The definitions, hypotheses and concepts discussed herein represent the most important and current concepts in the field of xenobiotic particle toxicology. We have strived to present them from the cardiovascular perspective, and wherever possible, from the microvascular perspective. As is the case with any subspecialty, exceptions and caveats exist that are outside the scope of this discussion. It is our greater hope that the reader will identify such exceptions or caveats in regard to their specific microvascular research interests, and pursue them. In this regard, we extend our assistance to all interested investigators.
Cardiovascular effects (but not microvascular effects) of human particle exposures have been well-documented for some time. Despite tremendous efforts to increase the quality of ambient as well as indoor air, particle exposures will persist. This may be the result of a variety of reasons ranging from the simple fact that population density continues to increase in some proportion with global energy demands; to the continual introduction or breakdown of new or existing products and protectants (i.e. technology, surfaces, paints, surfactants, insulation, flame retardants, etc.) in our workplaces and homes. Moreover, these statements pertain only to pulmonary exposures, yet we have made a clear case herein that not all particle exposures are pulmonary in origin, or completely contained in the lung. Regardless, an obvious and present threat to human health is developing that has the potential to transcend geographic, environmental, occupational, and domestic as well as socioeconomic boundaries. Whatever form or path this threat takes, we feel it is safe to speculate that the microcirculation will play a critical role, or be a major endpoint.
It is also important to indicate that at this time, the collective threat that particle exposures impose on human health are but a fraction of those generated by heart disease or cancer. With that said, it may be germane to briefly highlight the history of similar research. While research associated with smoking and tobacco use is under the same xenobiotic umbrella, it is an entirely different line of investigation. The series of events associated with tobacco policy are strikingly similar to the pattern that particle research is currently displaying. Obvious health effects associated were identified in 1950 [74
]. The mechanisms of these exposure-dependent health effects were elucidated in the following decades, yet the incidence of use increased [145
]. While multiple reasons exist for this latter effect, in regard to public impact and policy, the known morbidity and mortality rates were simply not high enough to change the momentum of popular opinion [111
]. Furthermore, the gross economic burden of tobacco related morbidities would not become obvious until the 1980’s [145
]; and it would not be until the 1990’s that strong public policy started to become commonplace in progressive regions to decrease the impact on human health [111
]. In all, it required greater than half a century for research to begin to impact public health policy.
While convenient to compare the two, particle research differs vastly from tobacco research in that the health effects, and epidemiological outcomes of particle exposure are already largely known, and repeatable. The general public opinion in regard to particle exposure is in favor of cleaner air, and safer personal and occupational environments. Research over the past two decades has and continues to assist policy decisions in countries throughout the world. Currently and unfortunately, the weakest link in particle research is definitive mechanisms, and these mechanisms are initially observed in basic research. We have only recently documented some of the mechanisms through which particle exposures induce systemic microvascular effects. However, our studies to date have at best scratched the surface of a very deep and broad field. First, consider that fossil fuels from different geographical or refining sources produce differential emissions. Second, not all emissions are regulated or even considered equally. Third, ENMs are being produced faster than their toxicity can be assessed in even a single vascular bed, let alone a tissue or whole organism. Fourth (but not finally), the environment we live in; either from the global or domestic perspective, changes constantly, and it is only reasonable to anticipate that it will continue to do so. Each of these require a pointed investigation to merely identify a mechanism(s), and only then is it prudent to consider a discovered mechanism in terms of development, sex, co-morbidities or any other possible factor that may interact with the microvascular effects of xenobiotic particle exposures. Therefore, any forward thinking process that considers the impact of particle exposure on future human health, should include a microvascular component. Given analogous history, it is hoped that future mortality rates and fiscal projections are not the rate limiting steps necessary to bring about effective policy changes that will prevent, diminish or treat the health effects of particle exposures. But rather, definitive microvascular studies will characterize the mechanisms though which xenobiotic particles induce biologic effect and thereby, serve as a contributing force that unifies basic, translational, and clinical science in effort to drive greater health effects policies.
Peer review has rightfully requested a “smoking gun” that links pulmonary particle exposures with systemic effects. This has proven to be a warranted, but daunting challenge. However, the scope of future investigations in our opinion has recently broadened with the explosion of ENMs. At a minimum, the production of ENMs and therefore, complex exposures to them has mandated that non-pulmonary routes be considered as important, if not more so in toxicologic assessments. Therefore, traditional dogma that the lung must be part of the physiologic axis in response to particles is no longer present. In essence, this opens virtually any possibility for microvascular scientists of all backgrounds to explore how xenobiotics influence their models.
In conclusion, the microvascular scientist is uniquely poised to examine the biologic changes, differences, and outcomes associated with acute and chronic xenobiotic particle exposures, reduce their intensities, and develop post-exposure treatments in a naive and/or pathological environment. The initial cardiovascular observations/associations have been made. In a period when extramural funding is perhaps at it’s most difficult; substantial Federal and private funding is available in this field. Moreover, there is no better time to initiate investigations than when the number and scope of scientific unknowns are the greatest. Please consider this review an official “call to arms” for microvascular scientists to the field of xenobiotic particle exposures.