinated mice receiving OVA-releasing scaffolds locally concentrated antigen-specific T H 2 T cells in the surrounding ischemic tissue. This resulted in local angiogenesis, increased perfusion in ischemic limbs, and reduced necrosis and enhanced regenerating myofibers in the muscle. These findings support the premise that antigen depots may provide a treatment for ischemic diseases in patients previously vaccinated with aluminum-containing adjuvants.
  • ... An infant will be exposed to a maximum of 1.2 mg of aluminium in any 60-day period during the first year of life. Several studies [43,44] have examined infant exposure to aluminium and determined that vaccinations do not raise aluminium levels to even the minimal risk levels. It is clear that the doses needed for toxicity are vastly greater than those delivered through vaccination. ...
    Article
    Full-text available
    In 2011 Shoenfeld and Agmon-Levin proposed a new syndrome as a way of grouping together a range of emerging autoimmune diseases with possible adjuvant-associated causes, Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants (ASIA). At present, there is no evidence to suggest that ASIA syndrome is a viable explanation for unusual autoimmune diseases. Since the initial paper, over 80 publications have discussed ASIA. This systematic review examines the research that has been done to investigate whether ASIA is a broad umbrella term with little clinical significance, or whether there is some underlying mechanism which could be utilised to reduce the occurrence of adjuvant mediated disease. Twenty-seven animal, epidemiological and case studies were reviewed. Unfortunately, a robust animal model of ASIA using biologically relevant doses of adjuvants has yet to be defined. It is also apparent that the broadness of the current ASIA criteria lack stringency and, as a result, very few cases of autoimmune disease could be excluded from a diagnosis of ASIA. The current studies involving human cases are so diverse, in both external stimuli and in resulting conditions, that there is currently a lack of reproducible evidence for any consistent relationship between adjuvant and autoimmune condition. The addition of a mandatory criterion requiring temporal association and clinically relevant adjuvant dose would allow better definition of what constitutes a diagnosis of ASIA. Copyright © 2015 Elsevier Ltd. All rights reserved.
  • ... The Alum N1.9 regimen tested here mimicked the number and order of immunizations performed in RV144 and our SIV-Alum Alh study, but while the gp120 boosts were maintained at the same dose as used in SIV-Alum Alh and RV144 (200 μg each), a much lower dose of Alum N was used in Study 1 (750 μg/dose). Although the FDA and CDC approve of no more than 850 μg of Alum Alhydrogel per dose in human vaccines [37,38], we used 5,000 μg/dose in SIV-Alum Alh to compensate for the welldocumented pharmacokinetic differences among differently sized species [27]. Counterintuitively, this typically means that a drug must be administered at a higher dose in smaller animals such as macaques to obtain the same effects elicited in larger species. ...
    Article
    Full-text available
    The ALVAC-HIV clade B/AE and equivalent SIV-based/gp120 + Alum vaccines successfully decreased the risk of virus acquisition in humans and macaques. Here, we tested the efficacy of HIV clade B/C ALVAC/gp120 vaccine candidates + MF59 or different doses of Aluminum hydroxide (Alum) against SHIV-Cs of varying neutralization sensitivity in macaques. Low doses of Alum induced higher mucosal V2-specific IgA that increased the risk of Tier 2 SHIV-C acquisition. High Alum dosage, in contrast, elicited serum IgG to V2 that correlated with a decreased risk of Tier 1 SHIV-C acquisition. MF59 induced negligible mucosal antibodies to V2 and an inflammatory profile with blood C-reactive Protein (CRP) levels correlating with neutralizing antibody titers. MF59 decreased the risk of Tier 1 SHIV-C acquisition. The relationship between vaccine efficacy and the neutralization profile of the challenge virus appear to be linked to the different immunological spaces created by MF59 and Alum via CXCL10 and IL-1β, respectively.
  • ... 31 The Centers for Disease Control and Prevention cited a study in which researchers calculated the aluminum exposure from vaccines during infancy and found the total to be far below the minimal risk levels established by the Agency for Toxic Substances and Disease Registry. 32 The aluminum-containing adjuvants are reported to have minimal adverse effects but are effective at improving the antibody response. 33 There are reports of a chronic local granulomatous inflammation known as macrophagic myofasciitis in a small number of patients after receiving intramuscular vaccines containing aluminum. ...
    Article
    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.
  • ... It is also found in preservative, emulsifying agents, colorants, and baking powders. Such widespread use of Al in consumable and non consumable items will eventually lead to entry and deposition in human body, (Gura, 2010;Mitkus et al., 2011;Riihimaki and Antero, 2012;Kramer and Heath, 2014;Sjogren et al., 2015;Mahor and Ali, 2015;Exley, 2016;Jakkala et al., 2016;Weidenhamer et al., 2017;Gouda et al., 2018;Mahor and Ali et al., 2018;Yan et al., 2019). ...
  • ... De manera natural, este elemento se encuentra en algunos vegetales y especias. Igualmente, puede estar presente en desodorantes, pastas dentífricas, cementos dentales y prótesis ortopédicas 5 . ...
  • ... Further, an error led to the use of an assumed safe tolerable limit of 1 mg/day (all sources), up from 1 mg/week [5]. Important studies impacting views on the tolerable doses of aluminum were impacted as this error propagated [35]. Flaws in the designs of studies that supported current aluminum amounts in vaccines are cause for grave concerns over widespread use of aluminum in vaccines in the current CDC schedule [36]. ...
