Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity
Abstract
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.
An unusual neuro-toxicological pattern limited to a low dose of Alhydrogel® was observed.
Neurobehavioural changes, including decreased activity levels and altered anxiety-like
behaviour, were observed compared to controls in animals exposed to 200 μg Al/kg but not at
400 and 800 μg Al/kg. Consistently, microglial number appeared increased in the ventral
forebrain of the 200 μg Al/kg group. Cerebral Al levels were selectively increased in animals
exposed to the lowest dose, while muscle granulomas had almost completely disappeared at 6
months in these animals.
We conclude that Alhydrogel® injected at low dose in mouse muscle may selectively induce
long-term Al cerebral accumulation and neurotoxic effects. To explain this unexpected result,
an avenue that could be explored in the future relates to the adjuvant size since the injected
suspensions corresponding to the lowest dose, but not to the highest doses, exclusively
contained small agglomerates in the bacteria-size range known to favour capture and,
presumably, transportation by monocyte-lineage cells. In any event, the view that
Alhydrogel® neurotoxicity obeys “the dose makes the poison” rule of classical chemical
toxicity appears overly simplistic.