To properly assign mechanisms or causes for toxic effects of nanoscale materials, their properties and characteristics both outside and within the biological environment must be well understood. Scientists have many tools for studying the size, shape, and surface properties of particulates outside of the physiological environment; however, it is difficult to measure many of these same properties in situ without perturbing the environment, leading to spurious findings. Characterizing nanoparticle systems in situ can be further complicated by an organism's active clearance, defense, and/or immune responses. As toxicologists begin to examine nanomaterials in a systematic fashion, there is consensus that a series of guidelines or recommended practices is necessary for basic characterization of nanomaterials. These recommended practices should be developed jointly by physical scientists skilled in nano characterization and biological scientists experienced in toxicology research. In this article, basic nanoparticle characterization techniques are discussed, along with the some of the issues and implications associated with measuring nanoparticle properties and their interactions with biological systems. Recommendations regarding how best to approach nanomaterial characterization include using proper sampling and measurement techniques, forming multidisciplinary teams, and making measurements as close to the biological action point as possible.

Although mineral oils are generally considered nontoxic and have a long history of use in humans, the mineral oil Bayol F (incomplete Freund's adjuvant, IFA) and certain mineral oil components (squalene and n-hexadecane) induce lupus-related anti-nRNP/Sm or -Su autoantibodies in nonautoimmune mice. In the present study, we investigated whether medicinal mineral oils can induce other types of autoantibodies and whether structural features of hydrocarbons influence autoantibody specificity. Female 3-month-old BALB/c (16-45/group) mice each received an i.p. injection of pristane (C19), squalene (C30), IFA, three medicinal mineral oils (MO-F, MO-HT, MO-S), or PBS. Sera were tested for autoantibodies and immunoglobulin levels. Hydrocarbons were analyzed by gas chromatography/mass spectrometry. IFA contained mainly C15-C25 hydrocarbons, whereas MO-HT and MO-S contained C20-C40, and MO-F contained C15-C40. Pristane and n-hexadecane were found in IFA (0.17% and 0.10% w/v, respectively) and MOs (0.0026-0.027%). At 3 months, pristane and IFA induced mainly IgG2a, squalene IgG1, and MOs IgG3 and IgM in sera. Anti-cytoplasmic antibodies were common in mice treated with MO-F, as well as those treated with pristane, squalene, and IFA. Anti-ssDNA and -chromatin antibodies were higher in MO-F and MO-S than in untreated/PBS, squalene-, or IFA-treated mice, suggesting that there is variability in the induction of anti-nRNP/Sm versus -chromatin/DNA antibodies. The preferential induction of anti-chromatin/ssDNA antibodies without anti-nRNP/Sm/Su by MO-S and MO-F is consistent with the idea that different types of autoantibodies are regulated differently. Induction of autoantibodies by mineral oils considered nontoxic also may have pathogenetic implications in human autoimmune diseases.

In theory, topical delivery has substantial potential to treat local and some systemic disease states more effectively than systemic delivery. Unfortunately many, if not most, drug candidates for topical delivery lack the requisite physicochemical properties that would allow them to permeate the skin to a clinically useful extent. One way to overcome this obstacle to effective topical delivery is to make a transient derivative of the drug, a prodrug, with the correct physicochemical properties. But what are those correct properties and can the directives for the design of prodrugs be applied to the design of new drugs, their analogs or homologs? For some time increasing the lipid solubility (S (LIPID)) or its surrogate, the partition coefficient between a lipid (LIPID) and water (AQ) (K (LIPID:AQ)), has been the standard working paradigm for increasing permeation of the skin, and the permeability coefficient (P = distance/time) has been the quantitative measure of the result. However, even the earliest reports on non-prodrugs such as alcohols showed that working paradigm was incorrect and that P should not be the relevant measure of permeation. The shorter chain and more water soluble alcohols exhibiting lower K (LIPID:AQ) values gave the greater flux values (J = amount/area x time; the more clinically relevant measure of permeation), regardless of whether they were applied neat or in an aqueous vehicle, while P showed opposite trends for the two applications. Subsequently a large volume of work has shown that, for prodrugs and non-prodrug homologs or analogs alike, S (AQ) (not solubility in the vehicle, S (VEH)) as well as S (LIPID) should be optimized to give maximum flux from any vehicle, J (MVEH): a new working paradigm. The dependence of J (MVEH) on S (AQ) is independent of the vehicle so that S (AQ) as well as S (LIPID) are descriptors of the solubilizing capacity of the skin or S (M1) in Fick's law. The inverse dependence of J (or P) on molecular weight (MW) or volume (MV) remains. Here we review the literature that leads to the conclusion that a new working paradigm is necessary to explain the experimental data, and argue for its use in the design of new prodrugs or in the selection of candidate analogs or homologs for commercialization.

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