Toxicology

Anne-Michelle Ruha, MD is a Professor of Internal Medicine and Emergency Medicine at the University of Arizona College of Medicine – Phoenix. She is board certified in emergency medicine, medical toxicology, and addiction medicine and primarily practices medical toxicology at Banner – University Medical Center Phoenix (BUMCP) and Phoenix Children’s Hospital. She serves as Chief of the Department of Medical Toxicology and Section Chief for Addiction Medicine at BUMCP. She is active in medical education, having spent 14 years as the director of the Medical Toxicology Fellowship Program at the University of Arizona College of Medicine – Phoenix. She continues to train fellows, residents and students in both the Medical Toxicology and Addiction Medicine fellowship programs. Dr. Ruha’s primary research focus is in the area of envenomations and antivenom. She is the Principal Investigator of the American College of Medical Toxicology’s (ACMT) Toxicology Investigator Consortium’s North American Snakebite Registry and has served as primary site investigator for clinical trials of snake and scorpion antivenoms. She has served as a Clinical Investigator with the University of Arizona VIPER Institute as well as a member of it’s Advisory Board. Dr. Ruha has published over 30 studies and case reviews in the peer-reviewed medical literature on the topic of envenomations, as well as chapters on snake, scorpion, and spider envenomations in leading medical textbooks including Goldfrank’s Toxicologic Emergencies and Critical Care Toxicology. In addition to envenomations, her other areas of clinical focus are the management of toxicity and withdrawal related to substance use disorders and acute care toxicology.

Xinxin Ding, PhD, department head, Pharmacology and Toxicology, College of Pharmacy—studies enzyme function, regulation and genetics as applied to translational research for drug safety and efficacy and genetic and environmental risks for chemical toxicity. Author of nearly 200 peer-reviewed papers, book chapters and articles, he serves as associate editor for “Drug Metabolism and Disposition” and “Acta Pharmaeutica Sinica B.” Grants from the National Cancer Institute and National Institute of Environmental Health Sciences of the National Institute of Health fund his work, in part. Former chair of the NIH XNDA study section (2016-2018), he currently chairs (2018-19) Drug Metabolism and Disposition Division of the American Society for Pharmacology and Experimental Therapeutics..

Donato Romagnolo, MSc, PhD, has served as a member of study sections for the National Institutes of Health, the U.S. Department of Defense, the Susan G. Komen Breast Cancer Foundation, and as a scientific reviewer for nutritional, cancer, and pharmacology and toxicology scientific journals. Dr. Romagnolo is a member of the Training Grant in Cancer Biology at the University of Arizona. Dr. Romagnolo's research focuses on: 1) mechanisms of epigenetic silencing of tumor suppressor genes by environmental and dietary xenobiotics, and 2) role of dietary bioactive food components in the etiology and prevention of cancer and inflammation. For the last 14 years, Dr. Romagnolo's research has been funded by grants from the National Institutes of Health, the U.S. Army Department of Defense, the Susan G. Komen for the Cure and the Arizona Biomedical Research Commission.Some of his research reveals humans are exposed to a complex mixture of ligands of the aromatic hydrocarbon receptor (AhR). Prototypical AhR agonists include the polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P), and the dioxin-like compound 2,3,7,8 tetrachlorodibenzene(p)dioxin (TCDD). Increased incidence of breast cancer is documented in human populations of industrialized areas where high levels of dioxins are found in the air, soil, drinking water, and cow milk. Unlike PAH, TCDD is not metabolized and it promotes tumor development. Population studies reported the presence of TCDD in breast milk, suggesting this agent may accumulate in breast tissue and be a potential risk factor in mammary neoplasia. The in-utero activation of the AhR with TCDD increased the susceptibility to mammary carcinogens in rat female offspring. The activation of the AhR pathway may increase the susceptibility to breast cancer through epigenetic silencing of tumor suppressor genes, including p16 and p53, while inducing transcription of the proinflammatory COX-2 gene.

