An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E₂, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates the expression of a diverse group of genes. Exogenous AHR ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent agonist, and the synthetic AHR antagonist N-2-(1H-indol-3yl)ethyl)-9-isopropyl-2- (5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351). As no experimentally determined structure of the ligand binding domain exists, homology models have been utilized for virtual ligand screening (VLS) to search for novel ligands. Here, we have developed an “agonist-optimized” homology model of the human AHR ligand binding domain, and this model aided in the discovery of two human AHR agonists by VLS. In addition, we performed molecular dynamics simulations of an agonist TCDD-bound and antagonist GNF351-bound version of this model in order to gain insights into the mechanics of the AHR ligand-binding pocket. These simulations identified residues 307–329 as a flexible segment of the AHR ligand pocket that adopts discrete conformations upon agonist or antagonist binding. This flexible segment of the AHR may act as a structural switch that determines the agonist or antagonist activity of a given AHR ligand.

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. Discussion: and 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

More needs to be done by the private sector to optimize the drug discovery and development pipeline. In addition, significant efforts should also be focused on the understanding of mechanism of diseases, on the characterization of unexplored biochemical pathways and on the validation of new protein targets. Chemical genomics, which uses chemical probes to help understand the complexity of biological systems at the gene and protein levels, has proven in recent years to be an important tool. Experimental and computational chemical genomic screenings have been used by the private sector and recently also by academia and non-profit institutions for drug repurposing or repositioning to find new indications for known drugs. A detailed overview of the current initiatives in drug repurposing, initiated by the major governmental funding agencies around the world is reported. The push towards greater efficiency is encouraging drug repurposing and other techniques in chemical genomics. Finding the best ways to improve translational research and accelerate the regulation of clinical phases means being able to launch safer drugs into the market faster.