The Eminent Toxicologist Lectures are historically relevant, high-quality presentations appropriate for senior undergraduate students, graduate students, or the scientifically oriented general public. This series of lectures was produced by the Education Committee Undergraduate Subcommittee in conjunction with the Eminent Toxicologist Working Group.
A bioassay was published in 1966 relying upon the respiratory reflex reactions due to stimulation of TNE during exposure to airborne chemicals, making it possible to measure the potency (abbreviated as RD50) of any airborne chemical as a sensory irritant. An excellent correlation between RD50 values and TLV values was demonstrated as the number of chemicals evaluated with this bioassay increased. In 2015, a QSAR was published using a database of RD50s for 145 chemicals, with excellent results. These updates should permit obtaining reliable estimates of TLVs for new chemicals prior to introducing them in the workplace, as well as for storing and transporting them.
Lecture Notes and Learning Objectives
“QSARs to Commemorate the Fiftieth Anniversary of the RD50” Recording
“QSARs to Commemorate the Fiftieth Anniversary of the 50” Slides
Table 1 2015 Update of the 1993 Schaper Database of RD50 and Their TLV
Table 2 2015 List of TLVs for Chemicals with URT Irritation Basis with No RD50 Values
Yves Alarie, PhD, DABT, ATS, is Professor Emeritus of the Environmental and Occupational Health Department, Graduate School of Public Health, University of Pittsburgh. In 1963 he received the PhD in Physiology from the Département de Physiologie, Faculté de Médecine, Université de Montréal. At the Hazleton Laboratories in Falls Church, Virginia, he developed the “mouse bioassay” or the “RD50 method” used to screen and evaluate the potency of airborne chemicals as sensory irritants. The method was widely used and tabulations of RD50 values are the largest published databases in inhalation toxicology. After joining the University of Pittsburgh in 1970 his research continued on the effects of inhaled chemicals at the surface of the respiratory tract, from the tip of the nose to the alveolar level. He published extensively on the use of animal models to estimate safe levels of exposure for airborne chemicals of industrial importance as well as investigating toxicity of smoke produced in fires and on the cause(s) of death in fire victims. He joined SOT in 1968 and received the SOT Achievement Award (1971), the Frank Blood Award (1974, 1981), the Enhancement of Animal Welfare Award (2000), and the Career Award from the Inhalation Section of SOT (2004).
This lecture examines my experience using quantitative models for understanding dose-response relationships, as well as touching on pharmacokinetics, pharmacodynamics, and new directions in cell pathway based models. Instead of postdoctoral work on shark hemoglobin, military service directed me to assess the toxicity of chemicals found onboard nuclear submarines. Training in modeling small and large molecule kinetics led me to question why probit analyses were used for dose response, why the logarithm of inhaled concentration is a measure of dose, and what is the relationship expected between inhaled concentration and chemical in tissue or between the amount of chemical and response? The main lessons of a long career are that models require us to state our ideas clearly and quantitatively and then to see if our ideas are correct or in need of revision. The use of these models repeatedly shows that it is even more important to know our ideas are wrong than simply to think they might be right.
Lecture Notes and Learning Objectives
“45 Years Modeling Dose-Response Relationships: An Unanticipated Career!” Recording
“45 Years Modeling Dose-Response Relationships: An Unanticipated Career!” Slides
Melvin Andersen, PhD, DABT, CIH, ATS, is Distinguished Research Fellow at ScitoVation LLC, Research Triangle Park, North Carolina. Previously, he was at The Hamner Institutes for Health Sciences. Over a 45-year career, he worked in government (US Navy, DoD, US EPA), industry (Chemical Industry Institute of Toxicology), academia (Colorado State University), and consulting (ICF Kaiser Consulting). Dr. Andersen introduced physiologically-based pharmacokinetic (PBPK) modeling. Other long-term interests include biologically realistic models of the uptake, distribution, metabolism, and biological effects of drugs and toxic chemicals and applying these models in safety assessments and quantitative health risk assessments. Dr. Andersen has mentored 13 graduate students and 13 postdoctoral researchers and served on an additional 11 graduate student research committees. He has served on or chaired many regulatory review panels, both domestic and international, regarding chemicals of environmental interest, including contributing to the 2007 National Academy of Sciences report “Toxicity Testing in the 21st Century: A Vision and a Strategy.” Author/co-author of 400 peer reviewed publications, 70 book chapters, and 30 technical reports, his work has more than 18,000 citations. He has received numerous SOT awards including the Frank Blood, Achievement, Arnold J. Lehman, Best Paper of the Year in Toxicological Sciences, and Merit.
