A central question for chemical risk assessment is whether substances might cause cancer in humans at environmentally-relevant doses. Mode of Action (MOA) analysis has become a critical component of this process, and applications of advanced MOA evaluation are rapidly expanding within the field of cancer risk assessment. Regulatory-driven cancer risk assessment includes MOA evaluation as one of the first and highly critical steps of the process, designed to inform the dose-response relationship (U.S. Environmental Protection Agency Guidance for Cancer Risk Assessment, 2005). The use of MOA in cancer risk assessment is also recognized internationally. The International Programme on Chemical Safety (IPCS) of the World Health Organization (WHO) initially advanced many MOA evaluation tools and recently developed the framework for analyzing the relevance of a cancer MOA for humans (2006). Exponent toxicologists use MOA analyses in the evaluation of specific exposure conditions to provide insights regarding general and specific disease causation, particular risk factors, co-exposures, and cancer risk. Descriptions of the mechanisms of the carcinogenic process provided by a cancer MOA analysis serve as the bases of biologically based dose-response models.
Exponent toxicologists have specific expertise for evaluating cancer MOAs that allow for risk assessment applications that reach beyond simple linear extrapolation methods. The diverse expertise at Exponent allows for the derivation of MOA analyses that consider the full weight of evidence (WOE), including:
- Bioactivation and detoxification mechanisms
- Activity of chemical metabolites
- Metabolic processes that affect tissue dosimetry
- The role of dual MOAs, which include multiple co-occurring mechanisms such as mutagenicity and regenerative proliferation
- Gene expression
- Species-specific differences in kinetics, dynamics, and sensitivity
- Dose-dependent differences in MOA due to saturable metabolism at higher doses; absorption, distribution, metabolism, and elimination (ADME) properties; and bioavailability
- Hierarchy-based approach for weighing the scientific evidence on whether mutation is a key event to the carcinogenic process
Exponent MOA evaluations specifically consider whether in vitro results are relevant to findings from in vivo studies, whether findings in animals are relevant to humans, and whether there is evidence for sensitive life stages or subpopulations. Thus, the resulting evaluation of the MOA is directly applicable to the dose-response evaluation and determination of a quantitative cancer risk assessment.
Recognizing that no single mutagenicity test is sufficient to determine whether a chemical causes cancer by a mutagenic MOA, the entire weight of evidence, including assays using genetically engineered animals and genomic microarrays, are used collectively to characterize the MOA. Exponent employs a science-driven approach to consider the full weight of evidence and identify critical uncertainties in the limitations of the available information. Our toxicologists collaborate closely with epidemiologists and physicians in examining studies of mutagenicity, human and animal toxicity, epidemiology, and clinical cases.
With the diverse expertise and extensive technical knowledge at Exponent, our toxicologists are uniquely positioned at the forefront of new risk assessment methodologies. Our development of innovative applications for MOA analyses enables us to assist our clients in addressing questions of whether a chemical causes cancer in humans at environmentally-relevant doses.