Non-linear dose-response of aluminium hydroxide adjuvant particles: Selective low dose neurotoxicity

Abstract

Nonlinear dose-response of aluminium hydroxide adjuvant particles: selective low dose neurotoxicity.Toxicology http://dx.doi.org/10.1016/j.tox. 2016.11.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 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.

Aluminum exposure for 60 days at human dietary levels impairs spermatogenesis and sperm quality in rats

“…For this, we have chosen a dose of Al exposure at a lower level, one that better characterized the reproductive dysfunction, and then we have compared with Al at a higher dose. Unexpectedly, but in accordance with recent discoveries about Al neurotoxicity [37], Al at the lower dose of 8.3 mg/kg bw/day had worse effects on the reproductive system. Specifically, the testis histoarchitecture of rats exposed to Al at 100 mg/kg bw/day was better organized with a larger number of sperm cells and without concomitant inflammation.…”

“…Crépeaux et al [37], by investigating the effects of the adjuvant aluminium oxyhydroxide This may seem as though the dose is not the most important issue regarding Al toxicity, but the exposure conditions, intrinsic and individual characteristics and, consequent distribution and bioavailability through the body. Our results suggest that current safety limits (e.g.…”

A self-aggregating peptide: implications for the development of thermostable vaccine candidates

“…On the other hand, new methodologies have been used such as subunit and recombinant vaccines that weakly stimulate the immune system and their immunological effect is of short durability, so they require the use of adjuvant to potentiate their effect. Currently available adjuvants may lead to unwanted effects such as the generation of granulomas, allergies and neurotoxicity due to the different components used [5,8,9]. However, even with the evolution of vaccines, vaccination continues to represent a high cost mainly for developing countries, due to the fact that they have the highest number of people vulnerable to infectious diseases [10][11][12].…”

The Manganese Salt (MnJ) Functions as A Potent Universal Adjuvant

“…The adjuvant activity of Aluminum was found by Alexander Glenny and his colleagues in 1926 41 , now almost one century later, we reported the adjuvant activity of another metal-Manganese. Adjuvant effect is essentially attributed by type I-IFN-promoted dendritic cell maturation and migration to prime adaptive immune responses along with 1) local up-regulation of chemokines, including CCL2 (MCP-1) and CCL3 (MIP-1α) to recruit immune cells to the injection site; 2) increase of antigen uptake by immune cells; 3) induction of monocyte differentiation into dendritic cells 8, 36, 37 . We found that Mn 2+ induced APCs to produce both IFNβ and various IFNαs, which were surprisingly not induced by LPS, together with many co-stimulatory and MHC molecules crucial for antigen presentation and chemokines for immune cell recruitment.…”

“…In fact, Alum is the only human adjuvant widely used, partly due to its minimal reactogenicity and inexpensiveness 7 . However, Alum-adjuvanted vaccines need repeated administrations which may cause or manifest its adverse effects including increased IgE production and neurotoxicity 8 . In addition, Alum mainly induces T helper 2 (TH2) cell response through NLPR3 inflammasome activation 9–11 , but not TH1 or cytotoxic T-lymphocyte (CTL) response 1, 12 .…”