    Article
    Full-text available
    Neurodevelopmental disorders, including Autism Spectrum Disorders, have a complex biological and medical basis involving diverse genetic risk and myriad environmental exposures. Teasing apart the role of specific stressors is made challenging due to the large number of apparently contributing associations, gene X environment interactions and phenomimicry [1]. Historically, these conditions have been rare, making causality assessment at the population level infeasible. Only a few vaccines have been tested for association with autism, and it has been shown that improved diagnosis only explains a percentage of the increase in diagnosis. Now, the rates are so high in some countries that public school programs cannot handle the large numbers of special needs students, and professionals are quitting their jobs due to security concerns. Here, I review evidence of the pathophysiology of autism that reconciles the apparent paradox between the high degree of causal heterogeneity in environmental toxins, the absence of common "autism gene," and the high degree of genetic concordance (heritability) of ASD and ASD-like traits. In brief, the sampling of environmental toxins, and thus the environmental toxin sampling liability for ASD varies among families involving different local exposures following injury to normal cellular endoplasmic detoxification and mitochondrial processes from toxic metals. The literature strongly supports that autism is most accurately seen as an acquired cellular detoxification deficiency syndrome with heterogeneous genetic predisposition that manifests pathophysiologic consequences of accumulated, run-away cellular toxicity. At a more general level, it is a form of a toxicant-induced loss of tolerance of toxins, and of chronic and sustained ER overload (ER hyper stress), contributing to neuronal and glial apoptosis via the unfolded-protein response (UPR). Inherited risk of impaired cellular detoxification and circulating metal retoxification in neurons and glial cells accompanied by chronic UPR is key. This model explains the aberrant protein disorder observed in ASD; the great diversity of genes that are found to have low, but real contributions to ASD risk and the sensitivity of individuals with ASD to environmental toxins. The hindrance of detoxification and loss of cellular energetics leads to apoptosis, release of cytokines and chronic neuroinflammation and microglial activation, all observed hallmarks of ASD. Interference with the development of normal complex (redundant) synapses leads to a pathological variation in neuronal differentiation, axon and dendrite outgrowth, and synaptic protein expression. The most general outcomes are overall simplification of gross synaptic anatomy and, neurofunctionally, a loss of inhibitory feedback and aberrations in long-term connections between distant regions of the brain. Failed resolution of the ER stress response leads to re-distribution of neurotoxic metals, and the impaired neurocellular processes lead to subsequent accumulation of a variety of additional types of toxins with secondary, sometime life-threatening comorbidities such as seizures, with overlapping (not mutually exclusive) causality. Reduction of exposure to toxins known to cause mitopathy (mercury) and endoplasmic reticulum dysfunction (mercury and aluminum) during pregnancy and during the early years of development will reduce the risk of ER overload and ER hyper stress, and of ASD diagnosis. This knowledge has immediate clinical translational relevance: post-vaccination symptoms should be heeded as a sign of susceptibility to toxin; Vitamin D can be increased to drive the healthy early phases of the UPR, and mutations in ASD genes encoding proteins with high intrinsic disorder may contraindicate the use of aluminum and mercury for carriers of risk alleles. Clinicians should be alert to a patient’s Vitamin D receptor (BSM) mutational status prior to recommending increased doses. Approaches to improving overall brain health in autistics must be de-stigmatized and given high priority. Reduction of lifetime exposures of industrial and agricultural toxins will improve brain health for the entire human population. Purely genetic studies of ASD, and studies that do not include vaccination as an environmental exposure with potential liability and interactions with genes, are unethical. To qualify as science, studies must test plausible hypotheses, and the absence of association from poorly designed, unethically executed, and underpowered and unsound whole-population association studies have been harmful distractions in the quest for understanding. Skilled paediatricians and ob/gyns will seek evidence of genetic predisposition to environmental susceptibility in the form of non-synonymous substitutions in brain proteins that require ER-folding, and they will provide informed cautions on exposures (from all sources) to environmental toxins to patients and parents of patients with signs of metal and chemical sensitivity. To aid in this, a list of ASD environmental susceptibility protein-encoded genes is presented. A clinical Exome sequence test, followed by loss of function prediction analysis, would point to individuals most susceptible to vaccine metal-induced ER hyper stress leading to failed cellular detoxification.
  • ... Further, an error led to the use of an assumed safe tolerable limit of 1 mg/day (all sources), up from 1 mg/week [5]. Important studies impacting views on the tolerable doses of aluminum were impacted as this error propagated [35]. Flaws in the designs of studies that supported current aluminum amounts in vaccines are cause for grave concerns over widespread use of aluminum in vaccines in the current CDC schedule [36]. ...
  • ... However, we detected an increase in liver Cxcl1 mRNA expression, indicating that the injection of Alum can also stimulate inflammatory responses distant from the site of administration. This finding is consistent with the presence of Alum in the circulation after its i.m. injection (47,48). This suggests that when coadministered, Alum and IL-36b may circulate, reach the liver, and synergistically transiently stimulate immune cells at distance. ...
    Article
    Full-text available
    Human and mouse neonates exhibit limited vaccine responses characterized by predominant Th2 and limited Th1 responses. Because IL-36 exerts a synergic adjuvant effect with IL-12, enhancing Th1 polarization in adult (AD) mice, we administered IL-36β to neonatal (1-wk old) and AD control mice at the time of immunization with tetanus toxoid adsorbed to aluminum hydroxide (TT/Alum). Unexpectedly, the combination of IL-36β with TT/Alum, which was well tolerated in AD mice, proved toxic and even lethal in neonates. This neonatal toxicity was associated with high Il36r mRNA expression in neonatal liver, resulting in increased cytokine production. Liver Il36r mRNA expression decreased with the termination of fetal liver hematopoiesis, and this decrease correlated with a complete protection from TT/Alum/IL-36β-induced mortality. The combination of IL-36β and TT/Alum induced the rapid production of TNF-α and IFN-γ by liver myeloid and lymphoid cells, respectively. These responses were less marked when IL-36β was used alone, with no adverse effect. The toxicity of IL-36β + TT/Alum was abrogated by the administration of a neutralizing anti-TNF-α Ab, confirming causality. In conclusion, liver myeloid cells in neonatal mice are an important source of proinflammatory cytokines that may lead to TNF-α-mediated toxicity and even lethality.
  • Article
    While vaccines would ideally only need to contain the antigens necessary to induce immunity, the reality of vaccine production requires the addition of other materials, sometimes called excipients. These excipients include a wide array of additives, usually in minute concentrations. Preservatives and other related substances are required to maintain vaccine stability and potency. Adjuvants may be necessary to induce adequate protective immunity. In addition, there are other materials sometimes introduced into the final products either as a result of the manufacturing process or packaging. The excipient materials found in vaccines have been a significant source of misunderstanding, and misinformation. Much of the controversy related to vaccine safety is a result of spurious associations between these vaccine additives and exaggerations of real, or perceived, side effects from immunization. While a few of these chemicals can be toxic in large quantities, most are only present in trace amounts in most vaccines. This chapter reviews some of the more common or controversial vaccine excipients, and related information regarding safety concerns. © 2013 Springer Science+Business Media New York. All rights reserved.
  • Aluminum oxyhydroxide (Alhydrogel(®)) is a nano-crystalline compound forming aggregates that has been introduced in vaccine for its immunologic adjuvant effect in 1926. It is the most commonly used adjuvant in human and veterinary vaccines but mechanisms by which it stimulates immune responses remain ill-defined. Although generally well tolerated on the short term, it has been suspected to occasionally cause delayed neurologic problems in susceptible individuals. In particular, the long-term persistence of aluminic granuloma also termed macrophagic myofasciitis is associated with chronic arthromyalgias and fatigue and cognitive dysfunction. Safety concerns largely depend on the long biopersistence time inherent to this adjuvant, which may be related to its quick withdrawal from the interstitial fluid by avid cellular uptake; and the capacity of adjuvant particles to migrate and slowly accumulate in lymphoid organs and the brain, a phenomenon documented in animal models and resulting from MCP1/CCL2-dependant translocation of adjuvant-loaded monocyte-lineage cells (Trojan horse phenomenon). These novel insights strongly suggest that serious re-evaluation of long-term aluminum adjuvant phamacokinetics and safety should be carried out.
