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Your Guide to Metabolomics

Chapter 8—Regulatory Applications of Metabolomics

Until now, this guide has been focused on the scientific applications of metabolomics across a range of disciplines, from basic science research to clinical trials to cosmetics. In this chapter, we’ll explore the ways in which metabolomics can help define and uphold governmental and agency regulations and guidelines.

FDA and Agency Standards

The United States Food and Drug Administration (FDA) oversees numerous activities,1 from the approval of new drugs to guidelines around safe food production. Utilizing metabolomics can help the FDA do its job more quickly and accurately, and there are several use cases for metabolomics:

  • Assuring safe, wholesome, sanitary, and properly labeled foods.1 Metabolomics techniques have been used to define the nutritional profile and quality of foods,2 detect microbial3 and environmental4 toxins in foods, and ensure that food manufacturers don’t cheat food labels5 by switching out high-end ingredients for cheaper ingredients and fillers to save money.
  • Ensuring safe and effective drugs and medical devices.1 Safe, efficacious drugs must elicit the desired physiological effect without exceeding acceptable toxicity levels. Metabolomics can identify and characterize drug metabolites and other host metabolites to profile the mechanism of action6 and define the toxicity profile7 of new drugs. Metabolomics can also play a key role in the quality control of manufactured drugs and has already been used in proof-of-concept quality control of natural product-derived medicines.8
  • Assuring safe, properly labeled cosmetics and dietary supplements.1 Similar to foods, metabolomics can ensure that cosmetics9 and dietary supplements10 are safe for human use and consumption and that labels are accurate.

It is important to note that systematic, standardized application of metabolomics in the regulatory setting hasn’t yet been achieved, despite the use cases presented above. Different stakeholders are working for regulatory buy-in by developing validated protocols and establishing the relevance of outcomes data from metabolomics studies.11 One of the most well-recognized efforts is the Metabolomics standards Initiative in Toxicology (MERIT). Although MERIT is a European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC)-supported project “providing guidance on best practice, quality standards, and the reporting of analytical and computational metabolomics methods used in regulatory toxicology,” it is an international effort that “relies on worldwide collaboration.”12 A follow-up to this, called the Metabolics Reporting Framework (MRF), was published by the Organisation for Economic Co-operation and Development (OECD) in 2021.13

Other organizations and associations are also contributing to a growing effort to support the widespread use of metabolomics (including regulatory applications). For example, the Metabolomics Society, which has over 1,000 members from across the globe, was founded to promote the growth of metabolomics internationally and help establish collaborations and partnerships across academia, government, and industry.14 The American Heart Association also released a scientific statement outlining the need for “strategies for determining the true clinical relevance of metabolites observed in association with cardiovascular disease outcome,”15 an achievement that would certainly impact the development and approval of new therapeutics.

Safety and Dangerous Substance Monitoring

Chemical risk assessment is the means by which the environmental and human health impacts of chemicals in the environment are assessed. Unfortunately, there are an incredibly large number of chemicals present in the environment. Traditional tests for detecting them are both expensive and time-consuming, and the use of animals for toxicity tests is also waning due to ethical concerns. Metabolomics is a sensitive, high-throughput alternative with huge potential for using this approach in environmental pollution and chemical safety applications. Scientists even suggest that metabolomics can make significant contributions to guide decision-making around chemical regulation and management.16

The OECD, which also developed the MRF discussed above, has coordinated an international Adverse Outcome Pathways (AOP) development effort, which acts as a framework for evaluating the biomolecular effects of chemicals on various levels, from macromolecular interactions to population-level.16 The ultimate goal is to use these AOPs to predict the future impacts of various chemicals and devise effective remediation strategies. Metabolomics is expected to play a key role in characterizing these AOPs; for example, researchers have used metabolomics to describe the AOPs of silver17 and other metal-bearing18 nanoparticles, selenium as it relates to brain toxicity,19 and the pharmaceutical spironolactone (ie, a water pill),20 to name just a few examples.

