Mechanistic Biology & Mode of Action

Exponent toxicologists have specific expertise in evaluating mechanistic data, modes of action (MoA), and Adverse Outcome Pathways (AOPs) for the purposes of human health risk assessment.  With diverse and extensive technical knowledge, our toxicologists are uniquely positioned at the forefront of new risk assessment methodologies. Our development of innovative applications for mode of action and AOP analyses enables us to assist our clients in addressing questions of whether a compound causes adverse outcomes – including cancer and developmental effects – in humans at environmentally-relevant or pharmacologically therapeutic doses.

Why Modes of Action Are Important for Assessing Potential Health Risks

Having a clear understanding of the molecular mechanisms – or mode of action – behind an observed effect is becoming ever more important in assessing the potential health risks due to compound exposure. In pharmaceutical development, recognizing the mode of action by which a compound causes both its pharmacologic and off-target effects in animals can be important in translating whether those same responses may be observed in humans. Insight into mode of action is also important in addressing environmental and occupational exposures.

The U.S. Environmental Protection Agency (EPA) first proposed in 2005 using information on a compound’s mode of action to assess its carcinogenic risk. More recently, the EPA and Organisation for Economic Cooperation and Development (OECD) both have focused on understanding the Adverse Outcome Pathways (AOPs) by which compounds may exert harmful effects on humans or the environment. AOPs take into account the sequential macro-molecular interactions that may occur because of compound exposure and the resulting responses that may be observed at the different levels of organization – that is, the cell, organ, organism, and population. Often, data on mode of action and molecular mechanisms are derived from in vitro studies and mechanistic investigations. This information must be integrated with data regarding compound metabolism, species sensitivity/selectivity, and exposure in order to accurately assess whether the mode of action – or AOP – will be relevant for the species of concern.

Although historically mode of action has been used primarily to determine the relevance of in vitro and animal findings for assessing carcinogenic risks related to potential environmental exposures, mode of action and AOPs are increasingly considered in assessing other types of health risks, including developmental risks and those associated with chronic compound exposure.