Human relevance framework

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Dellarco VL, McGregor D, Berry SC et al (2006) Thiazopyr and thyroid disruption case study within the context of the 2006 IPCS Human Relevance Framework for analysis of a cancer mode of action. Crit Rev Toxicol 36 793-801... 

These issues are ones of extrapolation and as noted by Preston (2005) such extrapolations are the Achilles heel of risk assessment (Preston 2005). The U.S. EPA, The International Program on Chemical Safety (IPCS), and The International Life Sciences Institute (ILSI), for example, have proposed a framework based on the mode of action of a chemical, the key events that define a particular mode of action, and a human relevance framework for assessing the plausibility of an animal mode of action to humans. It is this approach that will be described and discussed in this chapter. 

The majority of the tumor data available for conducting cancer risk assessments for exposure to enviromnental chemicals come from 2-year cancer bioassays using rats and mice. Thus, a MOA based on key events is inevitably developed for laboratory animals and not humans. There are, of course, a few exceptions for which human tumor data are available (NTP 2005). These human data are generally used together with rodent tumor data as part of dose-response characterization. Thus, the need in all cases is to demonstrate that the animal MOA is plausible in humans. This can be accomplished by use of a human relevance framework (described below in this section and in Table 13.1 and in Eigure 13.1). 

Figure 13.1. General schematic illustrating how the Human Relevance Framework can he used to assess whether or not an animal MOA has a human counterpart, thereby indicating if a quantitative risk assessment is required. [Adapted from Meek et al., (2003).]...

In summary, having established an animal MOA and human relevance for this MOA, it is appropriate to address dose-response assessment, human exposure analysis, and risk characterization. Thus, the purpose of the human relevance framework is to establish which chemicals (or chemical mixtures) should be considered for a quantitative risk assessment and which do not require further consideration because they present a minimal risk or no risk to humans. Several thoroughly worked examples are presented in Meek et al. (2003). 

Dellarco, V. L., and Baetcke, K. (2005). A risk assessment perspective application of mode of action and human relevance frameworks to the analysis of rodent tumor data. Toxicol Sci 86, 1-3. 

Life Sciences Institute (ILSI) Framework for Human Relevance Analysis of Information on Carcinogenic Modes of Actioif (Meek, etal., 2003 Cohen etal., 2003,2004), and Preamble to the lARC Monographs (2006 Section B.6. (Scientific Review and Evaluation Evaluation and Rationale)) provide a basis for systematic assessments that may be performed in a consistent fashion. The IPGS also convened a panel in 2004 to further develop and clarify the human relevance framework. However, the above documents are not intended to dictate answers, nor provide lists of criteria to be checked off. 

The mode of action (MoA) approach seeks to gain an understanding of the key events along a causal pathway that lead to a toxicological endpoint. Extensive reviews of MoA examples exist in the literature [18,19,20]. Additionally, The International Programme on Chemical Safety (IPCS) has published Human Relevance Frameworks [21, 22], a process that incorporates a weight of evidence approach relying heavily on robust mechanistic and experimental data. The evaluation sequence is listed below as a series of questions. 

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