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National Toxicology Program

National Toxicology Program

UPDATE NewsletterUPDATE NewsletterSeptember 2016

Research needed on low-dose chemical mixtures and cancer

By Virginia Guidry
Reprinted from Environmental Factor

Research is needed to determine if low doses of noncarcinogenic chemicals in the environment may be able to combine and lead to cancer, according to new recommendations published Aug. 12 in the journal Environmental Health Perspectives. The authors compiled the recommendations from a 2015 NIEHS-sponsored scientific workshop.

“The more we look into the mechanisms of different cancers and their origin, the more we can see the environment is playing a role,” said Mark Miller, Ph.D., NIEHS chief of staff and lead author on the paper. “By focusing only on individual carcinogens, we may be underestimating the cancer-related risks of the everyday exposures that people face.”

Many chemicals are treated as safe if they are not complete carcinogens, or chemicals that can cause cancer on their own. However, the authors said recent evidence suggests that approach should be revised. “It is no longer sufficient to assess chemical safety using individual chemicals,” they wrote.

The low-dose mixture theory

The low-dose mixture hypothesis suggests that environmental chemicals to which humans are normally exposed, which typically include many chemicals at low-levels, can trigger the hallmarks of cancer. Hallmarks are biological events necessary for the development of cancer, or carcinogenesis. Examples are when cells become resistant to normal cell death or send continuous signals to promote growth.

“Cancer develops in multiple steps,” explains William Bisson, Ph.D., assistant professor in computational chemical genomics at Oregon State University and a co-lead author of the paper with Miller. “Cancer risk assessment will only be successful if these complexities are fully understood.”

In June 2015, the Halifax Project published a series of articles in the journal Carcinogenesis that laid the foundation for the low-dose mixture theory. The articles showed that a number of seemingly safe chemicals have the ability to act on individual cancer hallmarks, and thus may contribute to carcinogenesis.

Nicole Kleinstreuer, Ph.D., deputy director of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), co-authored the paper. She published a 2013 study that confirmed cancer-causing chemicals in animal studies could be mapped to specific cancer hallmarks, based on their activity in the body. The evidence that seemingly noncarcinogenic chemicals may also act on hallmarks called into question the presumed safety of the chemicals.

“There is scientific evidence for the theory that there are potential carcinogenic contributions from a variety of chemicals people are exposed to in the environment, and this theory should be tested,” Kleinstreuer said.

Future research needs

Based on data from the literature-based Halifax Project, the authors recommended testing common environmental chemicals to see if they can trigger cancer hallmarks, either through individual exposures that follow one another, or through a combination of simultaneous exposures. They recommended further testing on chemicals shown to affect multiple hallmarks, as they are most likely to produce predictable carcinogenic outcomes.

The authors also laid out a number of other research priorities. For example, they said it is necessary to know how each hallmark contributes to cancer formation and progression. Scientists should better understand the early stages of cancer and the biological processes, such as immune system responses and DNA repair, that keep these early stages in check.

The report also calls for identifying more markers of genetic and epigenetic changes that may indicate the likely formation of aggressive tumors. Epigenetic changes alter when and how a gene is activated, or expressed. “We know that epigenetic control of normal gene expression can be tumor-promoting even if that gene is not mutated,” said Bisson.

“At this point, the data supporting the low-dose hypothesis are relatively limited,” said Miller. “But by identifying the tools needed to begin testing this hypothesis, we are gaining momentum behind the concept, so the research community can get onboard for a collective effort.”

Citation: Miller MF, Goodson WH 3rd, Manjili MH, Kleinstreuer N, Bisson WH, Lowe L. 2016. Low-dose mixture hypothesis of carcinogenesis workshop: scientific underpinnings and research recommendations. Environ Health Perspect; doi:10.1289/ehp411 [Online 12 August 2016].


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