R. Clark Lantz, PhD Exposure to environmental toxicants alters lung structure and function and leads to chronic lung disease, including cancer. Current investigations are examining the effects of exposure to environmentally relevant doses of arsenic and uranium. Arsenic is a naturally occurring metalloid found in water, soil and air. Exposure to inorganic arsenic occurs worldwide through environmental (contaminated drinking water, air, food and domestic fuel sources) and occupational exposures (smelting industries, pesticide production). In addition to its association with non-malignant diseases, arsenic is of major worldwide health concern because of its carcinogenic potential in humans. Epidemiologic studies have associated arsenic exposure with an increased risk of multiple human cancers including lung, skin, bladder, kidney, liver and stomach cancers. Our current research is focusing on two models to examine the effects of arsenic in the lung. One model relies on exposure to arsenic during lung development, both in utero and postnatally. We have shown that exposure of pregnant female mice and their offspring to 50 or 100 ppb as arsenic in drinking water resulted in altered pulmonary function in 28 day old animals. Airways were more responsive to bronchoconstriction. These changes were specific for exposure during development and were not reversible if arsenic was withdrawn. Associated with these functional changes, arsenic exposure resulted in a dose-dependent increase in airway smooth muscle and alterations in airway connective tissue expression. We are currently analyzing mediators that may be involved in this response to arsenic. In addition, we are beginning investigations into the effect of inhalation of arsenic on lung development. We are also currently using in vitro airway epithelial cell cultures to determine the effects of arsenic on wound repair and epithelial barrier function. In collaboration with Dr. Scott Boitano, we have been able to show that arsenic inhibits wound repair. This may be due in part to arsenic- induced alteration in calcium signaling. We have also been able to show that arsenic alters expression of epithelial junctional proteins and decreases epithelial barrier resistance. Research is also on going to identify protein alterations in lung lining fluid as biomarkers of exposure and effect. This study uses the technology of proteomics to evaluate and identify biomarkers of chronic environmental exposure to arsenic by evaluating large numbers of proteins simultaneously. We are comparing alterations in protein expression in exposed human populations in Arizona and Mexico, human cell lines, and in vivo rodent studies. Patterns of alterations in protein expression, both common and unique to these different test systems, will be identified. Finally, we are evaluating the chemical genotoxicity of uranium. In addition to its radioactive effects, uranium may also have adverse health effects because of its interactions with cellular macromolecules. We have found that uranium causes DNA damage through forming adducts which results in single strand breaks. In addition, uranium also inhibits double strand break DNA repair in airway epithelial cells. Keywords: pulmonary toxicology, arsenic, early life exposures

Walter T. Klimecki, DVM, PhD, is an Associate Professor in the Department of Pharmacology and Toxicology in the College of Pharmacy at the University of Arizona. Dr. Klimecki holds joint appointments in the College of Medicine, the College of Public Health, and the Arizona Respiratory Center. He is a Full Member of the Southwest Environmental Health Sciences Center (SWEHSC) where, together with BIO5 director Martinez and BIO5 Statistics Consulting Service director Billheimer, he leads the Integrative Health Sciences (IHS) Center at SWEHSC. The IHS is a translational research support core at SWEHSC, focused on lowering the “activation energy” for translational research.Dr. Klimecki’s research focuses on the toxicology of metals in the environment, an issue particularly relevant in our mining-intensive state. His research work has encompassed a wide range of experimental approaches, from epidemiological studies of arsenic-exposed human populations, to laboratory models including cell culture and rodents. Using cutting edge genetics tools, Dr. Klimecki’s group recently published the first report of an association between human ancestry and response to environmental toxicants. In this provocative work, his group found that individuals whose genomes were comprised of DNA with its origins in the indigenous American populations processed ingested arsenic in a less harmful manner than did individuals whose genomes had their origins in Europe. Using laboratory models his group made ground-breaking discoveries of the impact of arsenic exposure on a process known as autophagy, in which cells digest parts of their own machinery in a sort of “cash for clunkers” arrangement. The ability of arsenic to perturb this process is only now being appreciated by the toxicology community, thanks to the work of the Klimecki Lab. Dr. Klimecki was recently elected as a Vice President-elect to the Metals Specialty Section of the Society of Toxicology, the preeminent scientific toxicology organization in the world. Dr. Klimecki’s research is highly collaborative: his grants and publications have included many BIO5 members, including BIO5 director Fernando Martinez, and BIO5 members Donata Vercelli, Dean Billheimer, and Marilyn Halonen.

