Carcinogenesis & Genotoxicity
Exponent toxicologists have specific expertise for evaluating cancer mode of action (MoA) that allow for risk assessment applications that reach beyond simple linear extrapolation methods. Understanding how a substance causes cancer (e.g., MoA or adverse outcome pathway) may determine how that substance is regulated and classified. The MoA information can also assist in determining the human relevance (or lack thereof) of the tumor findings based on any qualitative or quantitative differences in the key events between animals and humans.
The diverse expertise at Exponent allows for the derivation of cancer MoA analyses that consider the full weight of evidence, 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 CAR or PPAR nuclear receptor activation and regenerative proliferation
- Species-specific differences in kinetics, dynamics, and sensitivity
The MoA Framework and Its Importance
Since publication of the revised 1999 US EPA Guidelines for Carcinogen Risk Assessment where the concept of the “mode of action (MoA) framework” was introduced for regulatory decision-making, the application of this framework has propelled forward a clear recognition that not all carcinogens operate via a linear MoA. Rather, some carcinogens may exhibit thresholds of toxicity, or nonlinear mode(s) of action.
“Knowledge of the biochemical and biological changes that precede tumor development (which include, but are not limited to, mutagenesis, increased cell proliferation, inhibition of programmed cell death, and receptor activation, etc.) may provide important insights for determining whether a cancer hazard exists and whether there is an appropriate consideration of the dose-response relationship below the range of observable tumor response.” (USEPA, 1999).
Knowing the observed and measurable key events, considering the temporal and dose-response concordance along that obligatory toxicity pathway, are foundational elements to anchor a more informed decision of the most appropriate and protective endpoint for risk assessments. For example, if the MoA is known, a chemical carcinogen may be regulated on an earlier, non-carcinogenic precursor key event that may be adequately protective of later adverse effects (e.g., tumors). In this situation, the chemical would be considered, “not carcinogenic at doses that do not cause the earlier precursor event” thus, avoiding the classification of being a linear carcinogen and the derivation of unit cancer risk.
The use of MoA in cancer risk assessment is recognized internationally. The International Programme on Chemical Safety (IPCS) of the World Health Organization (WHO) advanced many MoA evaluation tools and recently developed a 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.
- 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’s Experience with MoA
Exponent has a unique combination of hands-on regulatory and laboratory experience in identifying the minimal dataset to support a MoA and considering what is the acceptability of those studies for regulatory determinations of carcinogenic potential. Our staff has decades of strategic science and policy experience in working in the regulatory agency’s cancer and hazard review committees and experience at the laboratory bench in designing, monitoring and conducting these complex, innovative state of the art “fit-for-purpose” studies including transcriptomic analyses and application of genetically modified animals.
Our scientists are internationally recognized in the fields of genetic toxicology, ADME, carcinogenic mode(s)-of-action analyses, weight of evidence analyses and considering their relevance to humans. We can assist you in reviewing available genetic toxicology and other toxicological/mechanistic data on your molecules and assess their regulatory impact on cancer classification. Our staff is also experienced in designing state-of-the-art studies to elucidate MOAs in carcinogenesis; identify competent laboratories to perform these studies; and assist in data analysis, integration, and interpretation in support of regulatory submissions.
Whitwell J, Smith R, Jenner K, Lyon H, Wood D, Clements J, Aschcroft-Hawley K, Gollapudi B, Kirkland D, Lorge E, Pfuhler S, Tanir JY, Thybaud V. Relationships between p53 status, apoptosis and induction of micronuclei in different human and mouse cell lines in vitro: Implications for improving existing assays. Mutat Res Genet Toxicol Environ Mutagen. 2015:789-790:7-27.
Ji Z, LeBaron MJ, Schisler MR, Zhang F, Bartels MJ, Gollapudi BB, Pottenger LH. Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU. Mutagenesis. 2015 Jun 3. [Epub ahead of print] PubMed PMID:26040483.
Martus HJ, Hayashi M, Honma M, Kasper P, Gollapudi B, Mueller L, Schoeny R, Uno Y, Kirkland DJ. Summary of major conclusions from the 6th International Workshop on Genotoxicity Testing (IWGT), Foz do Iguaçu, Brazil. Mutat Res Genet Toxicol Environ Mutagen. 2015: 783:1-5.
Sura R, Settivari RS, LeBaron MJ, Rowlands JC, Carney EW, Gollapudi BB. A critical assessment of the methodologies to investigate the role of inhibition of apoptosis in rodent hepatocarcinogenesis. Toxicol Mech Methods. 2015:25:192-200.
Zeiger E, Gollapudi B, Aardema MJ, Auerbach S, Boverhof D, Custer L, Dedon P, Honma M, Ishida S, Kasinski AL, Kim JH, Manjanatha MG, Marlowe J, Pfuhler S, Pogribny I, Slikker W, Stankowski LF Jr, Tanir JY, Tice R, van Benthem J, White P, Witt KL, Thybaud V. Opportunities to integrate new approaches in genetic toxicology: An ILSI-HESI workshop report. Environ Mol Mutagen. 2015:56:277-85.
Gollapudi BB, Lynch AM, Heflich RH , Dertinger SD, Dobrovolsky VN, Froetschle R, Horibata K, Kenyon MO, Kimoto T, Lovell D, Stankowski Jr. LF, White PA, Witt KL, Tanir JY. The in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup. Mutat. Res. 2015:1;783:23-35.
Johnson GE, Slob W, Doak S, Fellows M, Gollapudi B, Heflich RH, Rees B, Soeteman-Hernández LG, Verma J, Wills J, Jenkins G, and White P. New Approaches to Advance the use of Genetic Toxicology Analyses for Human Health Risk Assessment and Regulatory Decision-Making, Toxicology Res., 2015: 4, 667-676.
Marion Joseph Fedoruk, MD, CIH, DABT, FACMT, FACOEMHealth SciencesPrincipal ScientistOrange County