  • Article
    Full-text available
    Currently, efficient wound-healing materials are booming due to increasing health care costs and world population aging, but also because of a sharp increase in the incidence of diabetes and obesity. Exacting demands are placed upon modern wound-healing materials as these should affect all stages of healing by accelerating them. In this paper, we demonstrate for the first time that drug entrapped magnetite xerogels can be effectively used for this purpose. To prepare a healing biocomposite, we have combined four medicaments in a magnetite matrix: chlorhexidine digluconate as an antimicrobial agent, lidocaine as a painkiller, prednisolone as an anti-inflammatory agent and chymotrypsin as a necrolytic agent. Compared to the control group, the wound healing rate with a biocomposite exhibited a $1.5-fold increase (21 and 14 days for complete healing, respectively). Moreover application of a magnetite-based biocomposite provided strong scar size decrease. Characteristics of the magnetite matrix as well as wound-healing composite material are fully described by XRD, XPS, SEM, TEM and N 2 physisorption analysis.
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    Full-text available
  • Chapter
    More than 80 years have passed since the initial discovery that aluminum salts, when injected together with an antigen, resulted in highly elevated specific antibody titers. Since then the aluminum adjuvants have achieved an undisputed status as the most commonly used adjuvants in human and veterinary vaccines. The present chapter compiles historical data on aluminum adjuvants from the very early start and data made obtainable thanks to the development of analytical tools for providing general insight into the mechanisms of the immune system. Applying these tools in adjuvant research have helped characterizing the aluminum adjuvants in terms of isotypic profiles, surface marker expression profiles, cytokine profiles and within the latest 5 years with the discovery of the NALP3 inflammasome its importance for the secretion of interleukin (IL)-1β and IL-18 as pro-inflammatory mediators in the early phases of the immune response. For decades very little was known about the mechanisms of action of aluminum adjuvants, and their use in vaccine design was predominantly based on empirical principles. The results from applying such analytical tools are about to take us to the next level of understanding aluminum adjuvants.
  • Article
    Increased ingestion of aluminum (Al) can lead to its accumulation in the human body, especially in people with kidney problems. Al is also associated with several nervous diseases and its negative influence on embryo development during pregnancy has been proven in animal models. Hibiscus sabdariffa L. petals are widely used alone or in fruit tea formulas, which are recommended for drinking during pregnancy instead of tea. Its petals can contain similar and even higher amounts of Al as tea, which is a known Al accumulator. Our research investigated whether the regular intake of H. sabdariffa infusion leads to increased burden of Al. Sixteen days of ingestion of H. sabdariffa infusion (c Al = 0.5 mg.L−1) led to increased but unbalanced levels (15–86 μg L−1) of Al in urine compared to a period when the infusion was not ingested. The highest amounts of Al excreted were observed every third day during the ingestion. Mild health problems, such as nausea and dizziness (which could be related to plant properties) were reported by more sensitive volunteers. Our results suggest that the tea infusion from H. sabdariffa petals increases body burden of Al and, therefore, sensitive individuals as pregnant women and people with kidney problems should be cautious with excessive consumption of hibiscus infusion or fruit teas containing this plant. However, further study including more individuals is needed to fully confirm our preliminary results.
  • Chapter
    The first vaccines were made from intact or weakened infectious agents. An improved understanding of the immune system has fostered the development of additional types of vaccines, which provide immunity without risk of infection. These newer types of vaccines can be helpful when immunizing special populations, such as newborns or geriatric patients, who may have weakened immune systems. Modern vaccines may also contain additional materials such as adjuvants, which enhance immunogenicity. Antibiotics and preservatives may be used to prevent contamination during manufacture or after distribution.
  • Thesis
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    Abstract Titel: Kinkhoestvaccinatie tijdens de zwangerschap Naam: Jevgenija Tugunova Interne promotor: Kelly Schoonbaert Externe promotor: Dr Elke Leuridan Probleemstelling: Ondanks vaccinaties blijft kinkhoest ook in de geïndustrialiseerde wereld een belangrijke kinderziekte die soms dodelijk kan zijn. Vooral baby’s jonger dan 3 maand zijn gevoelig (vaccinatie baby vanaf 8 weken). Volwassen vrouwen hebben zelf weinig antistoffen en dus is er weinig of geen transplacentaire overdracht van antistoffen. Er werden zeer goede resultaten geboekt door vaccinatie tijdens de zwangerschap maar de vaccinatiegraad blijft tot op heden nog onvoldoende. Vraagstelling: Is het aangewezen om alle zwangere vrouwen te vaccineren tegen kinkhoest? Welke vaccins kan men gebruiken? Zijn er risico’s verbonden aan de vaccinatie? Is het vaccin veilig? Is het effectief om te vaccineren (bv. minder gevallen, minder hospitalisaties). Onderzoeksmethodologie: Een literatuuronderzoek waarbij de databanken Science Direct, Pub Med, Cebam, EhBiB Search werden geraadpleegd. Bij elke zoekactie werd gelimiteerd op publicatiedatum tussen januari 2006 en september 2016. Er werden 46 artikels in het Engels, Frans en Nederlands geraadpleegd. Na screening op titel en abstract werden de artikels geselecteerd. Resultaten: Het is aangewezen om zwangere vrouwen te vaccineren tijdens het tweede of derde trimester van de zwangerschap (liefst tussen 28 en 38 weken). (WHO, 2015) Een apart kinkhoestvaccin is niet beschikbaar in België. Er bestaat alleen een gecombineerd vaccin tegen difterie, tetanus en acellulaire kinkhoest (dTpa): Boostrix®. (Belgisch Centrum voor Farmacotherapeutische Informatie ,2016). Er zouden geen belangrijke nevenwerkingen zijn en geen verhoogd risico op complicaties. (Maertens et al., 2015; Kharbanda et al., 2016; Donegan et al., 2014; WHO, 2015) De vroedvrouw speelt een cruciale rol in het informeren over vaccinatie tijdens de zwangerschap en over cocoonstrategie (De Martino, 2016; Larson, 2015; Green, 2015). Besluit: Gezien de hoge morbiditeit en de mogelijke mortaliteit van kinkhoest bij pasgeboren baby’s is het vaccineren van zwangere vrouwen sterk aanbevolen. Implicaties voor de praktijk: De vaccinatiestatus van de zwangere vrouwen moet gecontroleerd worden. Niet gevaccineerde vrouwen moeten doorverwezen worden naar hun arts. Zwangere vrouwen moeten informatie krijgen over kinkhoest, over hoesthygiëne en over het gevaar van andere hoestende personen in hun omgeving. De vroedvrouw moet zelf gevaccineerd zijn en zij moet op de hoogte zijn van de recentste aanbevelingen die zij moet delen met de zwangere vrouwen.
