ACTION(S)
A specific application of WoE approaches is that of conceptual frameworks based on the evidence for the toxicological mode of action(s) of a given substance. Due to the requirement of establishing an ED mode of action that is enshrined in the IPCS/WHO definition, it is of interest to review available approaches together with their potential applications and limitations.
4.2.1 MECHANISM, MODE OF ACTION AND KEY EVENTS
The term “mode of action” is sometimes used interchangeably with the term mechanism of action.
However in recent publications, a clear distinction between the two terms emerges. The mechanism of action is typically defined as the totality of mechanistic steps, whereas the mode of action refers to a less detailed sequence of key events within the mechanism. Key events can be defined as both measurable and necessary to elicit the apical toxicological effect of interest3. These definitions differ
1 Conrad JW, Jr., Becker RA. 2011. Enhancing Credibility of Chemical Safety Studies: Emerging Consensus on Key Assessment Criteria. Environmental Health Perspectives 119(6): 757-764.
2 World Health Organisation. 2005. Effects of Air Pollution on Children’s Health and Development. A Review of the Evidence. WHO, European Office, Bonn, Germany.
Intergovernmental Panel on Climate Change. 2007. Summary for policy makers. Climate Change: the Physical Science Basis. Contribution of Working Group 1 to the 4th Assessment Report of the Intergovernmental Panel on Climate Change, Cambridge University Press, Cambridge, United Kingdom.
3 Guyton KZ, Barone S, Brown RC, Euling SY, Jinot J, Makris S. 2008. Mode of action frameworks: A critical analysis. Journal of Toxicology and Environmental Health-Part B-Critical Reviews 11(1): 16-31.
Page 40 of 135 in terms of their inclusion of toxicokinetic steps. These concepts are best illustrated by Figure 2, adapted from Guyton et al (2008)1.
Figure 2. Illustration of mechanism and mode of action definitions. (a) Mechanism of action defined as all the steps between exposure and outcome. MOA is defined as “key event”. (b) An example of the MOA is the pesticide chemical vinclozolin and its male reproductive developmental effects in the rat. The MOA/key event is binding to the androgen receptor (AR) (adapted from Guyton et al, 2008).
Information about the mode of action can inform decisions regarding the shape of the dose-response curve, particularly at low doses, the relevance of effects observed in experimental animals to humans, and the variability of the response within the human population including susceptible subgroups. An additional area of interest is the use of information on mode of action to inform cumulative risk assessment for mixtures.
4.2.2 MODE OF ACTION ANALYSIS METHODOLOGY
Frameworks for analysing data on the mode of action were first developed to assess the WoE for a carcinogenic mode of action in experimental animals and its relevance to humans2. Such a framework has recently been developed to assess noncancer modes of action3 and is referred to in the Germany-United Kingdom proposal to assess human relevance for endocrine disrupting effects (see 6.4). The concept has been extended further to include quantitative descriptions of dose-response relationships for key events that may allow inferences about their shape, particularly at
1 Guyton KZ, Barone S, Brown RC, Euling SY, Jinot J, Makris S. 2008. Mode of action frameworks: A critical analysis. Journal of Toxicology and Environmental Health-Part B-Critical Reviews 11(1): 16-31
2 Boobis AR, Cohen SM, Dellarco V, McGregor D, Meek ME, Vickers C, et al. 2006. IPCS framework for analyzing the relevance of a cancer mode of action for humans. Critical Reviews in Toxicology 36(10): 781-792, Meek ME, Bucher JR, Cohen SM, Dellarco V, Hill RN, Lehman-McKeeman LD, et al. 2003. A framework for human
relevance analysis of information on carcinogenic modes of action. Critical Reviews in Toxicology 33(6): 591-653, Sonich-Mullin C, Fielder R, Wiltse J, Baetcke K, Dempsey J, Fenner-Crisp R, et al. 2001. IPCS conceptual framework for evaluating a mode of action for chemical carcinogenesis. Regulatory Toxicology and Pharmacology 34(2): 146-152.