What makes a career in environmental toxicology rewarding? In this lecture, Dr. Benson answers this question by discussing the value of working in a team, mentoring, and conducting the right science for the right purpose. He outlines important environmental and scientific challenges for the 21st century, using the specific example of predicting chemical risk with limited in silico, in vitro and/or in vivo data. The Adverse Outcome Pathway Model is offered as an example framework for relating the molecular initiating event of a chemical across the continuum of molecular, cellular, and physiological perturbations to facilitate risk assessment. Finally, a conceptual model approach of general wellbeing is provided to highlight the interconnections between ecological and human health, including potential positive and negative outputs of the natural and social systems. Throughout the lecture the importance of communicating science to the general public and the need for community involvement in regulatory decision making is highlighted.
Lecture Notes and Learning Objectives
“Exploration of the Interconnections between Human Health and Ecological Integrity” Recording
“Exploration of the Interconnections between Human Health and Ecological Integrity” Slides
William H. Benson, PhD, Fellow AAAS, is Director of the National Health and Environmental Effects Research Laboratory (NHEERL) within the US Environmental Protection Agency (EPA) Office of Research and Development. Dr. Benson is responsible for coordinating health and ecological effects research in NHEERL and working with national research programs, offices, laboratories, and centers to assure integrated research vital to the future of environmental protection. Prior to joining the EPA, Dr. Benson spent 15 years in academia. The University of Mississippi named a graduate student award in Dr. Benson’s name. Dr. Benson's research has been directed towards assessing the influence of environmental stressors on health and ecological integrity, including metal and pesticide bioavailability, reproductive and developmental effects in aquatic organisms, and endocrine disrupting chemicals. Dr. Benson is Past President (1995-96) of the Society of Environmental Toxicology and Chemistry (SETAC) and serves on the Research Oversight Committee for Genome Canada/Genome Québec. Dr. Benson was elected as a Fellow of the American Association for the Advancement of Science (1999), and is active in several other professional societies, including the Society of Toxicology.
Chemical carcinogenesis involves the production of multiple genetic errors in a single pluripotential (stem) cell in the target tissue, which can be produced either by direct DNA damage (DNA reactive) or by increased cell proliferation. Tumor suppressor genes and proto-oncogenes which safeguard against cancer are the genetic targets of chemical carcinogens. The incidence of chemical carcinogenesis can be enhanced through some inherited diseases, such as retinoblastoma or multiple polyposis coli in which mutations of tumor suppressors or proto-oncogenes occur in all cells. Polycyclic aromatic hydrocarbons are a well-studied class of chemicals that are bioactivated to produce chemical carcinogens. The impact of ethanol, cigarette smoke, and medical conditions such as obesity are also discussed. Model systems are used to predict chemical carcinogenicity and the resulting data may be extrapolated to humans.Lecture Notes and Learning Objectives
Samuel M. Cohen, MD, PhD, DABP, ATS, IATP, is professor in the Department of Pathology and Microbiology at the University of Nebraska Medical Center. He is also the Wall-Havlik Endowed Professor of Oncology. Dr. Cohen has made exemplary contributions to toxicology as a practicing surgical pathologist, researcher, teacher and mentor, scientific writer, and scientific advisor on important issues at the intersection of science and public policy. His research efforts have focused on the mechanisms by which chemicals can produce toxicity and cancer and how to extrapolate findings from in vitro and animal models to humans. He has served on numerous national and international committees and currently serves on the Board of Trustees of the Health and Environmental Sciences Institute and the Expert Panel of the Flavor and Extract Manufacturers Association. A member of SOT since 1987, he has been recognized with the SOT Lehman and Merit Awards as well as awards from SOT Regional Chapters. He also has received the Lifetime Achievement Award from the Society of Toxicologic Pathology, the Distinguished Scientist Award from the American College of Toxicology, and the Distinguished Cancer Research Scientist Award from Japan.
