Squalene has attracted the interest of arthritis researchers because of its ability to activate the immune system nonspecifically. It was one of the constituents used in the 1970s to create the first animal models of multiple sclerosis, known as experimental allergic encephalomyelitis (EAE) (Beck et al., 1976). Squalene is one of several adjuvants (such as incomplete Freund’s adjuvant) found to induce arthritis in susceptible rat strains and has been used in the generation of animal models of arthritis (Whitehouse et al., 1974; Lorentzen, 1999). The effect is so pronounced that researchers have coined the term “squalene-induced arthritis.” After a single intraarticular injection of 50 μL squalene into Lewis (Yoshino, 1996) and Dark Agouti rats (Yoshino and Yoshino, 1994), animals experienced moderate joint inflammation by day 6, followed by more severe chronic arthritis by day 21. The inflammation was marked by joint swelling and infiltration of CD5+ and αβ+ T cells. Similarly, intradermal injection of 200 μL squalene into Dark Agouti rats produced arthritis (Lorentzen, 1999). Although the mechanisms are not fully understood, the inflammation is blocked by agents that suppress T cells (Yoshino, 1996; Sverdrup et al., 1998). Animal studies do not report whether injection of squalene produces antisqualene antibodies.

In summary, there is limited published information about squalene toxicity. The human relevance of what has been published is unclear because of species differences in absorption. Squalene has been found to produce arthritis and neuropathology under select conditions in animals; the relevance to humans of these toxicity findings is uncertain.

Use of Squalene as a Vaccine Adjuvant

Squalene is currently being studied for a number of medical purposes including treatment of hypercholesterolemia (Chan et al., 1996); as an antidote to reduce the toxicity of accidentally ingested drugs (Kelly, 1999); and as an adjunctive therapy in cancer treatment to potentiate the cytotoxic activity of some chemotherapeutic agents (Kelly, 1999). The area of research that is of particular relevance to this chapter is the use of squalene as a vaccine adjuvant or as a component of a vaccine adjuvant.

The dose of an adjuvant is typically small (in the microgram range), and the route of administration is usually intramuscular. Squalene has been tested primarily as one component of the vaccine adjuvant MF59. MF59 is an oil-in-water microemulsion, consisting of squalene, polysorbate 80 (Tween 80, polyoxethylene sorbitan monooleate), and sorbitan trioleate (Graham et al., 1996). FDA has not yet approved any experimental vaccines with squalene-containing adjuvants.

The safety and efficacy of MF59 has been tested in a number of animal species with recombinant and natural antigens. Both short-term (approximately 2 weeks) and long-term (8 months) studies have been conducted and have detected some minor and transient changes in clinical laboratory parameters and histopathology (Ott et al., 1995). As described earlier in this chapter, a study by Ivins and colleagues (1995) on numerous combinations of adjuvants with the



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