Monteiro-Riviere with her new TEM scope .
By Vishwas Rai and Bozena B. Michniak-Kohn
Dr. Nancy A. Monteiro-Riviere is a Regents Distinguished Research Scholar and University Distinguished Professor of Toxicology and is one of the world’s leading nanotoxicologists in the field of investigative dermatology with an extensive understanding on the topic of engineered nanomaterials’ effects on human health and the environment. She is a pioneer in the field of safety assessment of nanomaterials. She has assessed the interactions and toxicity of environmental chemicals, drugs, and engineered nanomaterials using novel in vivo and in vitro methods, focusing on their skin absorption, penetration, and toxicity. In addition to this nanotechnology-focused research, she currently is developing alternative in silico and in vitro methods to study the safety of new dietary ingredients in pet food for dogs.
She has received more than $14 million in research funding from the National Institutes of Environmental Health Sciences, agencies of the Department of Defense, the Environmental Protection Agency (EPA), and other federal and industrial sponsors. She has presented her research at 145 international and national meetings and published over 280 manuscripts and book chapters in the fields of skin toxicology and nanotoxicology. Her work has been cited over 5,500 times. She is an editor of the books Toxicology of the Skin (Target Organ Series), Nanotoxicology: Characterization, Dosing and Health Effects, and the second edition of Nanotoxicology: Progress Toward Nanomedicine. She has trained numerous graduate students and postdoctoral fellows. In addition to being an associate editor for the journals WIREs Nanomedicine & Nanobiotechnology and Materials Science and Engineering: C, she serves on six editorial boards. She has also served on several national and international panels, including many in nanotoxicology for the National Research Council of the National Academies, the International Council on Nanotechnology, and NATO Advanced Research Workshop on Nanomaterials.
Dr. Monteiro-Riviere is a fellow in the American College of Toxicology and the Academy of Toxicological Sciences, where she was elected to its board of directors. She is a past president of both the dermal toxicology and in vitro toxicology specialty sections of the National Society of Toxicology.
She received Ph.D. in anatomy and cell biology from Purdue University, U.S.A., in 1981, followed by a two-year postdoctoral fellowship in toxicology at the Chemical Industry Institute of Toxicology (CIIT). She served North Carolina State University (NCSU) for over 28 years, culminating as a professor of investigative dermatology and toxicology. She is also an emeritus professor at NCSU and a professor in the UNC/NCSU Joint Department of Biomedical Engineering and a research adjunct professor of dermatology at UNC School of Medicine. She established the new Nanotechnology Innovation Center of Kansas State University (KSU) in 2012, where she currently is in the process of hiring new faculty members.
Q Please tell us about your undergraduate degree in science with a biology major. How did that shape your future career?
A I had a great undergraduate education in the basic sciences and fell in love with comparative anatomy at Stonehill College in North Easton, Massachusetts, which is a small private Catholic college founded by the Holy Cross fathers. My experience stimulated me to enter graduate school and to pursue a degree in that field.
Q How did you select Purdue University for higher studies? Tell us about your graduate research. Did you have any surprises, or was the experience as you had expected?
A My husband and I had applied to several institutions. My husband wanted a DVM and a Ph.D. combined degree so he could understand the whole animal for research. We both had been accepted at the University of Pennsylvania and Cornell University, but then Purdue offered us full scholarships. We were newly married and did not want to go into debt. Purdue made it a lot easier to make that decision! It had a veterinary college, and Indiana University Medical School was also located in that department. I had the best of both worlds, because I took all the veterinary gross and microscopic anatomy and neuroanatomy courses, but I also had all the human gross anatomy, human neuroanatomy, and human histology exposure. I wanted to be the best comparative anatomist.
Q What was the topic of your doctoral research?
A I studied the ultrastructural development of nerve fibers in the skin of pigs. During this time I helped to discover a new smooth muscle in porcine skin, which we termed “musculus interfollicularis” or interfollicular smooth muscle based upon its location and attachments. This muscle is found midway between the level of the sebaceous gland and the apocrine sweat gland, and it spans the triad of hair follicles. We postulated that this muscle upon contraction draws the base of the aligned follicles together into a triangular conformation and rotates the outer two follicles of the triad. It was exciting to discover a new muscle in an animal that has been extensively studied for decades.
