Elevated aluminum excretion in patients by long-term subcutaneous immunotherapy - A cross-sectional case-control study

Background: Aluminum (Al) adjuvants have been used in vaccines and subcutaneous immunotherapy (SCIT) for decades. Despite indisputable neurotoxic properties of Al, there is no clear evidence of a causal relationship between their use and any neurotoxic side effects. However, recent rat studies have shown an accumulation of Al from adjuvants in tissues, especially in bones. Objectives: Since the human toxicokinetics of Al-adjuvants are poorly understood, this study aimed to evaluate whether up-dosed or long-term SCIT with Al-coupled extracts leads to increased Al load in humans. Methods: This observational cross-sectional case-control study explored Al excretion in hymenoptera venom allergy patients recruited in 2020 before initiation (n = 10) and during ongoing (n = 12) SCIT with Al-based preparations. Urine samples were collected before and 24 h after the SCIT injections and analyzed for aluminum content by using atomic absorption spectrometry. The cumulative administered Al dose was extracted from patient records. Patients receiving long-term immunotherapy were treated between 2.8 and 13.6 years (mean 7.1). Other potential sources of Al exposure were surveyed. Results: Patients who had received Al-coupled immunotherapy for several years showed significantly (p < 0.001) higher Al excretion than the controls at initiation of immunotherapy (mean 18.2 mu g/gC vs. 7.9 mu g/gC) and predominantly (73%) were above the 95th percentile of the general populations' exposure (>15 mu g/gC), however, without reaching levels of toxicological concern (>50 mu g/gC). Taking both groups together excreted Al levels correlated with the cumulative administered Al dose from SCIT (linear regression: Al-urine = 8.258 + 0.133*Al-cum; p = 0.001). Discussion: These results suggest a relevant iatrogenic contribution of long-term SCIT to human internal Al burden and potential accumulation. Considering the medical benefits of Al-adjuvants and SCIT a differentiated risk-benefit analysis is needed. For certain scenarios of potential toxicological concern in clinical practice biomonitoring might be advisable.