  • Article
    Background: We conducted a phase I/II clinical trial to evaluate the safety and immunogenicity of a Madin-Darby canine kidney (MDCK) cell-grown inactivated H7N9 influenza vaccine for pandemic preparedness purposes. Methods: Between April 7, 2015 and May 27, 2016, healthy adults aged 20-60years were enrolled sequentially in phase I (n=40) and phase II (n=160) from three hospitals in Taiwan and randomized to receive 2 doses of whole-virus H7N9 vaccine (15 or 30μg hemagglutinin antigen (HA) with or without an aluminum hydroxide adjuvant) at 21-day intervals. Safety up to 180days and changes in hemagglutinin inhibition (HI) titers at 21days after each vaccination were determined. Results: Of the 200 randomized subjects, 193 (96.5%) received 2 doses of the study vaccine and were included in the intention-to-treat analysis for safety, and 190 (95%) were included in the per-protocol analysis for immunogenicity. Most adverse events were mild and transient; no death or vaccine-related serious adverse events were reported. Overall, higher immune responses were observed in the groups administered with 30μgHA formulation than in the other two groups administered with 15μgHA formulation. The highest immune response was observed in subjects who received 2 doses of the adjuvanted vaccine containing 30μgHA with HI titer, seroprotection rate, seroconversion rate, and seroconversion factor of 36.2, 64.6%, 64.6% and 5.7, respectively. Conclusions: Our study demonstrated that the H7N9 influenza vaccine containing 30µgHA with aluminum hydroxide adjuvant was immunogenic and safe in adults aged 20-60years. CLINICALTRIALS.GOV identifier: NCT02436928.
  • Article
    Objective: To evaluate relationships between whole blood (B-Al) and hair aluminum (H-Al) levels in healthy infants and their immunization history and development. Methods: We conducted a cross-sectional study of 9- to 13-month-old children recruited from an urban primary care center, excluding those with a history of renal disease or receipt of either aluminum-containing pharmaceuticals or parenteral nutrition. Aluminum levels were measured using inductively coupled plasma-mass spectrometry. Correlation with Bayley Scales of Infant and Toddler Development, Third Edition (BSID) and vaccine-related aluminum load was assessed via linear regression models. Results: The median age of 85 participants was 287 days. B-Al (median, 15.4 ng/mL; range, 0.9-952 ng/mL) and H-Al (median 42,542 ng/g; range, 2758-211,690 ng/g) were weakly correlated (Spearman ρ = 0.26; P = .03). There was no significant correlation between B-Al or H-Al and estimated aluminum load from vaccines. B-Al was not correlated with BSID composite or subscale scores. Although H-Al was not correlated with BSID scores in models including all data (n = 85), it was inversely correlated with motor composite (P < .02; Wald = 5.88) and the gross motor subscale (P = .04; Wald = 4.38) in models that excluded an extreme outlying H-Al value. Conclusions: Infant B-Al and H-Al varied considerably but did not correlate with their immunization history. Likewise, there was no correlation between B-Al and infant development or between H-Al and language or cognitive development. An inverse correlation between H-Al and BSID motor scores deserves further investigation.
  • Chapter
    Some have said that the Internet is an instrument of democracy. Taken literally, this statement is false. We have to add: it is an instrument of potential democracy. The motto of the Internet can be summarized in the words, paradoxical and politically incorrect, pronounced by Jesus: “Whoever has will be given more” (Matthew, XIII, 12). To navigate in the Internet, to distinguish the pearl from the sow’s ear, you already have to have had access to culture—an access which normally (and I speak from personal experience) is associated with social privilege. The Internet, which potentially could be an instrument that could attenuate cultural inequalities, in the immediate, exasperates them. Schools need the Internet, of course, but the Internet, to be used according to its potential (let’s say realistically one-millionth of its capacity), needs state schools that really teach.
  • Article
    Patients with Systemic Lupus Erythematosus (SLE) pose a unique dilemma pertaining to immunization against common pathogens. SLE patients are usually not immunized with vaccines based on the fear of either precipitating infection in this immunosuppressed patient population (with live vaccines) or aggravating autoimmunity and hence lupus flares (with any vaccines). However, elevated vulnerability to infection makes patients with SLE precisely the population that needs protection from vaccine-preventable diseases. A summary of guidelines from the Centers for Disease Control and Prevention, professional societies, review articles and expert opinions regarding use of individual vaccines applicable to adults with SLE is presented in this review.
  • Chapter
    Certain ingredients that are present in some vaccines (other than disease-specific antigens), such as gelatin or neomycin, can very rarely cause severe hypersensitivity reactions (e.g. anaphylaxis) in vaccinees with those specific allergies. In addition, some adjuvants can cause increased rates of local reactions, and alum containing adjuvants can cause nodules at the injection site. Vaccine ingredients, including the preservative thimerosal, do not cause autism. Ingredients in vaccines currently routinely recommended to the general population in the U.S. have not been shown to cause any other adverse events.
  • Article
    The immunogenicity and efficacy of vaccines is largely governed by nature and the amount of antigen(s) included. Specific immune-stimulating substances, so-called adjuvants, are added to vaccine formulations to enhance and modulate the induced immune response. Adjuvants are very different in their physicochemical nature and are primarily characterized by their immune-enhancing effects. In this report, adjuvants that are components of vaccines licensed in the EU will be presented and their mode of action will be discussed. Aluminum salts have been used for almost a century as vaccine adjuvants. In recent years numerous novel immune-stimulating substances have been developed and integrated into licensed human vaccines. These novel adjuvants are not only intended to generally increase the vaccine-induced antibody titers, but are also aimed at modulating and triggering a specific immune response. The search for innovative adjuvants was considerably stimulated during development of pandemic influenza vaccines. By using squalene-containing oil-in-water adjuvants (namely AS03 and MF59), pandemic influenza vaccines were developed that were efficacious despite a significant reduction of the antigen content. The development of novel adjuvants is a highly dynamic and essential area in modern vaccine design. Some years ago, vaccines for prevention of HPV-induced cervix carcinoma and hepatitis B were licensed that contained the toll-like receptor 4 agonist 3‑O-desacyl-monophosphoryl lipid A (MPL), a detoxified LPS version, as the adjuvant. Quite recently, a herpes zoster vaccine was licensed in Europe with a combination of MPL and the saponin QS21 as adjuvant. This combination of immune enhancers is also used in the formulations of the same manufacturer’s malaria and hepatitis B vaccine. © 2019, Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature.