Q What was the topic of your postdoctoral research? What made you choose your postdoctoral research topic(s)?
A My postdoctoral fellowship was at CIIT in Research Triangle Park, North Carolina. CIIT conducted many inhalation studies on numerous chemicals. I studied the pathogenesis of chemically induced toxicity of the respiratory system with special reference to the nasal passages. Since my degree was in comparative veterinary anatomy and cell biology, I felt well versed in all aspects of anatomy. I studied the ultrastructural characterization of the nasal respiratory epithelium in the rat. I conducted macroscopic, microscopic, and ultrastructural anatomy studies on the rat nasal cavity, which revealed three new cell types: nonciliated columnar, cuboidal, and brush cells that were not previously characterized in the rat nasal mucosa. Then I evaluated the acute toxicity of the rat respiratory epithelium exposed to formaldehyde gas.
Q From a modern-day perspective in which most scientists stay for only a few years in any one position, you spent 28 years at NCSU. That is quite an achievement.
A It all depends on how you look at it. I never thought I would stay at NCSU that long. It was located down south, and I was from Massachusetts and wanted to go back home with family. I still prefer the north, but once at NCSU, we adjusted to the hot and humid climate. We loved being close to the ocean and the beautiful Outer Banks of North Carolina. We enjoyed our new positions and made lifelong friends. Both my husband and I had several job opportunities in the past, and at times we did some hard thinking and were prepared to move. I felt as if the ocean kept calling us back. We built a beach home on the Outer Banks, which reminded us of home. However, we decided to stay in the area because we had started a family and were both comfortable in our jobs. We had some large grants, were publishing with great colleagues, and had a great team of technical staff.
Q Looking back, do you regret staying at one institution for such a long time?
A Staying at one institution has some positives and negatives. I think we could have moved ahead faster if we moved a few times, but we would also not have had the opportunity to develop mature research programs. There are obvious trade-offs in any decision we make.
Q Please share any advice for the upcoming generation of professionals heading to academic positions.
A Academia is the only environment I have experienced, so I don’t have anything else to compare it with. I felt that I did great in academia, but I do have the entrepreneurial spirit. In the early 1990s, we were approached to start our own company and looked into that for a while, but we were apprehensive about leaving two tenure-track positions and a great technical team, and of course relocating three small children! My career decisions were always made in the context of family. Staying at NCSU for so long did allow roots to be established and thereby provided stability for our family.
Q Please provide readers with a summary of your research work at NCSU. What were some of the highlights and their outcome? Any disappointments?
A My research at NCSU focused on skin drug delivery, toxicity, and nanotoxicology research. Initially, I was very interested in skin toxicology, whether it was assessing in vivo toxicity, skin absorption, dermal penetration, or in vitro toxicity of chemicals. I also was interested in working with 3D models of skin and assessed many of them for toxicity and absorption. I conducted numerous skin absorption and toxicity studies for industrial and pharmaceutical sponsors and the Department of Defense with chemical agents, pesticides, and jet fuels.
Over the years, my research area has shifted from chemical percutaneous absorption and toxicity to nanotoxicology. Nanomaterials are the building blocks of the next industrial revolution according to President Clinton’s National Nanotechnology Initiative in 2000. Nanomaterials have attracted a great deal of attention because they are stronger than steel but at a fraction of the weight. Nanoparticles, when engineered appropriately, exhibit a variety of unique and tunable chemical and physical properties. These characteristics have made engineered nanoparticles central components in an array of emerging technologies. These unique properties may also result in similarly unique biological effects. Although they have widespread potential applications in material sciences and engineering, the toxicology of these components has not been thoroughly evaluated under environmental and occupational exposure scenarios.
A major issue is the health impact to humans exposed to nanomaterials by dermal routes. There is limited literature available on the toxicology of unmodified manufactured nanoparticles. Since there is limited information on how nanotubes can react with living cells, our laboratory has assessed the interaction between multi-walled carbon nanotubes (MWCNTs) and human epidermal keratinocytes (HEKs) using transmission electron microscopy and the release of the proinflammatory cytokine interleukin 8 (IL-8) as an early marker of biological response. We have reported that chemically unmodified MWCNTs were present within cytoplasmic vacuoles of the HEKs at all the time points. The MWCNTs also induced the release of the proinflammatory cytokine IL-8 from HEKs in a time-dependent manner. The data clearly showed that MWCNTs, not derivatized nor optimized for biological applications, were capable of both localizing within and initiating an irritation response in a target epithelial cell, a primary route of occupational exposure for manufactured nanotubes.
