Cancer Risk Assessment: Are We Missing the Forest for the Trees?

In recent years, national and international environmental public health organizations (including the US Environmental Protection Agency and the World Health Organization) have begun to use the adverse outcome pathway (AOP) and/or mode of action (MOA) as unifying frameworks for chemical testing and risk assessment. While the details of these frameworks vary, their underlying ideas are similar: researchers link specific molecular changes caused by environmental chemicals with adverse outcomes at the organism level (ie: disease), and then risk assessment is conducted based on the premise that preventing the early molecular disruption will prevent the development of the end-stage adverse event.

While there are practical advantages and real logic to this mechanism-based approach, a new review article published in Carcinogenesis suggests that this strategy may be overly simplistic and could potentially hinder our ability to adequately identify chemicals that contribute to the development of cancer.

This international team of cancer biologists and environmental health scientists organized their discussion around the “Hallmarks of Cancer,” a list of acquired characteristics that commonly occur in cancer (for example: continued growth, resistance to cell death, and tissue invasion). For each key characteristic, they identified typical target sites for disruption as well as environmental chemicals that have been shown to act on those targets. The researchers focused their discussion solely on chemicals that were not already categorized as human carcinogens by the International Agency for Research on Cancer (IARC), and they took careful note of effects observed at low doses. In addition, they specifically mapped connections between different pathways to highlight cases in which alterations leading to a given cancer hallmark could also lead to another.

Their lengthy review provides an important overview of the procarcinogenic effects of numerous common chemicals, but perhaps the most significant conclusion of this work is to emphasize the pitfalls in the status quo for risk assessment. By focusing on categorizing single chemicals as ‘carcinogens,’ we neglect to acknowledge that combinations of chemicals that individually do not meet criteria to be categorized as ‘carcinogenic’ may act in synergistic ways to promote the development of cancer. Even recent efforts to evaluate the effects of chemical mixtures may be inadequate, as they mostly focus on chemicals with common cellular pathways or targets. What about the numerous compounds, as identified in this review, that act on disparate pathways and organs to contribute to a similar disease process in the body?

To address these problems, the authors propose several key principles for an improved framework for cumulative risk assessment, including consideration of the synergistic activity of:

  • chemicals that act via different pathways
  • chemicals that act on different target tissues
  • non-carcinogens that act at low doses to contribute to pro-carcinogenic processes
  • chemicals that are not structurally similar

Carcinogenesis, like many disease processes, is complicated, and identifying the numerous pathways and organs involved is – and will continue to be – an enormous scientific challenge. Slow progress can be made, nevertheless, with a shift towards testing real-world combinations of chemicals and by using the ‘Hallmarks of Cancer’ to guide relevant and appropriate research. New technologies, such as high throughput screening, computational modeling and systems biology-based analysis, can aid in this process. However, the authors stress that traditional in vivo testing still holds an important place in cancer-related research – at least until there is appropriate validation of these emerging tools.

This publication highlights that our current chemical testing and risk assessment system is overly narrow and negates the complexity with which chemicals can interact in the body. We must broaden our approach to acknowledge that distinct chemicals can act in distinct ways at distinct sites – even at low doses – to contribute synergistically to a specific disease process. Reframing our perspective is daunting, and it will emphasize our limited knowledge about the mixtures of chemicals that we are exposed to everyday. But, if we can look up to see the forest, we may begin to make our way towards safer territory.