Metabolomics protocols also contribute to improved registrations to the European Chemicals Agency’s (ECHA) REACH (registration, evaluation, and authorization of chemicals) Regulation, which governs the manufacture and import of chemical substances into the European Union. Metabolomics can be used to find similarities between biological responses to different chemicals to facilitate chemical grouping for read-across of adverse events,16 one of the most common methods used by the ECHA for data gap filling in REACH registrations.21 Metabolomics has facilitated chemical groupings for several chemical classes, including herbicides22 and bisphenols.23

Causation-Correlation Analysis

The precedent has been set for using metabolomics to establish causal relationships between single molecular traits and complex phenotypes because metabolomics is the only omics technique that measures phenotype.24 Although critical for information changes to regulatory standards and oversight, establishing causation, rather than simply correlation, isn’t as straightforward as defining causality between genome and phenotype. One reason for this is that different environmental exposures may be heavily correlated with each other or may act together, making the assignment of causality difficult, if not impossible, when studying them one at a time.25 Therefore, it is essential to find tools that can measure the cumulative impact of multiple exposures alongside their interactions with the genetic background of individuals. To identify causal links between environmental exposures and disease, the “meet-in-the-middle” (MITM) approach, which searches for intermediate biomarkers elevated in disease and then retrospectively searches for links between those biomarkers and environmental exposures, is one method that has been used for over 10 years.16

Metabolomics-based protocols have been reported for several MITM studies:

  • Air toxic exposure linked to oxidative stress associated with several common complex diseases and allergic respiratory diseases26
  • Identification of 10 biomarkers associating increased exposure by children and adolescents to industrial carcinogens with early carcinogenic biological events27
  • Linkage of six tryptophan and vitamin B3 pathway metabolites to air pollution exposure and decreased probability of live birth28
  • Arsenic exposure connected to male infertility29

This method, however, identifies what could more accurately be called associations, rather than causative relationships. To identify these associations, scientists suggest using approaches that can measure the cumulative impact of multiple exposures alongside their interactions with genetic elements.30 Regardless of which protocols are eventually developed and utilized, metabolomics will play a part.

What’s Next for Regulatory Applications of Metabolomics?

In this chapter, we discussed several ways metabolomics can and already is contributing to regulatory standards, monitoring of chemicals and other environmental pollutants, and establishing causative relationships between environmental elements and disease to further inform regulatory standards and governmental regulations. In the final installment of this guide, we’ll lay out everything you need to know to design a successful metabolomics-based study capable of delivering high-quality data and scientific insights.

Continue to Chapter 9 - Designing a Metabolomics Study

In the final installment of our metabolomics guide, we’ll walk you through the fundamentals of how to design and execute a robust metabolomics study to answer your research question(s).