This research was nationally and internationally recognized, incorporated into a nanotechnology exhibit at the London Science Museum, and highlighted in Science. The manuscript, published in Toxicology Letters, was the journal’s most cited paper for five years. This was an exciting feeling. A second well-cited paper in Toxicology and Applied Pharmacology detailed the interaction of nanoparticles with assay markers to cause erroneous results with classic cell viability assays. Science Direct identified this as one of their 10 Hottest Articles in 2010. I will continue to study dermal penetration and to assess cutaneous toxicology of many different types of nanomaterials. I hope to continue to have a leadership role in the field of consumer and occupational health exposure related to nanotechnology.
It was interesting how my nanomaterial research program began when I was an invited participant at the second annual National Academy of Sciences conference on “Designing Nanostructures at the Interface Between Biomedical and Physical Systems.” This conference was to encourage interdisciplinary learning and to initiate research collaborations between active researchers in different disciplines. I was awarded a highly competitive grant from the Keck Futures Initiative with a Rice University collaborator, Dr. Andy Barron, which provided seed money to acquire preliminary data in nanotoxicology research. This was truly the seed that allowed my research program to grow.
Another seminal project that secured my international reputation in this emerging field was being a U.S. partner on the European Union NANOMMUNE Project based at the Karolinska Institute in Stockholm, Sweden. This has initiated friendships and collaborations that persist today.
Q You have been doing a lot of traveling recently. Please share with us some highlights from your recent trips.
Nancy Monteiro-Riviere with her husband, Jim Riviere,
visiting Longmen Grottoes in China.
A Of course, I attended the CRS Annual Meeting in Hawaii in July. My big trip was to Asia in October. I was invited to lecture at the National Center for Veterinary Drug Safety Evaluation and at the China Agricultural University in Beijing. I also traveled to speak at the 12th Chinese Society for Veterinary Pharmacology and Toxicology Congress in Zhengzhou. Then I lectured on the comparative anatomical factors that affect drug delivery at Huazhong Agricultural University in Wuhan. After that, I traveled further south to lecture at the South China Agricultural University in Guangzhou. Then I spent the weekend in Macau and moved on to Hong Kong and then Nagoya, Japan, to speak at the 6th International Symposium on Nanotechnology, Occupational and Environmental Health. Finally, I visited Tokyo for the first time. I saw many sites along the way and climbed the Great Wall of China, saw the Summer Palace, Forbidden City, Olympic sites, Beijing National Stadium, Temple of Heaven, and Tiananmen Square. I ate Peking duck, dumplings, and many different types of food. In Zhengzhou, I saw the Shaolin monastery; I saw the kung fu masters as well as the Pagoda Forest. In Wuhan, we climbed the Yellow Crane Tower and visited East Lake, the Hubei Museum, and the Botanical Gardens. Then we went to Luoyang to see the White Horse Temple and the large Buddhas at Longmen Grottoes. In Guangzhou, we took a cruise down the Pearl River and saw Canton Tower, Baiyun Mountain, and a Vegas-style show at the Chimelong International Circus. All of these places were fascinating, and we had wonderful hosts who took great care of us to make sure we had fun in between the lectures. I ate so many different things that they are too numerous to mention, but I did try snake. It really wasn’t that bad, but do not eat the skin—that was terrible!
Q Please list some of the most important publications from your lab that you feel have had the highest impact. Please let us know why you selected these particular journal articles.
A Here are six journal articles selected for their impact and relevance in the field.
Monteiro-Riviere, NA, Nemanich, RJ, Inman, AO, Wang, YY, Riviere, JE. Multi-walled carbon nanotube interactions with human epidermal keratinocytes, Toxicol. Lett. 155: 377-384 (2005). This was one of the first papers that showed that nanomaterials not derivatized nor optimized for biological applications are capable of localizing within and initiating an irritation response in a target epithelial cell.
Monteiro-Riviere, NA, Inman, AO, Zhang, LW. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line, Toxicol. Appl. Pharmacol. 234: 222-235 (2009). This study showed that classic cytotoxicity assays can interact with nanoparticles to give inaccurate results, making extrapolating in vitro data to in vivo exposure or risk assessments problematic.