This lecture traces the development of the field of immunotoxicology from its beginning and early years to current research. The immune system protects the host from viral and microbiological agents, certain cancers, and the rejection of transplanted tissue. It is sensitive to injury by certain drugs or environmental agents. Immunotoxicology is the study of events that can lead to undesired effects because of the interactions between xenobiotics (i.e., chemicals or substances that are foreign to the organism or biological system) and the immune system. Drivers for the field were public concern about accidental exposure to several environmental chemicals such as dioxin or Agent Orange, polybrominated biphenols, certain cytotoxic drugs, and other agents. Topics of the lecture include the major scientists and laboratories, formative meetings, and chemicals studied during these early years. The development of regulatory guidelines for the testing of new environmental chemicals and drugs is also discussed.
Jack H. Dean, PhD, HonScD, DABT, Fellow ATS, is a Professor in the Department of Pharmacology & Toxicology, College of Pharmacy at the University of Arizona. He retired in 2006 as President, US Science and Medical Affairs, Sanofi-Aventis, Malvern, PA, and as the Global Director of Preclinical Development for Sanofi-Aventis, SA (Paris). He also led the Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC, and the Immunotoxicology Section, National Institute of Environmental Health Services and National Toxicology Program, Research Triangle Park. Early in his career Dr. Dean conducted research in tumor biology, cancer drug evaluation, and immune function in cancer patients at Litton Bionetics, Bethesda, MD. He has edited five books and published 233 peer reviewed journal articles and book chapters. Recognition includes Chevalier of the Legion of Honor from the French Republic for his contribution to medical and pharmaceutical research, the American College of Toxicology’s Distinguished Service Award, an honorary Doctor of Science degree from the College of Pharmacy at the University of Arizona, and the Mildred S. Christian Achievement Award from the Academy of Toxicological Sciences. He was president of the Society of Toxicology and received the Vos Achievement Award from the Immunotoxicology Specialty Section, of which he was founding president, as well as an officer of other organizations.
John Doull, MD, PhD, FAACT, ATS, is Professor Emeritus of Pharmacology and Toxicology at the University of Kansas Medical School. A charter member of SOT, he was 1986–1987 President and has received numerous awards in recognition of his important and extensive contributions to toxicology. Among the SOT awards are the Merit Award (1993), the Founders Award (2008), and the John Doull Award (1992). He has also received the ATS Mildred Christian Achievement Award (2013), the Samuel Kuna Award (1989) from Rutgers University/Robert Wood Johnson Medical School, the International Achievement Award (1990) from the International Society for Regulatory Toxicology and Pharmacology, the Commanders Award for Public Service (1990) from the Department of the Army, the Distinguished Medical Alumnus Award (1992) from the University of Chicago, the Stockinger Award (1990)from the American Conference of Governmental Industrial Hygienists, the Founder's Award from CIIT (1996), the Meritorious Service Award from ACGIH, and the Distinguished Service Award from the American College of Toxicology.The founding co-editor of Casarett and Doull’s Toxicology: The Basic Science of Poisons, he has served on scientific advisory boards for Congress, the White House, NRC, NIH, EPA, NIOSH, and many others and consults with many organizations. He is a national associate of the National Academies.
Pesticides are chemicals that, while necessary for modern agriculture, are accompanied by risks due to their potential toxicity. SOT Past President Marion Ehrich, PhD, DABT, ATS, discusses organophosphate pesticides, their mechanism of action, antidotes, and potential long-term motor/physiological/cognitive effects, such as delayed neuropathy that have resulted from accidental and intentional exposures. She also identifies potential benefits to medical research that have resulted from organophosphate compounds and discusses the risk-benefit analysis of pesticides versus risks to the environment and health. This lecture was recorded in March 2015.
