Framework analysis human relevance

Once a MOA for an animal model (most frequently rodent) has been developed, an assessment needs to be made to establish if this same MOA cannot be reasonably excluded or is plausible in humans. This has to be done for most chemical carcinogens because, as mentioned above, only a small minority of chemicals have been shown to be carcinogenic in humans. This plausibility was, until recently, conducted 

This HRF has been applied to DNA-reactive and nonDNA-reactive carcinogens (Meek et al. 2003 Preston and Williams 2005) and to noncancer effects (Seed et al. 2005). It has also been applied to the three examples in Section 13.2.4.6 that were used to exemplify the use of the MOA framework and key events. 

Metabolism by In mice metabolism by GS fll-I Enzyme is present, at lower 

GSTTI-I in target tissues for tumor levels than in mouse target 

DNA damage DNA-protein crosslink and single DNA-protein crosslinks not 

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Meek ME, Bucher JR, Cohen SM et al (2003) A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol 33 591-653... 

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. 

Meek, M.E., J.R. Bucher, S.M. Cohen, V. Dellarco, R.N. Hill, L. Lehman-McKeeman, D.G. Longfellow, T. Pastoor, J. Seed, D.E. Patton. 2003. A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev. Toxicol. 33(6) 591-653. 

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... 

FRAMEWORK ANALYSIS FOR DETERMINING MODE OE ACTION AND HUMAN RELEVANCE... 

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. 

Some variants of the LOPA methodology determine the harm more precisely in terms of harm caused to people and harm to the environment. This approach, which is required by the tolerability of risk framework for human safety. Reducing risks, protecting people, requires consideration of additional factors such as the probability of ignition, the performance of containment systems, and the probability of fatality. For a similar perspective of environmental issues assessors should consult the relevant Environment Agency sector BAT guidance. All of these factors may be subject to considerable uncertainty, and the way the LOPA is carried out needs to reflect this uncertainty. Uncertainties are present in all calculations but sensitivity analysis can be used to help understand the uncertainty. 

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