Using the Key Characteristics of Carcinogens to Develop Research on Chemical Mixtures and Cancer

Abstract

BACKGROUND: People are exposed to numerous chemicals throughout their lifetimes. Many of these chemicals display one or more of the key characteristics of carcinogens or interact with processes described in the hallmarks of cancer. Therefore, evaluating the effects of chemical mixtures on cancer development is an important pursuit. Challenges involved in designing research studies to evaluate the joint action of chemicals on cancer risk include the time taken to perform the experiments because of the long latency and choosing an appropriate experimental design. OBJECTIVES: The objectives of this work are to present the case for developing a research program on mixtures of environmental chemicals and cancer risk and describe recommended approaches. METHODS: A working group comprising the coauthors focused attention on the design of mixtures studies to inform cancer risk assessment as part of a larger effort to refine the key characteristics of carcinogens and explore their application. Working group members reviewed the key characteristics of carcinogens, hallmarks of cancer, and mixtures research for other disease end points. The group discussed options for developing tractable projects to evaluate the joint effects of environmental chemicals on cancer development. RESULTS AND DISCUSSION: Three approaches for developing a research program to evaluate the effects of mixtures on cancer development were proposed: a chemical screening approach, a transgenic model-based approach, and a disease-centered approach. Advantages and disadvantages of each are discussed.

Protracted Impairment of Maternal Metabolic Health in Mouse Dams Following Pregnancy Exposure to a Mixture of Low Dose Endocrine-Disrupting Chemicals, a Pilot Study

“…Research on maternal metabolic health following gestational EDC exposures should utilize real-world mixtures, along with integrated metabolic assessments, to determine the influence of complex EDC mixtures on women's health. The current findings indicate that enhanced effects of MIX exposure may result from multiple small hits at different molecular targets that together converge to disrupt the homeostasis of integrated metabolic endpoints, such as serum hyperglycemia and dyslipidemia [87]. Mechanistic studies focused on mixtures should integrate multiple aspects of metabolic physiology, including assessments of the pancreas, liver, and serum lipids, at baseline to understand how such convergence occurs.…”

“…Despite higher means, there were no statistically significant increases in weight or visceral adipose. This study was a proof-of-concept experiment focused on a disease-centered approach to mixture studies aimed at investigating how EDCs with diverse molecular targets integrate across multiple signaling pathways in a complex system to evaluate joint effects on later-life maternal metabolic health [87][88][89]. More work is needed to replicate this study with a larger sample size and to investigate how additional EDC mixtures with diverse molecular modes of action may converge downstream to alter maternal health during gestation and across the lifespan.…”

Key Characteristics of Cardiovascular Toxicants

“…2017 ). The KC framework also enables study of the CV effects of mixtures comprising chemicals that exhibit different KCs, as was recently described for studies of the carcinogenic effects of mixtures ( Rider et al. 2021 ).…”

A Framework for Cumulative Risk Assessment: Exploring the Carcinogenic Effects of Chemical Mixtures

“…Accordingly, researchers have long been interested in the complex task of studying how mixtures affect disease end points. 1 Cynthia Rider and colleagues recently proposed in Environmental Health Perspectives 2 a research program on mixtures and cancer based on the key characteristics of carcinogenic chemicals. 3 …”