  • Article
    Concerns about vaccine safety can lead to decreased acceptance of vaccines and resurgence of vaccine-preventable diseases. We summarize the key evidence on some of the main current vaccine safety controversies in the United States, including (1) measles, mumps, and rubella vaccine and autism; (2) thimerosal, a mercury-based vaccine preservative and the risk of neurodevelopmental disorders; (3) vaccine-induced Guillain-Barré syndrome (GBS); (4) vaccine-induced autoimmune diseases; (5) safety of human papillomavirus vaccine; (6) aluminum adjuvant-induced autoimmune diseases and other disorders; and (7) too many vaccines given early in life predisposing children to health and developmental problems. A possible small increased risk of GBS following influenza vaccination has been identified, but the magnitude of the increase is less than the risk of GBS following influenza infection. Otherwise, the biological and epidemiologic evidence does not support any of the reviewed vaccine safety concerns.
  • Article
    Full-text available
    Aluminium (Al) is frequently accessible to animal and human populations to the extent that intoxications may occur. Intake of Al is by inhalation of aerosols or particles, ingestion of food, water and medicaments, skin contact, vaccination, dialysis and infusions. Toxic actions of Al induce oxidative stress, immunologic alterations, genotoxicity, pro-inflammatory effect, peptide denaturation or transformation, enzymatic dysfunction, metabolic derangement, amyloidogenesis, membrane perturbation, iron dyshomeostasis, apoptosis, necrosis and dysplasia. The pathological conditions associated with Al toxicosis are desquamative interstitial pneumonia, pulmonary alveolar proteinosis, granulomas, granulomatosis and fibrosis, toxic myocarditis, thrombosis and ischemic stroke, granulomatous enteritis, Crohn’s disease, inflammatory bowel diseases, anemia, Alzheimer’s disease, dementia, sclerosis, autism, macrophagic myofasciitis, osteomalacia, oligospermia and infertility, hepatorenal disease, breast cancer and cyst, pancreatitis, pancreatic necrosis and diabetes mellitus. The review provides a broad overview of Al toxicosis as a background for sustained investigations of the toxicology of Al compounds of public health importance.
  • Article
    Full-text available
    In spite of a common view that aluminum (Al) salts are inert and therefore harmless as vaccine adjuvants or in immunotherapy, the reality is quite different. In the following article we briefly review the literature on Al neurotoxicity and the use of Al salts as vaccine adjuvants and consider not only direct toxic actions on the nervous system, but also the potential impact for triggering autoimmunity. Autoimmune and inflammatory responses affecting the CNS appear to underlie some forms of neurological disease, including developmental disorders. Al has been demonstrated to impact the CNS at every level, including by changing gene expression. These outcomes should raise concerns about the increasing use of Al salts as vaccine adjuvants and for the application as more general immune stimulants.
  • Article
    Moreno A, Domínguez C, Ballabriga A. Aluminium in the neonate related to parenteral nutrition. Acta Pædiatr 1994;83:25–9. Stockholm. ISSN 0803–5253 Sources of aluminium loading and exposure in preterm and full-term newborns were studied. Parenteral nutrition solutions were the main source of aluminium representing 88.7% of total aluminium intake. Blood and urine aluminium levels were followed over a 28-day period in a group of 26 preterm and 9 term infants while receiving parenteral nutrition (duration 15.6 ± 8.7 days) and later when being formula fed. Urine levels were followed up to 13 weeks in a subgroup of the neonates. Serum aluminium levels (0.86 ± 0.38 μmol/l) and urine aluminium/crcatinine ratio (1.52 ± 0.81 μmol/ mmol) were increased when the infants were receiving parenteral nutrition compared with the control group (p<0.001). The urine aluminium/creatinine ratio remained high up to 10 weeks following withdrawal of parenteral nutrition and suggested tissular loading. This was confirmed after high aluminium levels were found in post-mortem brain and bone samples from two preterm and one full-term infant. We conclude that both preterm and full-term neonates are susceptible to accumulation of aluminium in tissue while receiving parenteral nutrition.
  • Article
    Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1beta to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy.
  • Article
    The study reported here was done: to evaluate maternal toxicity and fetal toxicity of AlCl3 in mice; to determine the ability of Al, administered to the mother, to accumulate in the fetus; to quantitate and compare maternal-placental-fetal Al content following gestational exposure to AlCl3; and to determine the influence of route of administration (oral vs intraperitoneal) on the above parameters. Total fetal Al content was significantly increased to maternal Al content following both ip and oral routes of maternal exposure to AlCl3. In Utero exposure of mice to AlCl3, at levels which do not cause maternal toxicity, resulted in decreased fetal weight and increased incidence of fetal resorptions. Differences in ip versus oral dosing were observed in placental and fetal weight changes, maximum fetal Al burden, placental Al content, and maternal liver Al content. In every case, changes were greater with ip dosing. In comparison with published studies on rats, mice appear to be more resistant to the toxic effects of AlCl3.
  • Article
    To investigate the possibility that premature infants may be vulnerable to aluminum toxicity acquired through intravenous feeding, we prospectively studied plasma and urinary aluminum concentrations in 18 premature infants receiving intravenous therapy and in 8 term infants receiving no intravenous therapy. We also measured bone aluminum concentrations in autopsy specimens from 23 infants, including 6 who had received at least three weeks of intravenous therapy. Premature infants who received intravenous therapy had high plasma and urinary aluminum concentrations, as compared with normal controls: plasma aluminum, 36.78 +/- 45.30 vs. 5.17 +/- 3.1 micrograms per liter (mean +/- S.D., P less than 0.0001); urinary aluminum:creatinine ratio, 5.4 +/- 4.6 vs. 0.64 +/- 0.75 (P less than 0.01). The bone aluminum concentration was 10 times higher in infants who had received at least three weeks of intravenous therapy than in those who had received limited intravenous therapy: 20.16 +/- 13.4 vs. 1.98 +/- 1.44 mg per kilogram of dry weight (P less than 0.0001). Creatinine clearances corrected for weight did not reach expected adult values until 34 weeks of gestation. Many commonly used intravenous solutions are found to be highly contaminated with aluminum. We conclude that infants receiving intravenous therapy have aluminum loading, which is reflected in increased urinary excretion and elevated concentrations in plasma and bone. Such infants may be at high risk for aluminum intoxication secondary to increased parenteral exposure and poor renal clearance.