3 Boobis AR, Doe JE, Heinrich-Hirsch B, Meek ME, Munn S, Ruchirawat M, et al. 2008. IPCS framework for analyzing the relevance of a noncancer mode of action for humans. Critical Reviews in Toxicology 38(2): 87-96.
Page 41 of 135 low doses. These inferences are made on the basis of considerations of dose-dependent transitions in kinetic or dynamic processes related to the toxic response1.
This WoE approach applies the Bradford Hill criteria to a postulated mode of action responsible for the toxicological effect of the test substance. In short, specific considerations include concordance between the dose-response relationships of key events and the toxicological response, temporal relationships between the key events, the strength, consistency and specificity of the association between the toxicological response and key events as well as the biological plausibility and coherence for the mode of action.
To assess the human relevance of the postulated mode of action, the evidence collated within the framework is queried in sequence for the sufficiency of evidence to establish a mode of action in the experimental animal, whether human relevance of this mode of action could be reasonably excluded on the basis of fundamental qualitative differences in key events between experimental animals and humans, and finally whether the relevance of the mode of action in experimental animals could be reasonably excluded on the basis of quantitative differences either in toxicokinetic or toxicodynamic factors between experimental animals and humans. The key default assumptions are considered to be protective as significant and convincing data are necessary to deviate from these default positions. However, these mode-of-action frameworks suffer from the same criticism as other WoE approaches in that the sufficient evidence is poorly if at all defined. Although they do offer some level of transparency about the rationale for the decision about human relevance, expert judgement is nonetheless still essential for that decision.
Interestingly, the approach has also been applied to life-stage specific hazard characterisation2. Relevant human and experimental animal studies are examined to identify critical windows of development for the observed outcome, lifestage-specific toxicokinetic and toxicodynamic data, mode of action information, variability and latency of effects. The aim is to determine the overall WoE of association between early life exposures and adverse outcomes on the basis of the adequacy, strength and completeness of the database. Because concerns following exposure to EDCs arise from the critical organisational role of hormones during development, the application of such an approach is particularly relevant to the hazard characterisation of EDCs (section 4.4).
Further, a worked case study of the application of such a framework revealed that the consideration of multiple outcomes for a given mode of action in experimental animals uncovered that some endpoints are relevant to humans while others are not. This is important when considering those human diseases for which there is no adequate animal experimental model but evidence for a specific mode of action3 (see also section 4.7).
While most approaches consider alternative modes of action for a given outcome, an often voiced criticism is that they do not allow for the integration of multiple modes of action. The underlying
1 Guyton KZ, Barone S, Brown RC, Euling SY, Jinot J, Makris S. 2008. Mode of action frameworks: A critical analysis. Journal of Toxicology and Environmental Health-Part B-Critical Reviews 11(1): 16-31.
2 U.S. EPA. 2006. A framework for assessing health risk of environmental exposure to children. Office of Research and Development, National Center for Environmental Assessment, Washington, DC; EPA/600/
R-05/093F.
3 Seed J, Carney EW, Corley RA, Crofton KM, DeSesso JM, Foster PMD, et al. 2005. Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data. Critical Reviews in Toxicology 35(8-9): 663-672.
Page 42 of 135 assumption appears to be that modes of action are mutually exclusive and the possibility that different modes of action may act in an interactive manner is not considered in currently available approaches. Another weakness is the lack of consideration of the known causes of human disease and the potential for chemical exposures to act additively with background exposures, disease or endogenous processes.
Finally, it should be recognised that the meaningful application of such frameworks to the hazard characterisation of chemicals will require extensive data that is unlikely to be available for most chemicals. It would therefore require a substantial effort to expand the knowledge base. It nonetheless offers an interesting approach to assess evidence from a viewpoint that specifically addresses hazardous properties that underlie the level of concern over EDCs such as effects at low doses and exposure during critical windows of development. The possibility of adapting such a framework to assess interspecies differences could also be applied in order to integrate evidence of effects from both human toxicology and ecotoxicology.