Marion F. Ehrich, PhD, DABT, ATS, is a Professor in the Biomedical Sciences and Pathobiology Department at Virginia-Maryland Regional College of Veterinary Medicine and a practicing registered pharmacist and pharmacy consultant to the Laboratory for Neurotoxicity Studies at Virginia Tech. Her research interests include biochemical neurotoxicology, especially immediate and delayed neurotoxic effects of organophosphate pesticides. In addition, she has been a pioneer in the use of in vitro systems for mechanistic studies and safety assessment in neurotoxicology, with potential contributions to a diminished need for animal use in chemical safety assessments. She is often called upon by both government and industry for her expertise in these areas. Her publications span 35 years, including 300 book chapters, reviews, research, and educational publications. Dr. Ehrich joined SOT in 1979. She served as SOT President from 2003–2004 and received the Merit Award in 2010 for her many contributions to toxicology throughout her career. She is a member of the American Veterinary Medical Association and received a national teaching award from their student organization in 2006.
Toxicology has a long and intriguing history from the use of toxins and toxicants from plants, metals, and venoms by the ancient peoples to the understanding and use of modern derivatives in hunting, warfare, murders, and suicides in the present day. Modern experimental toxicology and analytical chemistry expanded along with introduction of food and industrial products in the past century. Synthetic estrogens, pesticides, and several drugs, including sulfanilamide, were in use by 1940. The 1956 Gordon Research Conference on Toxicology and Safety Evaluation formed the nexus of SOT, founded in 1961. Scholars had the vision to see the wisdom of an expanded scientific and professional organization with a focus on toxicology. The Thalidomide disaster, the publishing of Silent Spring, the Delaney Amendment of the FDCA, the advent of the Pill, Agent Orange and the Vietnam War, and hazardous waste sites (Love Canal and others) drove toxicology and regulations into the 1970s and 1980s. Molecular and cellular toxicology expanded throughout the remainder of the 20th century with outstanding work on carcinogenesis, mutagenesis, endocrine disruption, and the fetal origin of childhood and adult diseases. The 21st century dawned with genomic studies and the age of ‘omics which has elucidated several exciting approaches to and understanding of mechanisms of toxicity.
Michael A. Gallo, PhD, ATS, DABT, whose avocation is the history of toxicology, has practiced toxicology and risk assessment for several decades. He earned his PhD in Experimental Pathology and Toxicology from the Albany Medical College of Union University, Albany, NY. Dr. Gallo is Emeritus Professor of Toxicology at Rutgers-Robert Wood Johnson Medical where he was a founding member the School of Public Health and the Environmental and Occupational Health Sciences Institute (EOHSI). He was the Interim Director (Founding) of the Cancer Institute of New Jersey, Director of the National Institute of Environmental Health Sciences (NIEHS) Center of Excellence at Rutgers and Senior Dean for Research of the Robert Wood Johnson Medical School. Dr. Gallo served on the Society of Toxicology (SOT) Council and multiple committees and received the SOT Education Award. He has served on the NIEHS Council and multiple NIH, NIEHS, NCI, US EPA, and National Academy of Sciences/National Research Council committees, panels, and working groups, including as the chair of the Scientific Advisory Committee of the National Toxicology Program. Dr. Gallo’s contributions to the state of New Jersey include service on the NJ Department of Environmental Protection Public Health Advisory Committee and other state bodies.
This lecture presents the historical development of humane science (in vitro and alternative approaches) in the toxicological evaluation of xenobiotics. Animal testing methodologies, once widely accepted, are less able to be extrapolated to humans than once assumed, and several studies, such as the Draize ocular toxicity assay and the Local Lymph Node Assay, have fallen out of favor. This, together with ethical considerations for the use of animals have resulted in an effort to replace, reduce, or refine studies so that fewer animals are used in research. These changes have resulted in increased acceptance of alternatives to animal testing and increased pressure for regulatory agencies to validate and utilize these tests. The National Academy of Sciences publication Toxicity Testing in the 21st Century became the tipping point for broader acceptance of in vitro approaches in toxicology. The presentation describes, with multiple examples, how the field developed, documents the major advances in practice, and provides a glimpse into the future of new technologies.
