Inherited susceptibilities, environmental factors, and age play a role in the development of major diseases (Schwartz et al., 2004
), and the National Toxicology Program (NTP) has played an important role in identifying the environmental factors that contribute to these diseases. While probably best known for its cancer bioassay program, the NTP also conducts studies to address other diseases and disorders (i.e., reproduction toxicity, immunotoxicity, neurotoxicity, etc.) and is interested in enhancing its assessment of environmental influences on other major diseases. Heart disease, respiratory disease, and disorders of metabolism such as diabetes consistently rank in the top 10 leading causes of morbidity and mortality for both men and women in the United States and have significant associated personal and financial costs. For these reasons, the NTP is in the process of identifying and incorporating biomarkers for diseases of the heart, lung, and lipid/carbohydrate metabolism to enhance its toxicology testing program. It is important to emphasize that while NTP studies have a default or “core” selection of end points that are consistent across studies (see “NTP Studies” in background materials at http://ntp.niehs.nih.gov/go/20940
and ), the majority of studies also include adjunct components ranging from the collection of additional selective end points to the use of novel technologies. For example, in a study of ephedra (a dietary supplement), telemetry was utilized to measure cardiovascular responses (Howden et al., 2005
). The NTP is also assessing and evaluating enhanced in vivo
test protocols for assessing QT interval prolongation. While these measurements are not typical, a major goal of the workshop was to identify end points that could be added routinely to toxicity studies to provide more confidence that NTP studies are adequately screening for changes in heart and lung disease/function and lipid and carbohydrate metabolism.
Routine End Points for the Evaluation of Heart, Lung and Lipid/Carbohydrate Metabolism
On 20–21 September 2006, the NTP organized a workshop “Biomarkers for Toxicology Studies” to help address this task (the workshop agenda, presentations, background materials, roster of the invited panel and other attendees, and other related information can be found on the NTP Web site [http://ntp.niehs.nih.gov
see “Meetings & Workshops” or directly at http://ntp.niehs.nih.gov/go/20940
]). The specific purpose of the workshop was to identify biomarkers related to heart, lung, and lipid/carbohydrate metabolic function and injury that could be included in subchronic (90-day) rodent toxicology studies to better characterize end points of environmentally induced disease or biological processes related to human disease etiology. This workshop is the fourth in a series the NTP has organized as part of implementing the NTP Roadmap to critically evaluate its testing program and determine whether any refinements or new strategies are needed to maximize its impact on public health (http://ntp.niehs.nih.gov/go/20940
An ideal biomarker should qualitatively or quantitatively measure biologic, pathologic, or pharmacologic responses (De Gruttola et al., 2001
) and be a specific and sensitive indicator of a disease process (Kraemer, 1992
). Biomarkers may measure upstream events prior to the onset of a disease or downstream disease events. Biomarkers may measure nonspecific biological variations or adverse effects characteristic of disease processes. For NTP purposes, biomarkers can be used to (1) improve detection of disease and disease processes, (2) maximize the information derived from toxicology studies used for hazard identification, (3) aid in understanding mechanisms of disease processes, and (4) detect changes early in disease development. This includes not only biomarkers for specific diseases but also biomarkers that measure common mechanisms in multiple disease processes. The ideal biomarker would also need to be both appropriate to measure disease in model systems (e.g., rodents) and predictive of an analogous disease process or altered function in humans. The biomarker may be the same across species (e.g., insulin, troponin) or have an analogue in rodents and humans (e.g., α2-macroglobulin in the rat and C-reactive protein in humans). Additional desirable biomarker attributes include the ability for samples to be easily collected and assays that can be conducted in a timely and cost-effective manner.
Prior to the workshop, NTP staff summarized candidate disease biomarkers from a review of the literature (see topic specific worksheets in “Background Materials” at http://ntp.niehs.nih.gov/go/20940
) that included a broad look at the field of biomarkers in physiological measurements, serum and tissue analyses, and noninvasive techniques (e.g., imaging). An expert panel from academia, industry, and government was convened for each topic (heart, lung, lipid/carbohydrate). Following a plenary session that provided an overview of the biomarkers for each topic, workshop participants met in their respective discussion groups to identify the most useful biomarkers that NTP could consider incorporating into its studies. Discussions focused not only on biomarkers for specific diseases but also biomarkers that measure common mechanisms in multiple disease processes such as inflammation. The following summaries focus on breakout group discussions. For complete details of the proceedings, see the meeting Web site (http://ntp.niehs.nih.gov/go/20940