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Your Environment. Your Health.

Combined Exposures and Mixtures Program

Public Health Significance

People are continuously exposed to mixtures of chemical and nonchemical stressors (e.g., psychosocial stress) throughout their lifetimes, and there is clear evidence that combined exposures can have cumulative effects (e.g., asbestos and tobacco smoke on lung cancer). Because most toxicity studies and risk assessments address only single chemical exposures, the scientific community may be underestimating the effects of exposure to multiple substances on human health and disease progression.

Challenges persist in characterizing exposures to mixtures, evaluating their toxicity and hazard, and assessing associated risk. Limitations in our understanding have led to inconsistent use of available mixture methods and significant uncertainties in their application. Lack of harmonized terminology and methods comparisons complicates the synthesis of information across disciplines and impedes the use of mixtures data in decision-making.

 

Program Objectives

To tackle these problems in understanding the potential health effects of mixtures, the Combined Exposures and Mixtures (CEM) Program is structured around the following three objectives:

  1. Develop and apply a disease-centered systems biology approach for prioritizing mixtures for toxicological and hazard characterization to inform cumulative risk evaluation. This approach starts with a disease of interest and aims to identify and evaluate the joint effects of factors that contribute to disease development; it contrasts with component-based mixtures approaches that focus exclusively on structurally or mechanistically similar chemicals.
  2. Develop and apply methods for complex mixtures testing and data interpretation to inform risk assessment of whole mixtures. Methods include targeted and nontargeted chemical analyses, complex mixture read-across (i.e., determining sufficient similarity), polypharmacokinetics (i.e., pharmacokinetics of multicomponent exposures), and bioassay-guided fractionation to identify toxic constituents.
  3. Apply component-based approaches by experimentally evaluating defined mixtures and using predictive modeling approaches (e.g., dose addition, response addition) and compare the results with alternative whole-mixture evaluation.

Ultimately, the CEM Program is aimed at using a systems biology approach to predict which chemicals might act additively when present in mixtures, developing and refining whole-mixture evaluation and complex mixture read-across approaches, and strengthening predictive models of mixture toxicity by decreasing uncertainty in the application of component-based models.

Background

The Division of the National Toxicology Program (DNTP) mixtures portfolio offers a unique opportunity to inform literature-based evaluations in addressing human health effects from exposure to mixtures and is geared toward informing decision-making related to component-based and whole-mixture risk assessment. Assessing mixtures requires collaborative engagement across scientific disciplines, and multidisciplinary team science is a core value at DNTP.

Approaches for complex mixture read-across applied in the CEM Program represent leading-edge science. Broad public health implications involved in mixtures research ensure that DNTP trainees involved in mixtures projects gain experience in translational research. Thus, the CEM Program is well aligned with the mission and goals of DNTP to incorporate the use of predictive models and emphasize the translational nature of our research.

Select Studies

Study Description Findings/Supporting Files
Converging on cancer In vitro assays informing an in vivo study that explores whether chemicals targeting different cancer-related pathways contribute cumulatively to cancer development in a manner not accounted for by individual chemical evaluation.

Using the key characteristics of carcinogens to develop research on chemical mixtures and cancer. Environ Health Perspect. 129(3):35003. [Abstract Using the key characteristics of carcinogens to develop research on chemical mixtures and cancer. Environ Health Perspect. 129(3):35003.]

April 2019 workshop to inform project development.

Personal care products — literature-based assessments

Scoping reviews on timing of pregnancy and fetal growth that consider different methods of assessing exposure to personal care products and their individual constituents.

Literature screening and data extraction efforts for scoping reviews of timing of puberty and fetal growth, ongoing.

Sufficient similarity — botanical dietary supplements

Development of tools and approaches (chemical analysis, in vitro assays, and statistical methods) for comparing across variable and complex mixtures.

A combination of in vitro assays and non-targeted chemical analysis were useful in evaluating the variability across related complex mixtures and in selecting test articles and extrapolating findings from studies with a single test article to other variants.

Collins BJ, Kerns SP, Aillon K, Mueller G, Rider CV, DeRose EF, London RE, Harnly JM, Waidyanatha S. 2020. Comparison of phytochemical composition of Ginkgo biloba extracts using a combination of non-targeted and targeted analytical approaches. Anal Bioanal Chem 412(25):6789-6809. [Abstract Collins BJ, Kerns SP, Aillon K, Mueller G, Rider CV, DeRose EF, London RE, Harnly JM, Waidyanatha S. 2020. Comparison of phytochemical composition of Ginkgo biloba extracts using a combination of non-targeted and targeted analytical approaches. Anal Bioanal Chem 412(25):6789-6809.]

Waidyanatha S, Pierfelice J, Cristy T, Mutlu E, Burback B, Rider CV, Ryan K. 2020. A strategy for test article selection and phytochemical characterization of Echinacea purpurea extract for safety testing. Food Chem Toxicol. 137:111125. [Abstract Waidyanatha S, Pierfelice J, Cristy T, Mutlu E, Burback B, Rider CV, Ryan K. 2020. A strategy for test article selection and phytochemical characterization of Echinacea purpurea extract for safety testing. Food Chem Toxicol. 137:111125.] 

Ryan KR, Huang MC, Ferguson SS, Waidyanatha S, Ramaiahgari S, Rice JR, Dunlap PE, Auerbach SS, Mutlu E, Cristy T, Peirfelice J, DeVito MJ, Smith-Roe SL, Rider CV. 2019. Evaluating sufficient similarity of botanical dietary supplements: Combining chemical and in vitro biological data. Toxicol Sci 172(2):316-329. [Abstract Ryan KR, Huang MC, Ferguson SS, Waidyanatha S, Ramaiahgari S, Rice JR, Dunlap PE, Auerbach SS, Mutlu E, Cristy T, Peirfelice J, DeVito MJ, Smith-Roe SL, Rider CV. 2019. Evaluating sufficient similarity of botanical dietary supplements: Combining chemical and in vitro biological data. Toxicol Sci 172(2):316-329.]

Smith-Roe SL, Witt KL, Rider CV. 2018. How similar is similar enough? A sufficient similarity case study with Ginkgo biloba extract. Food Chem Toxicol 118:328-339. [Abstract Smith-Roe SL, Witt KL, Rider CV. 2018. How similar is similar enough? A sufficient similarity case study with Ginkgo biloba extract. Food Chem Toxicol 118:328-339.]

Polycyclic aromatic compound mixtures assessment program (PAC-MAP)

Evaluation of the assumptions in current component-based risk assessment approaches to inform their application and refinement.

PAC-MAP website

Hsieh JH, Sedykh A, Mutlu E, Germolec DR, Auerbach SS, Rider CV. 2021. Harnessing in silico, in vitro, and in vivo data to understand the toxicity landscape of polycyclic aromatic compounds (PACs). Chem Res Toxicol 34(2):268-285. [Abstract Hsieh JH, Sedykh A, Mutlu E, Germolec DR, Auerbach SS, Rider CV. 2021. Harnessing in silico, in vitro, and in vivo data to understand the toxicity landscape of polycyclic aromatic compounds (PACs). Chem Res Toxicol 34(2):268-285.]

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