Numerous drug-induced and environmental exposure-related toxicities are the result of inter-individual variation in the ADME processes of absorption, distribution, metabolism and elimination that control the fate of these compounds from the body. Alterations in these processes provide the mechanistic basis for individual variability in response to drugs and environmental exposures. A common perception is that variability in response is due to genetic polymorphisms within the drug metabolizing enzyme and transporter genes. While there are numerous examples of these differences that play a major role in the susceptibility of genetic subpopulations for specific toxicities, the potential for transient phenotypic conversion due to temporary environmental changes, such as inflammation and disease, are often overlooked.Due to the ensuing liver damage caused by the progressive stages of NAFLD, gene expression patterns can change dramatically resulting in a phenoconversion resembling genetic polymorphisms. Because the liver plays such a key role in the metabolism and disposition of xenobiotics, this temporary phenoconversion could lead to the inability of patients to properly metabolize and excrete drugs and environmental toxicants, increasing the risk of some adverse drug reactions and environmental toxicities.

Jefferey L. Burgess, MD, MS, MPH is a Professor and Division Director of Community, Environment and Policy within the University of Arizona Mel and Enid Zuckerman College of Public Health. Dr. Burgess’ research focuses on improving occupational health and safety, with a special focus on firefighters, other public safety personnel and miners. Areas of current and past research include: reduction of occupational exposures, illnesses and injuries; respiratory toxicology; environmental arsenic exposure; and hazardous materials exposures including methamphetamine laboratories. In addition to multiple research grants, Dr. Burgess is the Principal Investigator (PI) for the Centers for Disease Control and Prevention-funded Mountain West Preparedness and Emergency Response Learning Center and a joint PI for the National Institute for Occupational Safety and Health-funded Western Mining Safety and Health Resource Center. Dr. Burgess is internationally recognized for his research evaluating the health effects of firefighting and methods for reducing firefighter exposures and other hazards, including but not limited to improved respiratory protection and injury prevention. He is also internationally known for his work on mining health and safety, and is a co-PI on a large Science Foundation Arizona grant supporting mining risk management, exposure assessment and control and economic analysis of health and safety systems. A separate ongoing grant is focused on comparing exposures and health effects associated with the use of diesel and biodiesel blend fuels in underground mining. He also has carried out multiple research projects on the adverse effects of low-level arsenic exposure in drinking water and more recently has begun to evaluate exposures from dietary arsenic sources.

Paloma I. Beamer, Ph.D., joined the College of Public Health in 2007 as an assistant professor in Environmental Health Sciences. The central motivation behind her research is in the development of tools that can help provide more robust exposure and dose estimates and improve the demonstration of a relationship between measured environmental concentrations and resulting health effects, particularly amongst children and underserved populations. Currently Dr. Beamer is using both computer modeling and laboratory techniques in her research. She is currently using GIS techniques to assess the risk of wheezing from exposure to traffic pollutants in early childhood. As an expert in micro-activity patterns she is examining the activity patterns of older children and utilizing them to estimate dust ingestion. Dr. Beamer has built a laboratory to characterize exposure and risk of water-borne contaminants. Currently she is using this laboratory to measure the concentration of tricholoethylene in breastmilk and water contaminants in Nogales. Dr. Beamer is also involved field sampling and exposure modeling projects aimed at understanding children's exposures to pesticides in agricultural communities and metals near hazardous waste sites. Dr. Beamer has served as Academic Councilor on the Board of the International Society of Exposure Science. She has been a long time member of the Society for Hispanic Professional Engineers and the Society for the Advancement of Chicanos and Native Americans in Science. She has received the "Scientific Technological Achievement Award" from US EPA, "Mentored Quantitative Research Development Award" from NIH, and the "40 under 40" Award from the Arizona Daily Star and Tucson Hispanic Chamber of Commerce.