  • Article
    To assess aluminum toxicity to the Al-exposed pregnant female and her developing offspring, pregnant rabbits received 20 sc Al lactate injections (0, 25, 100, or 400 mumol Al/kg/inj) between Days 2 and 27 of gestation. Fifty-eight percent perinatal mortality resulted from the highest dose. At 2 days postpartum litters were culled to six offspring. Three of the offspring of Al-treated does were cross-fostered to a non-Al-treated doe in exchange for three of the non-Al-treated doe's offspring. Tissue Al concentrations in 0- to 2-day-old offspring positively correlated with their does' Al exposure, but were lower than Al concentrations in placental tissue or in does 5 weeks postpartum, suggesting that the placenta partially protects the fetus from Al. Offspring of 25 mumol group does gained body weight faster than controls, whereas 400 mumol group does and their offspring gained weight less rapidly than controls. The weight of milk consumed by offspring inversely correlated with their does' Al exposure. Learning a classically conditioned reflex was facilitated by lower and impaired by higher Al exposure in offspring conditioned at 7 and 11 weeks of age. Offspring receiving higher Al exposure also showed impaired memory of the learned reflex. Aluminum appears to distribute into the developing fetus where it accumulates and can produce delayed effects which may be beneficial following lower but detrimental following higher exposure concentrations.
  • Article
    During a 40-day balance study, eight adult males were fed two levels of aluminium: 5 mg/day for 20 days (control diet) and 125 mg/day for 20 days (test diet). Every subject excreted more than 96% and more than 74% of his aluminium intake in his faeces when fed the test and control diets, respectively. Subjects excreted two- to five-fold more aluminium in their urine and had significantly higher levels of aluminium in their sera when fed the test diet rather than the control diet. No retention of aluminum was detected when faecal and urinary losses of aluminium were compared with intakes.
  • Article
    An estimate of glomerular filtration rate has been derived for children from body length (L, in centimeters) and plasma creatinine (Pcr, in milligrams per deciliter): GFR = 0.55 L/Pcr. The near universality of this estimate in children led us to seek a similar formula for estimating GFR in full-term infants during the first year of life. We measured Pcr in 137 healthy infants and performed creatinine clearance (Ccr) studies in 63 of them aged greater than or equal to 5 days. Beyond the first week, Pcr averaged 0.39 +/- 0.01 (0.10 SD) mg/dl. The estimate of GFR from 0.55 L/Pcr overestimated Ccr by 24% (P less than 0.001). Based on the calculation of a new constant from Ccr X Pcr/L, GFR was more accurately estimated from 0.45 L/Pcr (mean difference of Ccr - 0.45 L/Pcr = -0.4 +/- 3.7 (SE) ml/min X 1.73 m2) in full-term infants between 1 and 52 weeks of age. Because the constant 0.45 and Pcr do not change significantly during this period, GFR can be approximated at the bedside from body length of the healthy full-term infant (GFR = 0.45 L/0.39 = 1.1 L).
  • Article
    1. 26Al and 67Ga were given as citrates to a healthy male volunteer by intravenous injection. The retention of both tracers was studied by body radioactivity measurement. Levels in blood and excreta were determined by gamma-ray spectrometry and/or accelerator mass spectrometry. 2. More than half of the 26Al had left the blood after 15 min and the decline continued, leaving < 1% in blood after 2 d; the losses occurred both to renal excretion and through uptake by other compartments. Estimated excretion up to 13 d was 83% (urine) and 1.8% (faeces). Whole-body retention of 15% at 13 d declined to approximately 4% at 1178 d, when the daily reduction corresponded to a biological half-life of 7 y, suggesting that sustained intake of dietary aluminium may lead to a progressively increasing internal deposit. 3. The metabolism of 67Ga differed markedly from that of 26Al in all aspects studied.
  • Article
    Sources of aluminium loading and exposure in preterm and full-term newborns were studied. Parenteral nutrition solutions were the main source of aluminium representing 88.7% of total aluminium intake. Blood and urine aluminium levels were followed over a 28-day period in a group of 26 preterm and 9 term infants while receiving parenteral nutrition (duration 15.6 +/- 8.7 days) and later when being formula fed. Urine levels were followed up to 13 weeks in a subgroup of the neonates. Serum aluminium levels (0.86 +/- 0.38 mumol/l) and urine aluminium/creatinine ratio (1.52 +/- 0.81 mumol/mmol) were increased when the infants were receiving parenteral nutrition compared with the control group (p < 0.001). The urine aluminium/creatinine ratio remained high up to 10 weeks following withdrawal of parenteral nutrition and suggested tissular loading. This was confirmed after high aluminium levels were found in post-mortem brain and bone samples from two preterm and one full-term infant. We conclude that both preterm and full-term neonates are susceptible to accumulation of aluminium in tissue while receiving parenteral nutrition.
  • Article
    Full-text available
    Aluminium hydroxide (AH) and aluminium phosphate (AP) adjuvants, labelled with 26Al, were injected intramuscularly (i.m.) in New Zealand White rabbits. Blood and urine samples were collected for 28 days and analysed for 26Al using accelerator mass spectrometry to determine the absorption and elimination of AH and AP adjuvants. 26Al was present in the first blood sample (1 h) for both adjuvants. The area under the blood level curve for 28 days indicates that three times more aluminium was absorbed from AP adjuvant than AH adjuvant. The distribution profile of aluminium to tissues was the same for both adjuvants (kidney > spleen > liver > heart > lymph node > brain). This study has demonstrated that in vivo mechanisms are available to eliminate aluminium-containing adjuvants after i.m. administration. In addition, the pharmacokinetic profiles of AH and AP adjuvants are different.
  • Article
    There is concern that environmental and dietary aluminum (Al) might cause developmental toxicity. To better understand this concern, we reviewed published studies which administered Al compounds to pregnant animals and measured accumulation of Al in mother, fetus, or born offspring. A total of 7 studies were identified which administered Al during gestation and evaluated fetal accumulation. Another 7 studies administered Al at least until birth and then evaluated accumulation in mothers and/or pups. These 14 studies included 4 different Al compounds (hydroxide, chloride, lactate, and citrate) administered by 4 different routes (gavage, feed, intraperitoneal injection, and subcutaneous injection) with total doses ranging from 13.5 to 8,400 mg/kg. Fetal Al levels were not increased in 6 of 7 studies and pup Al levels were not increased in 4 of 5 studies in which they were measured. Maternal Al levels were increased in some studies, but there was no consistent pattern of organ-specific accumulation and several positive studies were contradicted by subsequent reports from the same laboratory. Placental levels were increased in 6 of 9 studies and were greater than corresponding fetal levels. The weight of evidence in these studies suggests that environmental and dietary Al exposures are unlikely to pose risks of Al accumulation to pregnant animals or their fetuses.