Alan Goldberg, PhD, ATS, is a professor of Toxicology and the founding director (emeritus) of the Johns Hopkins Center for Alternatives to Animal Testing and a lead on the Berman Institute Global Food Ethics Policy Program at the Johns Hopkins University. Dr. Goldberg has served in several administrative positions at Johns Hopkins, including the Associate Chair of the Department of Environmental Health Sciences, Director of the Division of Toxicology, and an Associate Dean at the Bloomberg School of Public Health. As a Dean, he was responsible for research with specific responsibility for technology transfer, conflicts of interest, and working with the private sector. His current work includes the ethics of food and feeding the growing world population. He has served on numerous committees for national and international organizations charged with protecting public health. Dr. Goldberg received the Society of Toxicology Enhancement of Animal Welfare Award. Other awards include the inaugural Russell and Burch Award in 2001 from the Humane Society of the United States, the Society of Toxicology MidAtlantic Regional Chapter Ambassador of Toxicology Award, and the Doerenkamp-Zbinden Foundation Award. He is the author of more than 150 scientific articles and editor of numerous books.
For several decades mechanistic toxicology has relied on the use of surrogate animals with extrapolation to humans, an approach followed for many years by the author. However, new paradigms for human health risk assessment require biochemical and molecular studies carried out on human materials. Considering toxicity as a consequence of a cascade of events starting with exposure and ending with the expression of a toxic endpoint, it is clear that not only is gene expression an important endpoint but knowledge of metabolism and metabolic interactions are critical to understanding the entire process in humans. Metabolic studies utilizing human liver cell fractions were carried out on a number of agrochemicals, including insecticides such as chlorpyrifos, fonofos, and fipronil, as well as the repellent DEET and the diesel fuel component naphthalene. The most striking interaction based on inhibition is the inhibition of steroid hormone metabolism in hepatocytes by chlorpyriphos. Interactions based on induction included the induction of CYP isoforms by, for example, fipronil, DEET, and endosulfan. Effects on gene expression by DEET and fipronil were studied by microarray and RNAseq techniques. Throughout all of the studies human variation was studied by utilizing hepatocytes and hepatocyte fractions from different donors.
Lecture Notes and Learning Objectives
“We Are Not Rodents: Environmental Toxicants and the Role of Human Studies” Recording
“We Are Not Rodents: Environmental Toxicants and the Role of Human Studies” Slides
Ernest Hodgson, PhD, is Distinguished Professor Emeritus, Environmental and Molecular Toxicology and the Department of Applied Ecology, North Carolina State University, Raleigh. He received his PhD from Oregon State University and his postdoctoral research was at the University of Wisconsin, Madison. He is renowned for research in the metabolism of toxicants in the human liver, especially human metabolism of agrochemicals. In addition to editing and part-authoring two textbooks of toxicology and contributing to a variety of review books, dictionaries, and electronic databases, Dr. Hodgson is editor of the Journal of Biochemical and Molecular Toxicology. He has contributed to the education of numerous toxicologists; former students and postdocs are distributed among a variety of academic, industrial, and government positions. He serves on advisory committees and review panels. Significant recognition at his own institution is his being named to the prestigious endowed William Neal Reynolds Professorship. Recognition from the Society of Toxicology includes the Education (1984), Merit (1994), and Distinguished Toxicology Scholar (2012) Awards. Other major awards include the Baxter, Burdick & Jackson International Award and Sterling Hendricks Award (American Chemical Society, 1989, 1997) and the Frederick J. DiCarlo International Service Award (International Society for the Study of Xenobiotics , 2004).
Curtis D. Klaassen, PhD, DABT, ATS, was a Distinguished Professor at the University of Kansas Medical Center and was instrumental in establishing his department as one of the top departments for research and training in toxicology in the world. Dr. Klaassen’s research interests have centered on how we adapt to chemicals in the environment. His studies have included the hepatobiliary disposition of xenobiotics, the toxicity of cadmium, the hepatotoxicity of chemicals, and mechanisms of chemical-induced thyroid tumors. Dr. Klaassen is editor of Casarett and Doull’s Toxicology: The Basic Science of Poisons, considered the premier textbook in the field. He has twice been named a “Highly Cited Researcher” (2002, 2007) by the Institute for Scientific Information, a designation held by less than one half of one percent of all researchers. He has been elected to 27 different positions in professional organizations, including President of SOT from 1990–1991 and President of IUTOX 1992–1995. An SOT member since 1969, his Society recognition includes the Achievement Award, Merit Award, Education Award, the Burroughs Welcome Toxicology Scholar Award, the Women in Toxicology Mentoring Award, and numerous Regional Chapter and Specialty Section awards.
