Updated aluminum pharmacokinetics following infant exposures through diet and vaccination

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.

Introduction

In the first year of life, infants receive vaccinations according to a schedule recommended by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention [2]. Some of these vaccines utilize aluminum salts as adjuvants (for example, aluminum hydroxide, Al(OH)₃, or aluminum phosphate, AlPO₄). The particular vaccines (and therefore aluminum exposures) that an infant may receive at any point in the immunization schedule may vary depending on the vaccine chosen by the health care provider, parents, and caregivers from the available FDA-licensed vaccines. Potential aluminum exposures associated with vaccine administration, however, are different from dietary exposures to aluminum, since aluminum in vaccines does not have to pass through the walls of the gastrointestinal tract, which is a significant barrier to systemic aluminum absorption. Rather, it is expected that the whole amount of aluminum in the adjuvant will be absorbed from muscle into the blood following vaccination, albeit at some rate over time.

In an effort to evaluate the relative contribution to aluminum levels in infants from vaccines and from diet, Keith et al. [1] analyzed the pharmacokinetics of aluminum for infant dietary and vaccine exposures and compared these exposures to the level set by the Agency for Toxic Substances and Disease Registry, which is called the minimal risk level or MRL (ATSDR [29]). Exposures below this level are considered to be safe, but levels of exposure at or slightly above the MRL may also be safe due to safety factors that are built into the process of calculating the MRL. Keith et al. [1] concluded that the calculated body burden from aluminum exposures in infants from vaccines is below the MRL equivalent curve for all but a few brief periods during the first year of life. We updated the analysis of Keith et al. [1] with a current vaccination schedule, a more recent aluminum retention function from human volunteers, incorporation of infant glomerular filtration rates, an adjustment for the kinetics of aluminum efflux from the site of injection, contemporaneous MRLs, and the most recent infant body weight data for children 0–60 months of age [3].

Aluminum is a ubiquitous environmental metal with no known nutritional role in humans. Because of aluminum's abundance in the environment, it is frequently consumed as an incidental component of water or food, including infant formula [4]. Aluminum is also intentionally added to food as a caking or emulsifying agent. As a result, bread made with aluminum-based baking powder can contain up to 15 mg aluminum per slice, and processed American cheese can contain as much as 50 mg aluminum per slice [5]. Another potential means of exposure to aluminum in humans can occur through vaccination. Certain vaccines may contain specific aluminum salts (primarily aluminum hydroxide and aluminum phosphate) as an adjuvant. Aluminum adjuvants are important components of vaccines, since they stimulate the immune system to respond more effectively to protein or polysaccharide antigens that have been adsorbed to the surface of insoluble aluminum particles. Specifically, these coated particles are phagocytized by cells of the innate immune system (e.g., macrophages) and activate intracytoplasmic sensors of pathogen-associated molecular patterns located within the cells, such as the nucleotide-binding domain leucine-rich repeat-containing family of sensors ([6]; Schroder and Tschopp [30]). The functional consequence of activation of this intracellular system is the activation of certain enzymatic caspases that cleave pro-interleukin (IL)-1β to interleukin (IL)-1β. The secretion of the mature cytokine, IL-1β, leads to an inflammatory reaction and a downstream Th2-dependent antibody response [7], which amplify the immune response to the antigen. Adjuvanted aluminum, therefore, plays a vital role in facilitating the response that underlies the immunoprotection afforded by vaccines.

Dietary exposure to aluminum (usually as the citrate) results in small amounts of aluminum being absorbed from the gut (<1%) and reaching the bloodstream [4]. Following enteral absorption, aluminum is transported mainly in the plasma in association with the iron-binding protein transferrin [8]. Aluminum is distributed well throughout the body with the skeleton and lungs (due to inhalation exposures) containing the highest mass of aluminum (approximately 50% and 25% of the body burden, respectively). As for many divalent and polyvalent metals, the skeleton can be a long-term storage depot for aluminum, with the half-life of aluminum in bone being on the order of years [5]. It is anticipated that bone will serve as a stable depot for aluminum in infants, as well as adults, due to the increase in bone mass and volume that takes place during an infant's rapid growth and development. With regard to the non-skeletal compartment, the half-life of aluminum in soft tissues such as the liver is short (<2 days), which indicates very little accumulation in these organs. The majority of bioavailable aluminum is excreted shortly after exposure, primarily in the urine [5], and there appears to be little difference in the renal clearance of aluminum in infants and adults at low exposures [9]. Although aluminum accumulates in the brain as well as bone over time, the concentration of aluminum in brain is lower than that in many other tissues of the body (e.g., liver, spleen), and only 1% of whole-body aluminum is present in the brain or central nervous system at any given time [8], [5].

The toxicity of aluminum depends largely on the route and length of exposure. Following single injections, occasional irritation (dermal) at the site of injection is the only adverse effect that has been reported in the published literature. Neurotoxicity in rats has been demonstrated following long-term injections of aluminum leading to aluminum overload or aluminum toxicosis [10], [11]. However, the doses tested in these studies were much higher than the maximal exposures that infants might be exposed to from vaccines, and the dosing schedules, the species of aluminum (soluble), and the routes of exposure (intraperitoneal) tested were not relevant to how infants might be exposed to aluminum through vaccination. There is no evidence for neurotoxic effects in humans who may be exposed to aluminum following single, episodic injections [12]. In addition, while aluminum hydroxide has been detected in biopsy samples of muscle obtained from some children with macrophagic myofasciitis (MMF), a rare inflammatory myopathy characterized by clinical symptoms of myalgia or arthralgia and an inflammatory infiltrate at muscle biopsy, this condition has not been shown to be caused by aluminum in vaccines [13]. The clinical symptoms that have been observed in the limited number of patients that have been diagnosed with this rare condition are considered to be due to separate, coincidental immune or neurological disorders that are unrelated to the presence of aluminum in vaccines [14], [15].