  • Article
    Borak J, Wise JP. 1998. Does aluminum exposure of pregnant animals lead to accumulation in mothers of their offspring? Teratology 57:127–139 In response to the article referenced above, Drs. M. Golub and J. Domingo wrote a Letter to the Editor (Teratology 1998;58:225). Included in that letter was the following statement: “We also urge Drs. Borak and Wise to fulfill their ethical obligation to acknowledge sources of support when submitting manuscripts for publication.” This comment would not have been necessary if the article by Borak and Wise had included an acknowledgment of their outside support in their article. The authors had disclosed this outside support in the cover letter to the editor when the manuscript was supplied initially and later after revisions. They did not include an Acknowledgment section in the manuscript. The editorial office should have suggested that they do that. We apologize for any confusion this caused.
  • Article
    This MiniReview updates and expands the MiniReview of aluminium toxicokinetics by Wilhelm et al. published by this journal in 1990. The use of 26Al, analyzed by accelerator mass spectrometry, now enables determination of Al toxicokinetics under physiological conditions. There is concern about aluminium in drinking water. The common sources of aluminium for man are reviewed. Oral Al bioavailability from water appears to be about 0.3%. Food is the primary common source. Al bioavailability from food has not been adequately determined. Industrial and medicinal exposure, and perhaps antiperspirant use, can significantly increase absorbed aluminium. Inhalation bioavailability of airborne soluble Al appears to be about 1.5% in the industrial environment. Al may distribute to the brain from the nasal cavity, but the significance of this exposure route is unknown. Systemic Al bioavailability after single underarm antiperspirant application may be up to 0.012%. All intramuscularly injected Al, e.g. from vaccines, may eventually be absorbed. Al distributes unequally to all tissues. Distribution and renal excretion appear to be enhanced by citrate. Brain uptake of Al may be mediated by Al transferrin and Al citrate complexes. There appears to be carrier-mediated efflux of Al citrate from the brain. Elimination half-lives of years have been reported in man, probably reflecting release from bone. Al elimination is primarily renal with < or = 2% excreted in bile. The contribution of food to absorbed Al needs to be determined to advance our understanding of the major components of Al toxicokinetics.
  • Article
    We studied rat retinal changes due to aluminum (Al) toxicosis with a transmission electron microscope (TEM) and an energy dispersive X-ray analyzer (EDXA). Normal 4-week-old Wistar Kyoto rats were divided randomly into Al toxicosis and control groups. The Al toxicosis group was injected ip with 0.3 ml of 4% aluminum chloride (AlCl3) per day every day for 16 weeks. The retina was examined with a TEM and EDXA at 8, 12, and 16 weeks after starting injections with AlCl3. There was a statistically significant increase in the serum Al concentration in the Al toxicosis group (p < 0.001). We observed prominent pathologic changes at 16 weeks after the first injections. Thin retinal pigment epithelium (RPE), and disappearance of the photoreceptor outer and inner segments and nuclei were observed. There were high-density irregular granules in the outer and inner plexiform layers and in the inner nuclear layer. We found dense granules in the cells, which remained between the RPE and the inner nuclear layer. EDXA detected Al in the high-density irregular granules in these areas. Al injected ip caused accumulation of Al in the rat retina and the destruction of photoreceptor cells. These findings indicate that Al is toxic to the retina.
  • Article
    Some vaccines contain aluminum adjuvants to enhance the immunological response, and it has been postulated that this aluminum could contribute to adverse health effects, especially in children who receive a vaccination series starting at birth. The pharmacokinetic properties and end-point toxicities of aluminum are presented. In assessing the relevance of dietary and medical aluminum exposure to public health, we estimated infant body burdens during the first year of life for breast milk and formula diets and for a standard vaccination schedule. We then compared those body burdens with that expected for intake at a level considered safe for intermediate-duration exposure. The methodology blends intake values and uptake fractions with an aluminum retention function derived from a human injection study using radioactive 26Al. The calculated body burden of aluminum from vaccinations exceeds that from dietary sources, however, it is below the minimal risk level equivalent curve after the brief period following injection.
  • Article
    Full-text available
    Aluminum (Al) has been etiologically and epidemiologically related to several neurologic conditions, including Alzheimer's disease (AD). The effects of Al long-term exposure were investigated to describe the associated behavioral and brain modifications. Adult rats were intraperitoneally injected three times a week for 6 months with ecological doses of Al gluconate (0.85 mg/kg). The Al overload was confirmed by the significantly increased level of Al in serum. We assessed fear conditioning, spatial memory and emotional reactivity by shuttle-box task, Morris water maze, and open-field, respectively. The performance of the experimental animals at the shuttle-box task was significantly lower (p <.01) compared to that of control. The experimental animals had impaired spatial memory, with lower and more fluctuant performance at Morris water maze. The noxious-driven behavior of the experimental animals was also altered, with significantly lower activity scores (p <.05), and high emotionality scores (p <.01) at the open-field. We recovered and processed the brain for aluminum and amyloid deposits. The brains of experimental animals, studied by optical microscopy, displayed a massive cellular depletion in the hippocampal formation, particularly, the CAl field, and also in the temporal and parietal cortex. We observed numerous ghost-like neurons with cytoplasmic and nuclear vacuolations, and with Al deposits. The hippocampus contained extracellular accumulations of Al and amyloid surrounded by nuclei of degenerating cells, which we interpreted as neuritic plaques. The cerebrovasculature was distorted, with a significant thickening of the wall of capillaries, associated with amyloid deposits. These behavioral and neuropathological modifications associated with long-term exposure to Al are reminiscent of those observed in AD.
  • Article
    Full-text available
    Although aluminum is the most abundant metal in nature, it has no known biological function. However, it is known that there is a causal role for aluminum in dialysis encephalopathy, microcytic anemia, and osteomalacia. Aluminum has also been proposed to play a role in the pathogenesis of Alzheimer's disease (AD) even though this issue is controversial. The exact mechanism of aluminum toxicity is not known but accumulating evidence suggests that the metal can potentiate oxidative and inflammatory events, eventually leading to tissue damage. This review encompasses the general toxicology of aluminum with emphasis on the potential mechanisms by which it may accelerate the progression of chronic age-related neurodegenerative disorders.