Dr. Nancy Monteiro-Riviere introduces the exciting field of nanotechnology which has been transforming many aspects of everyday life, ranging from cosmetics and sunscreens to new electronics and nanomedicines. Nanomaterials are substances less than 100nm in size that exhibit physical, chemical, and /or biological characteristics associated with the nanostructure. This lecture focuses on how the safety of these novel nanomaterials is vastly different from traditional chemicals and drugs. Because the skin is the major route of exposure where many nanomaterials interact with the body, her research focuses on this organ. The role of the physicochemical parameters that modify cellular uptake and lead to biomolecular corona formation and interactions with cells are discussed. Having worked in this field since its inception now over a decade ago, she tracks how the latest techniques in cell culture, in vitro absorption systems, biomarkers, electron microscopy, analytical chemistry, and animal model development have been applied to this problem with varied levels of success.
Nancy Monteiro-Riviere, PhD, ATS, is the Regents Distinguished Research Scholar and University Distinguished Professor and Director of the Nanotechnology Innovation Center of Kansas State. Previously she was Professor of Investigative Dermatology and Toxicology at North Carolina State University (NCSU), Professor in the Joint Department of Biomedical Engineering at UNC-Chapel Hill/NCSU, and Research Adjunct Professor of Dermatology at UNC-Chapel Hill School of Medicine. Her research interests involve in vivo and in vitro studies of skin absorption, penetration, and toxicity of chemicals, nanoparticles, biocorona uptake, and cellular responses. Editor of three books and author of 300 manuscripts, she appears on Thomson Reuters’s 2014 list of the top 1% most highly cited researchers in pharmacology and toxicology. Dr. Montiero-Riviere serves on national and international expert review panels as well as having editorial duties for eight journals. Her awards include the Purdue University Inaugural Distinguished Women Scholars Award and KSU Woman of Distinction. SOT service includes the Nomination Committee (2001–2002), the Board of Publications, and President of Dermal (2004–2005) and In Vitro (2001–2002) Specialty Sections. Dr. Monteiro-Riviere is a Fellow in The Academy of Toxicological Sciences and elected to its Board of Directors.
Regulatory pharmaceutical toxicology provides a framework for testing and registration of new medicines to ensure patient and volunteer safety. In silico, in vitro, and in vivo toxicology studies are conducted sequentially, building a picture of the toxicity profile of each potential new drug. Although regulatory toxicology testing is specified by a set of international guidelines (defined by the International Council for Harmonization), each candidate drug requires a unique package of scientific tests that are designed, performed, and analyzed by skilled regulatory toxicologists. Most drugs that are not approved fail during this critical period due to safety and efficacy concerns. How well do animal tests predict clinical outcome? And how will we move towards replacing animals in drug safety testing? The framework for regulatory toxicology testing and the challenges are outlined with potential solutions.
Ruth A. Roberts, PhD, ATS, ERT, FBTS, FRSB, FRCPath, combines her role as Chair of Drug Discovery at the University of Birmingham, UK, with codirecting ApconiX, an integrated nonclinical consultancy with research labs focusing on ion channels in the context of cardiotoxicology. She has a broad interest in innovative new ways to bring effective new medicines to market, with a focus on reducing attrition due to safety/toxicity. This interest and expertise was developed over 20 years at the forefront of international research and regulatory toxicology across pharmaceutical, agrochemical, and industrial chemical fields. She previously worked with Aventis and more recently as Global Head of Regulatory Safety for AstraZeneca. Dr. Roberts serves on the Society of Toxicology (SOT) Council as secretary. She is past president of the British Toxicology Society and EUROTOX and president-elect of Academy of Toxicological Sciences. With more than 130 publications in peer-reviewed journals, Dr. Roberts has received numerous awards including the SOT Achievement Award (2002) and the EUROTOX Bo Holmstedt Award (2008) for outstanding contribution to understanding mechanisms of toxicity.
Lecture Notes and Learning Objectives
“Environmental Epigenomics: The Developmental Origins of Health and Disease” Recording
“Environmental Epigenomics: The Developmental Origins of Health and Disease” Slides