Defining the molecular structure of the transmissible spongiform encephalopathy (TSE) agent is important both for underpinning risk assessments and for developing and understanding decontamination strategies. Recent studies have shown that oligomeric particles comprising 14-28 prion protein (PrP) molecules are much more infectious than larger fibrils (prion rods) or indeed smaller oligomers (trimers) and PrP monomers. Here, results from deactivation studies (with alkali, heat, hexane or formaldehyde) are interpreted in terms of the infectious nucleation seed comprising 14-28 PrP molecules held together by interactions with amphipathic phospholipid (PL) or more probably sphingolipid (SL) from the host. According to the PrP/lipid hypothesis, the strength of the protein/lipid interactions accounts for the high thermostability of TSE infectivity and for differences in thermostability between strains. The implications of the molecular biophysics data for environmental TSE risk assessments are discussed with respect to behaviour in soil. While formaldehyde appears to cause inactivation of scrapie infectivity by increasing the ID50, the dose-response is complicated by apparent heterogeneity between hamster subpopulations in susceptibility. The process of inactivation by formaldehyde may be due to cross-linking the highly infectious 14-28 PrP oligomers into larger, but less infectious aggregates. This process appears more reversible in some hamster subpopulations than others.