  • Article
    Until 1990 biokinetic studies of aluminium metabolism and biokinetics in man and other animals had been substantially inhibited by analytical and practical difficulties. Of these, the most important are the difficulties in differentiating between administered aluminium and endogenous aluminium-especially in body fluids and excreta and the problems associated with the contamination of samples with environmental aluminium. As a consequence of these it was not possible to detect small, residual body burdens of the metal following experimental administrations. Consequently, many believed aluminium to be quantitatively excreted within a short time of uptake in all, but renal-failure patients. Nevertheless, residual aluminium deposits in a number of different organs and tissues had been detected in normal subjects using a variety of techniques, including histochemical staining methods. In order to understand the origins and kinetics of such residual aluminium deposits new approaches were required. One approach taken was to employ the radioisotope (67)Ga as a surrogate, but this approach has been shown to be flawed-a consequence of the different biological behaviours of aluminium and gallium. A second arose from the availability, in about 1990, of both (26)Al-a rare and expensive isotope of aluminium-and accelerator mass spectrometry for the ultra-trace detection of this isotope. Using these techniques the basic features of aluminium biokinetics and bioavailability have been unravelled. It is now clear that some aluminium is retained in the body-most probably within the skeleton, and that some deposits in the brain. However, most aluminium that enters the blood is excreted in urine within a few days or weeks and the gastrointestinal tract provides an effective barrier to aluminium uptake. Aspects of the biokinetics and bioavailability of aluminium are described below.
  • Article
    Aluminium adjuvants are the most widely used adjuvants in both human and veterinary vaccines. These adjuvants have been used in practical vaccination for more than 60 years and are generally recognized as safe and as stimulators of Th2 immunity. The present review gives a short introduction to the pioneering research at the start of the use of aluminium compounds as adjuvants, including references on the chemistry of these compounds. Analytical methods for identifying the most commonly used aluminium compounds, such as boehmite and aluminium hydroxyphosphate, are mentioned. Emphasis is placed on the important factors for antigen adsorption and on the latest work using gene-deficient mice in the research of the mechanism of aluminium adjuvants in terms of cytokine and T-cell subset stimulation. Key references on the ability of aluminium adjuvants to stimulate IgE and also in vivo clearing of aluminium adjuvants are discussed. Furthermore, the review addresses the issue of local reactions in the context of injection route and local tissue disturbance. Possible new applications of aluminium adjuvants in, for example, combined aluminium-adsorbed protein and DNA oligonucleotide vaccines as well as the possible use of aluminium adjuvants in combination with IL-12 to stimulate Th1-type immune responses are mentioned.
  • Article
    Full-text available
    Objectives After completing this article, readers should be able to: 1. Recognize age-related changes in pharmacokinetics and pharmacodynamics of drugs. 2. Describe the dynamics of rational drug dosing for neonates and children. 3. Identify areas of challenge where more drug research is needed during development.
  • Article
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    Macrophagic myofasciitis (MMF) is an inflammatory myopathy related to aluminum-containing vaccines. Described in 1998, most cases were reported in adults, with only 22 cases being reported in children. Three children aged between 13 months and 3(1/2) years were investigated in our institution for neuromuscular symptoms. They underwent thorough clinical, familial, and laboratory investigations, electroneuromyography, muscle biopsy with transmission electron microscopy, scanning electron microscopy/energy dispersive spectroscopy (SEM/EDS), and, in one case, brain magnetic resonance imaging. They had received regular immunizations. Two patients were hypotonic and one presented with myotonia. Muscle biopsy of all patients presented macrophagic infiltrates with intracytoplasmic aluminum content as revealed by SEM/EDS analysis. Their diverse clinical picture does not support a direct relationship between local morphologic findings and systemic symptoms. The atypical clinical presentation of these children may not result from the superposition of MMF upon a background systemic neuromyopathy, suggesting instead that they are two coincident and independent conditions. Although the finding of macrophage infiltrates in muscle tissue is not new, the identification of aluminum content is recent. The use of tissue sections for aluminum detection and mapping by SEM/EDS is conclusive for, diagnosis; it has not been reported previously in a pathology journal, to the authors' knowledge.
  • Article
    Full-text available
    Note: This article was originally published with an incorrect version of the Acknowledgments, which appeared on p. 218 of the print version. The correct version of the Acknowledgments appeared on pp. 1–2. The corrected article is available below.
  • Article
    Macrophagic myofasciitis is a novel, "inflammatory myopathy" described after a variety of vaccinations, almost exclusively in adults. We examined the relevance of histological findings of this myopathy to the clinical presentation in pediatric patients. Muscle biopsies from 8 children (7 months to 6 years old) with histological features of macrophagic myofasciitis were reviewed and correlated with the clinical manifestations. Patients underwent quadriceps muscle biopsy for suspected mitochondrial disease (4 patients), spinal muscular atrophy (2 patients), myoglobinuria (1 patient), and hypotonia with motor delay (1 patient). All biopsies showed identical granulomas composed of periodic acid-Schiff-positive and CD68-positive macrophages. Characteristic aluminum hydroxide crystals were identified by electron microscopy in 2 cases. The biopsy established diagnoses other than macrophagic myofasciitis in 5 patients: spinal muscular atrophy (2), Duchenne muscular dystrophy (1), phospho-glycerate kinase deficiency (1), and cytochrome c oxidase deficiency (1). Three children with manifestations and/or a family history of mitochondrial disease had otherwise morphologically normal muscle. All children had routine vaccinations between 2 months and 1 year before the biopsy, with up to 11 intramuscular injections, including the biopsy sites. There was no correlation between histological findings of macrophagic myofasciitis in biopsies and the clinical symptoms. We believe that macrophagic myofasciitis represents a localized histological hallmark of previous immunization with the aluminum hydroxide adjuvants contained in vaccines, rather than a primary or distinct inflammatory muscle disease.
  • Article
    Full-text available
    Neonatal drug dosing needs to be based on the physiological characteristics of the newborn and the pharmacokinetic parameters of the drug. Size-related changes can in part be modelled based on allometry and relates to the observation that metabolic rate relates to weight by a kg 0.75 trend. Until adult metabolic activity has been reached, ontogeny, i.e. isoenzyme-specific maturation and maturation of renal clearance also contributes to drug metabolism, making isoenzyme-specific documentation of maturation necessary. Changes in body composition and ontogeny are most prominent in neonates. The body fat content (/kg) is markedly lower and the body water content (/kg) is markedly higher in neonates. These findings have an impact on the distribution volume of both lipophilic and hydrophilic drugs. Drugs are cleared either by metabolism or elimination. While the first is mainly hepatic, the second route is mainly renal. Both hepatic metabolism and renal clearance display maturation in early life although other covariables (e.g. polymorphisms, co-administration of drugs, first pass metabolism, disease characteristics) further contribute to the interindividual variability in drug disposition. Documentation of these maturational processes based on in vivo 'case' studies is of value since these drug-specific observations can subsequently be extrapolated to other drugs which are either already being prescribed or even considered for use in neonates by the introduction of these observations in 'generic physiologically-based pharmacokinetic' models.
  • Article
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    Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.