ABSTRACT
Today, nanotoxicology is a recognized specialty within the field of toxicology. As a specialized field of study, it was brought to the forefront when inhalation toxicologists recognized that ultrafine particulate matter, recognized as contributing factors to the etiology of respiratory and cardiovascular diseases, existed at the nanoscale [6]. This, and additional experimental evidence of potential adverse effects, were later expanded on in the first-ofits-kind review in the journal Science [7] to include potential genotoxicity, inflammation, generation of neoantigens and autoimmunity, mitochondrial dysfunction, and oxidative stress. Of key interest in our own laboratory is that nanoparticles, unlike their bulk counterparts, because of their size and unique physico-chemical properties and unique pharmaco/toxicokinetics [8], may gain access to the central nervous system. While desired therapeutically to circumvent the blood-brain barrier (BBB), it may be potentially detrimental, depending on the particle chemistry, coating, and accumulation [9]. Many published reviews and studies have reiterated or demonstrated these effects in experimental models, in vivo and in vitro. However, of concern and of need for remediation is the observation that those involved in toxicological studies, with environmental chemical assessment backgrounds, often concentrate their efforts only on environmentally/occupationally relevant chemical species (e.g., metal oxides: manganese, nickel, titanium), usually as simple single entities, whereas those in the nanopharmaceutical sphere appear to be more focused on the therapeutic agent, with little consideration for the chemical nature of the nano-carrier, outside its efficiency in being a carrier. This phenomenon appears to have spilled over to reviewers at funding agencies as well. It is understandable that the US Environmental Protection Agency (EPA) is interested in particular chemical classes of nanomaterials under the Toxic Substances Control Act (TSCA), relevant to ambient air or water or soil pollution, and seek to regulate their emissions [10]. However, it is incomprehensible why a reviewer (or reviewers) for the National Institute of Health (NIH) may insist that an experimental paradigm to evaluate intravenous chitosan or silver or gold, potential
delivery systems for pharmacotherapeutics, is only valid if done through inhalation exposure because the preponderance of published in vivo toxicological studies are of inhalation toxicology studies. This begs the question, can the specialties of environmental and ecological nanotoxicology provide expertise to those in the specialty of nanopharmaceutics (and the converse), or must they each occupy themselves with their individual trees? 57.3 Embracing the ForestIn light of the unique properties of nanomaterials (vs. bulk), some of these challenges with the therapeutic use and safety assessment of nanomaterials, including something as basic as how one defines dose, have been highlighted in editorials and commentaries published in recent years [11, 12], where more than Paracelsus’ adage and mainstay of toxicity/safety studies “sola dosis facit venenum” (the dose makes the poison) are at play. This is further compounded by the fact that in the realm of nanomedicine, it is not the behavior and safety of the nanoparticle alone per se that is concern, but also the combination of nanoparticle and therapeutic agent or multifunction nanoformulations, or what has been termed by some toxicologists as “sophisticated materials” [13]. This not unlike the assessment of individual environmental toxicants while ignoring the real-world of human exposure to complex mixtures that has only been acknowledged in the last decades.While some headway is being made in attempts to arrive at unified screening and testing assays for high throughput evaluation of nanotoxicity and have been the topic of several task forces in Europe and the US [14-17], many of these committees evidence little Pharma participation. Again, many of the testing paradigms appear to be for simple materials and rely on alternative toxicological screens (e.g., zebra fish, cell culture proliferation, and oxidative stress assays), rather than reflecting the complexity of nanoformulated therapeutics and the complexities of behavior in model surrogates of the intended target organism. Even when in vivo or in vitro studies are conducted, few studies provide adequate characterization of the nanomaterial in the wet phase
(as compared to the dry synthesis product), which is of greater relevance to the test condition. In that regard, it is gratifying to see that many publications require chemical characterization of test material be included for peer-review [11]. Furthermore, the benefit of predictive models based on quantitative structure-activity relationships (QSAR) and physiologically based pharmacokinetic (PBPK) modeling, core to many drug and nondrug research and development efforts, while promising, remain in their infancy and are often contradictory and equivocal in the realm of nanomaterial assessment [18, 19].
