Low-Dose Mixture Hypothesis of Carcinogenesis Workshop: Scientific Underpinnings and Research Recommendations

Abstract

Background:The current single-chemical-as-carcinogen risk assessment paradigm might underestimate or miss the cumulative effects of exposure to chemical mixtures, as highlighted in recent work from the Halifax Project. This is particularly important for chemical exposures in the low-dose range that may be affecting crucial cancer hallmark mechanisms that serve to enable carcinogenesis.Objective:Could ongoing low-dose exposures to a mixture of commonly encountered environmental chemicals produce effects in concert that lead to carcinogenesis? A workshop held at the NIEHS in August 2015 evaluated the scientific support for the low-dose mixture hypothesis of carcinogenesis and developed a research agenda. Here we describe the science that supports this novel theory, identify knowledge gaps, recommend future methodologies, and explore preventative risk assessment and policy decision-making that incorporates cancer biology, environmental health science, translational toxicology, and clinical epidemiology.Discussionand Conclusions: The theoretical merits of the low-dose carcinogenesis hypothesis are well founded with clear biological relevance, and therefore, the premise warrants further investigation. Expert recommendations include the need for better insights into the ways in which noncarcinogenic constituents might combine to uniquely affect the process of cellular transformation (in vitro) and environmental carcinogenesis (in vivo), including investigations of the role of key defense mechanisms in maintaining transformed cells in a dormant state. The scientific community will need to acknowledge limitations of animal-based models in predicting human responses; evaluate biological events leading to carcinogenesis both spatially and temporally; examine the overlap between measurable cancer hallmarks and characteristics of carcinogens; incorporate epigenetic biomarkers, in silico modelling, high-performance computing and high-resolution imaging, microbiome, metabolomics, and transcriptomics into future research efforts; and build molecular annotations of network perturbations. The restructuring of many existing regulatory frameworks will require adequate testing of relevant environmental mixtures to build a critical mass of evidence on which to base policy decisions.Citation:Miller MF, Goodson WH III, Manjili MH, Kleinstreuer N, Bisson WH, Lowe L. 2017. Low-Dose Mixture Hypothesis of Carcinogenesis Workshop: scientific underpinnings and research recommendations. Environ Health Perspect 125:163–169; http://dx.doi.org/10.1289/EHP411

Environmental carcinogenesis and pH homeostasis: Not only a matter of dysregulated metabolism

“…Furthermore, as stated above, the combined effects of environmental chemicals due to their diversity and widespread distribution may potentially make an important contribution to the overall process of cancer development. Hence, as recently stressed by the Halifax project consortium [4,5], there is an urgent need to develop studies on the biological and toxicological effects of these contaminants to increase our knowledge about their action mechanisms, notably with regard to carcinogenesis.…”

Association between heavy metal and metalloid levels in topsoil and cancer mortality in Spain

“…The risk resulting from chronic exposure to a mixture of potentially toxic items in topsoil confronts one with the problem of choosing a paradigm different to the prevailing one of “single chemical as carcinogen” (Miller et al 2016). Regulatory measures governing tolerable/permitted-to-toxic environmental levels are based on this paradigm, and its reconsideration has thus to be based on a process of proper evaluation/testing which highlights the importance of mixtures of toxic elements.…”

Application of the Key Characteristics of Carcinogens to Per and Polyfluoroalkyl Substances

“…In a study of 86 agents known to cause cancer in humans, on average, each agent exhibited four key characteristics [211]. This is particularly important for assessing the adverse health effects of exposure to chemical mixtures, given that mixtures of different chemicals may contribute to cancer development [212,213]. Recently, research by the Halifax Project environmental mixtures task force highlighted that chemicals commonly present in human environment cause a variety of effects associated with hallmarks of cancer [194,214].…”