Identification and characterization of adverse effects in 21st century toxicology.

The practice of toxicology is changing rapidly, as demonstrated by the response to the 2007 NRC report on "Toxicity Testing in the 21(st) Century." New assays are being developed to replace animal testing; yet the use of data from these assays in decision making is not clear. A Health and Environmental Sciences Institute committee held a May 2011 workshop to discuss approaches to identifying adverse effects in the context of the NRC report. Scientists from industry, government, academia, and NGOs discussed two case studies and explored how information from new, high data content assays developed for screening can be used to differentiate adverse effects from adaptive responses. The terms "adverse effect" and "adaptive response" were defined, as well as two new terms, the relevant pathways of toxicological concern (RPTCs) and relevant responses for regulation (RRRs). RPTCs are biochemical pathways associated with adverse events and need to be elucidated before they are used in regulatory decision making. RRRs are endpoints that are the basis for risk assessment and may or may not be at the level of pathways. Workshop participants discussed the criteria for determining whether, at the RPTC level, an effect is potentially adverse or potentially indicative of adaptability, and how the use of prototypical, data-rich compounds could lead to a greater understanding of RPTCs and their use as RRRs. Also discussed was the use of RPTCs in a weight-of-evidence approach to risk assessment. Inclusion of data at this level could decrease uncertainty in risk assessments but will require the use of detailed dosimetry and consideration of exposure context and the time and dose continuum to yield scientifically based decisions. The results of this project point to the need for an extensive effort to characterize RPTCs and their use in risk assessment to make the vision of the 2007 NRC report a reality.

A data-based assessment of alternative strategies for identification of potential human cancer hazards.

The two-year cancer bioassay in rodents remains the primary testing strategy for in-life screening of compounds that might pose a potential cancer hazard. Yet experimental evidence shows that cancer is often secondary to a biological precursor effect, the mode of action is sometimes not relevant to humans, and key events leading to cancer in rodents from nongenotoxic agents usually occur well before tumorigenesis and at the same or lower doses than those producing tumors. The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) hypothesized that the signals of importance for human cancer hazard identification can be detected in shorter-term studies. Using the National Toxicology Program (NTP) database, a retrospective analysis was conducted on sixteen chemicals with liver, lung, or kidney tumors in two-year rodent cancer bioassays, and for which short-term data were also available. For nongenotoxic compounds, results showed that cellular changes indicative of a tumorigenic endpoint can be identified for many, but not all, of the chemicals producing tumors in two-year studies after thirteen weeks utilizing conventional endpoints. Additional endpoints are needed to identify some signals not detected with routine evaluation. This effort defined critical questions that should be explored to improve the predictivity of human carcinogenic risk.