Ryman-Rasmussen, JP, Riviere, JE, Monteiro-Riviere, NA. Surface coatings determine cytotoxicity, and irritation potential of quantum dot nanoparticles in epidermal keratinocytes, J. Invest. Dermatol. 127: 143-153 (2007). This paper showed that the surface coating of nanoparticles is the primary determinant of cytotoxicity and immunotoxicity.
Zhang, LW, Monteiro-Riviere, NA. Mechanisms of quantum dot nanoparticle cellular uptake, Toxicol. Sci. 110: 138-155 (2009). This was one of the first papers that provided the mechanism of quantum dot nanoparticle cellular uptake and showed that the surface coating, size, and charge of these nanoparticles are important physicochemical parameters in determining cell uptake in mammalian cells for cancer diagnosis, cancer treatment, and drug delivery.
Monteiro-Riviere, NA, Wiench, K, Landsiedel, R, Schulte, S, Inman, AO, Riviere, JE. Safety evaluation of sunscreen formulations containing titanium dioxide and zinc oxide nanoparticles in UVB sunburned skin: An in vitro and in vivo study, Toxicol. Sci. 123: 264-280 (2011). Because of the concern that nanoparticles in sunscreens may be hazardous, this paper showed that in vitro and in vivo skin studies with titanium dioxide and zinc oxide formulations had minimal penetration but no transdermal absorption.
Xia, XR, Monteiro-Riviere, NA, Riviere, JE. An index for characterization of nanomaterials in biological systems, Nat. Nanotechnol. 5: 671-675 (2010). This study provided nanodescriptors for an adsorption index that can be used to develop pharmacokinetic and safety assessment models for nanomaterials.
Q As a leader in the field of investigative dermatology, what are some of the primary challenges currently faced by the scientific community?
A The need for human studies to assess the true safety of nanomaterials. In vitro and animal studies can only go so far.
Q Please tell us about your recent move to KSU. What are some of your roles and responsibilities there?
A I have only been at KSU for a little over one year. I was hired to establish a new nanotechnology research center from the ground up. This is an exciting opportunity. I spent the majority of my time trying to get my laboratory up and running. That means starting all over again by going out for bids for new equipment and ordering the new instruments and supplies. Setting up my new transmission and scanning electron microscopes took several months. This included working with engineers to create new rooms to house these scopes. Requesting permission from U.S. Customs and Border Protection and answering over 30 pages of questions on the uses of the TEM scope was quite a feat. During this time, I had to maintain my grant funding with EPA and an industrial sponsor and keep on task with reports. Moving to a new university meant that many tests were required for health and safety compliance, chemical safety compliance, and so on. I had to write more IACUC protocols and take over 40 modules of university procedures. We have a lot of new rules to follow. I had to hire a new lab manager, technicians, and postdoctoral fellows. This also meant writing new descriptions for these positions, preparing advertisements, selecting candidates, and making hiring decisions. In addition, I created my web page (nicks.ksu.edu). It meant a lot of busy work all at once rather than slowly over the years. Currently, I am in the process of selecting candidates for my EM scientist position and selecting seven new faculty members for our cluster hire for the new centers. However, this is an exciting and invigorating experience, because KSU has provided some 15,000 square feet of new space and substantial funding to initiate and sustain these new programs.
Q Please share some of your views on personal and professional life management with young professionals.
A My personal life management motto is to work hard but play hard too. I have raised three children (an engineer, a pharmacist, and a communication major) during my career. Now it is time for me to do what I want. So my husband and I started a new career by moving to Kansas with a new challenge of establishing new research centers.
Q Do you have time for any particular hobbies?
By the lotus pond at East Lake in Wuhan, China.
A What is that? I just about have time to read the newspaper. My husband and I love to go to Las Vegas occasionally. I enjoy going to our oceanfront beach home on the Outer Banks of North Carolina to walk on the beach, view the birds and dolphins, and sometimes we get lucky and see whales from our deck. I spend many hours on my deck reading and reviewing journal papers, grants, and so on. Thank God for the Internet: I can be reached anywhere and take conference calls from anywhere in the world while sitting on an oceanfront deck.