Testing the low dose mixtures hypothesis from the Halifax project

In 2013, 60 scientists, representing a larger group of 174 scientists from 26 nations, met in Halifax, Nova Scotia to consider whether - using published research - it was logical to anticipate that a mixture of chemicals, each thought to be non-carcinogenic, might act together in that mixture as a virtual carcinogen. The group identified 89 such chemicals, each one affecting one or more Hallmark(s) - collectively covering all Hallmarks of Cancer - confirming the possibility that a chemical mixture could induce all the Hallmarks and function as a virtual carcinogen, thereby supporting the concern that chemical safety research that does not evaluate mixtures, is incomplete. Based on these observations, the Halifax Project developed the Low-Dose Carcinogenesis Hypothesis which posits "...that low-dose exposures to [mixtures of] disruptive chemicals that are not individually carcinogenic may be capable of instigating and/or enabling carcinogenesis." Although testing all possible combinations of over 80,000 chemicals of commerce would be impractical, prudence requires designing a methodology to test whether low-dose chemical mixtures might be carcinogenic. As an initial step toward testing this hypothesis, we conducted a mini review of published empirical observations of biological exposures to chemical mixtures to assess what empirical data exists on which to base future research. We reviewed studies on chemical mixtures with the criteria that the studies reported both different concentrations of chemicals and mixtures composed of different chemicals. We found a paucity of research on this important question. The majority of studies reported hormone related processes and used chemical concentrations selected to facilitate studying how mixtures behave in experiments that were often removed from clinical relevance, i.e., chemicals were not studied at human-relevant concentrations. New research programs must be envisioned to enable study of how mixtures of small doses of chemicals affect human health, starting, when at all possible, from non-malignant specimens when studies are done in vitro. This research should use human relevant concentrations of chemicals, expand research beyond the historic focus on endocrine endpoints and endocrine related cancers, and specifically seek effects that arise uniquely from exposure to chemical mixtures at human-relevant concentrations.