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Nomination Summary for Assessing the carcinogenic potential of exposure to chemical mixtures at environmentally relevant dose levels (N21604)

Nominated Substances: No Specific Substances or Agents are Selected for this Nomination

Nomination Date: 03/31/2016

Nominator: Environmental Working Group

Rationale: Classic toxicological/carcinogenic evaluations typically involve exposure to a single agent, often at high doses. Yet in reality the public’s exposure to environmental substances occurs in complex mixtures at relatively low doses. Research focused on the carcinogenicity and toxicity of a single compound, while critically important, is bound to miss interactions and synergies that are reasonably anticipated to occur in real life. For example, while a single agent may not act as a carcinogen per se, it could significantly contribute to cancer by perturbing one or more key biological pathways that play an important role in the etiology of the disease. The “Hallmarks of Cancer” (Hanahan and Weinberg 2000, 2011) describes the common features of cancer cells (self-sufficiency in growth signaling, insensitivity to anti-growth signals, evading apoptosis, limitless replication potential, sustained angiogenesis, tissue evasion and metastasis, evasion of immune destruction, dysregulated metabolism) and characteristics that can enable carcinogenesis (genomic instability, tumor-promoting inflammation). It is plausible that the molecular processes that underpin these phenotypes could collectively be affected by mixtures of environmental agents that, working together, could lead to cancer development. This hypothesis was explored by a group of scientists during the “Halifax Project” meeting funded by NIEHS. The framework is further supported by a recent series of articles published in Carcinogenesis which identified environmental chemicals reported to disrupt key pathways that are important in carcinogenesis (Goodson 2015). And a recently published computational toxicology model demonstrated that perturbations in hallmark-related targets using high-throughput assays predict rodent carcinogenesis (Kleinstreuer 2013). The World Health Organization’s International Agency for Research on Cancer recently published another relevant framework that identifies key properties of known carcinogens (Smith 2015). As would be expected, there is significant overlap between these properties and the “hallmark” features: known carcinogens are electrophilic directly or after metabolic activation; genotoxic; alter DNA repair or cause genomic instability; induce epigenetic alterations; induce oxidative stress; induce chronic inflammation; be immunosuppressive; modulate receptor-mediated effects; cause immortalization; and alter cell proliferation, cell death, or nutrient supply. These properties could assist in the identification of candidate test chemicals that are not recognized carcinogens but could nonetheless contribute to the disease. If environmentally relevant mixtures of chemicals are causing or substantially contributing to cancer, the public health consequences are profound. Biomonitoring data, including that collected from the CDC’s NHANES survey, clearly show that the general population is exposed to a vast array of compounds that could affect myriad biological processes. A NTP testing program focused on evaluating whether or not mixtures of substances with specific reported biological activity could cause disease, such as cancer, could have extremely important implications for risk and exposure assessments. This is particularly true when cumulative exposure is an important consideration in assessing and estimating risk. The testing framework could also be more broadly applied to investigate the role of mixtures in diseases where mechanistic data are known. For example, this framework could be useful in identifying chemical mixtures that may affect pathways mapped in the Adverse Outcome Pathway paradigm. EWG encourages NTP to select chemicals for mixture testing that are ubiquitous in the environment, consumer products, and/or for which biomonitoring data are available. Data sources could include NHANES biomonitoring data and the EPA’s Chemical Data Reporting inventory. In selecting test substances relevant to specific hallmarks, NTP could consider a prioritized approach. For example, priority pathways may include limitless replication potential and apoptosis evasion, and NTP may select substances shown to perturb these biological events. However, mixture composition should also be guided by exposure and biomonitoring information, and testing mixtures that are relevant to each hallmark may be informative particularly if it reflects real world exposure. In addition, NTP should consider if the chosen substances should selectively disrupt individual targets or should be more promiscuously active. Choosing compounds with characteristics that overlap with those laid out by IARC may also serve as a framework for compound selection. EWG has consulted a number of stakeholders and authors of the Carcinogenesis papers who are supportive of this nomination and have expressed a willingness to provide input on mixture selection strategies and study design as NTP sees fit. References/Supporting files (submitted as attachments) Goodson et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis. 2015 Jun;36 Suppl 1:S254-96. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. Kleinstreuer NC, Dix DJ, Houck KA, Kavlock RJ, Knudsen TB, Martin MT, Paul KB, Reif DM, Crofton KM, Hamilton K, Hunter R, Shah I, Judson RS. In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis. Toxicol Sci. 2013 Jan;131(1):40-55. Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. Environ Health Perspect. 2015 Nov 24. [Epub ahead of print].

NTP Principles: 1, 3, 5, 6