CIIT at The Hamner
The Chemical Industry Institute of Toxicology (CIIT) was founded as a private, not-for-profit research organization by visionary chemical industry leaders in 1974. For over 30 years, CIIT has been a leader in developing better scientific understanding of how environmental chemicals impact human health. Beginning in 2000, CIIT adopted a systems biology approach to human health effects research. The hallmark of the systems biology paradigm is seamless integration of functional genomics, computational biology, and bioinformatics to guide research and to provide integrative, quantitative tools for assessing human health risks. With the formation of the Hamner Institutes fro Health Sciences, CIIT at The Hamner became one of the cornerstone Institutes with a mission to develop contemporary approaches for risk and safety assessments.
Research Context for Reducing Uncertainties in Risk Assessment
The construction and experimental validation of biological and computational models explaining and predicting the behavior of biological systems has been the overall goal of the computational systems biology effort at CIIT. Achieving integration of theory, computation, and experiment remain the hallmark of our systems biology vision to the conduct and interpretation of research into adverse responses to chemical exposures (Fig. 1). A systems biology approach is critical for developing and conducting integrated research programs on environmental health and for improving dose-response assessments for chemicals. A similar set of systems biology tools can be applied for chemical risk assessment or for safety assessment with pharmaceutical compounds.
Fig. 1: Schematic representation of systems integration interrelationships needed to determine health outcomes.
The linking of physiologically based pharmacokinetic (PBPK), computational fluid dynamic (CFD) and other dosimetry models with tissue response models, as pursued by CIIT staff with formaldehyde, hydrogen sulfide, dibutylphthalate and chlorine, has provided examples of systems approaches to identifying and reducing uncertainties in risk assessment. These systems oriented activities heavily rely on evaluating genomic responses to chemical exposures, assessing the signaling pathway(s) perturbed by chemicals, and evaluating the downstream consequences of perturbations in these toxicity pathways by chemical exposures. One institutional goal for 2008 is completing a systems approach for dose response assessment using oxidative stress responses of respiratory tissues to chlorine. This goal feeds into and extends some of the recent recommendations for new approaches to toxicity testing from a committee of the National Academy of Sciences. (Toxicity Testing in the Twenty-First Century: A Vision and Strategy, National Academies Press, 2007).
Research studies in cell biology in particular have progressed to a stage where many problems in understanding cellular functions are amenable to computational analyses of the affected signaling networks. The overall goal of these computational models is to understand the shape of the dose-response curves for biological perturbations at low doses and to use this information quantitatively to develop new risk assessment approaches based on knowledge of human biological systems. Research to develop computational models is increasingly re-iterative where specific hypotheses are developed and tested in biological systems computationally via appropriate quantitative modeling tools (Fig. 1).
Linkage of Program to Key Risk Assessment Issues
The goal of the CIIT research program has been to develop and implement interdisciplinary research programs of high scientific merit that are aligned with and responsive to the human health issues of highest priority to the chemical industry and society at large. Our current portfolio encompasses several areas of emphasis, all closely linked to health risk assessment priorities.
The program in respiratory toxicology has provided insight into lung dosimetry and biological responses of the respiratory tract to inhaled materials. In the past year, we have had increased emphasis on risks that may be posed by inhalation of nanoparticles. CIIT nanoparticle studies on generation systems, on cellular uptake, on the impact on co-exposure with other pulmonary stressors, and on regional lung dosimetry are providing basic information to refine research questions and develop new research tools for these materials. Pathway mapping and development of a computational model of the oxidative stress signaling module activated by hypochlorous acid is also underway. These integrated studies with a pulmonary irritant are directed towards acquiring the necessary research to complete a computational systems biology oriented risk assessment based on perturbations of key signaling pathways.
New tools are rapidly being developed that have the potential to provide important information on using of mode of action studies at the genome-wide level to improve risk assessment. These tools also have the potential for use solely in hazard identification and could easily cause alarms about chemical exposures. Our investment in a core microarray facility and in the infrastructure to support a range of functional genomic applications has produced pro-active opportunities for showing how these tools might be used in hazard identification, in mode of action studies assessing dose-dependent transitions in toxicity (with chlorine, formaldehyde, and arsenic), and in dose response modeling based on changes in gene families (e.g., with The Hamner's BMD Express Software). The pathway mapping, automated signal transduction model building, benchmark dose genomic software, and proposed development of packages to look at cross-species commonality in gene complements in target tissues are contributions in bioinformatics with potential for broad use in mode of action based risk assessment in years to come.
Our biomonitoring initiative, dating to 2005 with the addition of Dr. Harvey Clewell to lead a CIIT Center for Human Health Assessment, has brought internationally recognized talent to CIIT to work on developing new tools for interpreting biomonitoring results with respect to exposure and risk. We will apply these tools for interpreting biomonitoring results developed by CHHA staff for volatiles to a broader array of compounds in order to distinguish issues common to all compounds and those unique to specific classes of compounds. The general approaches were described in a CIIT Course, "Interpretation of Biomonitoring Data Using Physiologically Based Pharmacokinetic Modeling." A one-day version of this course will be presented at the International Society for Exposure Assessment (ISEA) Meeting in North Carolina, October 2007. It bears some emphasis that the real controversy with biomonitoring is not the presence of low levels of chemicals throughout the environment. It is the inability of current approaches to confidently predict risks at low levels of exposures. Improved approaches to predicting response at low doses and generic low dose extrapolation models are needed to place biomonitoring results into a human health perspective.
In one of the continuing projects, a team of CIIT scientists are producing a mode of action based risk assessment that focuses heavily on the body of research done at CIIT on dibutylphthalate. This risk assessment project serves to co-ordinate a variety of research efforts that were involved in our reproductive and developmental toxicity program with implications for children's health. In 2008, one short term project focuses on interspecies differences in developmental toxicity of a class of endocrine active compounds. This formal mode-of-action oriented risk assessment emphasis is expected to be a mainstay of future toxicology research programs. A heavy emphasis will be placed on identifying projects that require consortia funding of research to improve risk assessment for individual compounds or to develop new methods for broad applications in chemical risk assessment. These projects would include both conduct of in life and mode of action studies, integrated to enhance their use in supporting contemporary risk assessments.