References

  1. (2021, June 28). What does FDA do? https://www.fda.gov/about-fda/fda-basics/what-does-fda-do Accessed December 28, 2022.
  2. Pedrosa MC, Lima L, Heleno S et al. Food Metabolites as Tools for Authentication, Processing, and Nutritive Value Assessment. Foods. 2021;10(9):2213. doi:10.3390/foods10092213
  3. Jadhav SR, Shah R, Karpe AV et al. Detection of Foodborne Pathogens Using Proteomics and Metabolomics-Based Approaches. Front Microbiol. 2018;9:3132. doi:10.3389/fmicb.2018.03132
  4. Zhan J, Yu XJ, Zhong YY et al. Generic and rapid determination of veterinary drug residues and other contaminants in raw milk by ultra performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2012;906:48–57. doi:10.1016/j.jchromb.2012.08.018
  5. Emwas AHM, Al-Rifai N, Szczepski K et al. You Are What You Eat: Application of Metabolomics Approaches to Advance Nutrition Research. Foods. 2021;10(6):1249. doi:10.3390/foods10061249
  6. Alarcon-Barrera JC, Kostidis S, Ondo-Mendez A et al. Recent advances in metabolomics analysis for early drug development. Drug Discov Today. 2022;27(6):1763–1773. doi:10.1016/j.drudis.2022.02.018
  7. Ramirez T, Daneshian M, Kamp H et al. Metabolomics in Toxicology and Preclinical Research. ALTEX. 2013;30(2): 209–225. doi:10.14573/altex.2013.2.209
  8. Lee KM, Jeon JY, Lee BJ et al. Application of Metabolomics to Quality Control of Natural Product Derived Medicines. Biomol Ther. 2017;25(6):559–568. doi:10.4062/biomolther.2016.249
  9. Bouslimani A, da Silva R, Kosciolek T et al. The impact of skin care products on skin chemistry and microbiome dynamics. BMC Biology. 2019;17(1):47. doi:10.1186/s12915-019-0660-6
  10. Steg A, Oczkowicz M, and Smołucha G. Omics as a Tool to Help Determine the Effectiveness of Supplements. Nutrients. 2022;14(24):5305. doi:10.3390/nu14245305
  11. Viant MR, Ebbels TMD, Beger RD et al. Use cases, best practice and reporting standards for metabolomics in regulatory toxicology. Nat Commun. 2019;10(1):3041. doi:10.1038/s41467-019-10900-y
  12. Beger RM, Viant T, Ebbels J et al. MEtabolomics standaRds Initiative in Toxicology (MERIT). Metabolomics 2018, Seattle, WA, June 24 – 28, 2018.
  13. (2021 May). The Organisation for Economic Co-operation and Development. Metabolomics Reporting Framework (MRF). https://www.oecd.org/chemicalsafety/testing/metabolomics-reporting-framework.pdf Accessed December 27, 2022.
  14. https://metabolomicssociety.org
  15. Cheng S, Shah SH, Corwin EJ et al. Potential Impact and Study Considerations of Metabolomics in Cardiovascular Health and Disease: A Scientific Statement From the American Heart Association. Circ Cardiovasc Genet. 2017;10(2):e000032. doi:10.1161/HCG.000000000000003
  16. Bedia C. Metabolomics in environmental toxicology: Applications and challenges. Trends in Env Anal Chem. 2022;34:e00161. doi:10.1016/j.teac.2022.e00161
  17. Maria VL, Licha D, Scott-Fordsmand JJ et al. Multiomics assessment in Enchytraeus crypticus exposed to Ag nanomaterials (Ag NM300K) and ions (AgNO3) – metabolomics, proteomics (& transcriptomics). Environ Pollut. 2021;286:117571. doi:10.1016/j.envpol.2021.117571
  18. Dekkers S, Williams TD, Zhang J et al. Multi-omics approaches confirm metal ions mediate the main toxicological pathways of metal-bearing nanoparticles in lung epithelial A549 cells. Environ Scie: Nano. 2018;5:1506–1517. doi:10.1039/C8EN00071A
  19. Li X, Liu H, Li D et al. Dietary seleon-L-methionine causes alterations in neurotransmitters, ultrastructure of the brain, and behaviors in zebrafish (Danio rerio). Environ Sci Technol. 2021;55:11894–11905. doi:10.1021/acs.est.1c03457
  20. Davis JM, Ekman DR, Skelton CA et al. Metabolomics for informing adverse outcome pathways: androgen receptor activation and the pharmaceutical spironolactone. Aquat Toxicol. 2017;184:103–115. doi:10.1016/j.aquatox.2017.01.001
  21. Sperber S, Wahl M, Berger F et al. Metabolomics as read-across tool: An example with 3-aminopropanol and 2-aminoethanol. Regul Toxicol Pharmacol. 2019;108:104442. doi:10.1016/j.yrtph.2019.104442
  22. van Ravenzwaay B, Sperber S, Lemke O et al. Metabolomics as a read-across tool: a case study with phenoxy herbicides. Regul Toxicol Pharm. 2016;81:288–304. doi:10.1016/j.yrtph.2016.09.013
  23. Oliveira Pereira EA, Labine LM, Kleywegt S et al. Metabolomics reveals that bisphenol pollutants impair protein synthesis-related pathways in Daphnia magna. Metabolites. 2021;11(10):666. doi:10.3390/metabo11100666
  24. Auwerx C, Sadler MC, Reymond A et al. Exploiting the mediating role of the metabolome to unravel transcript-to-phenotype associations. Preprint. bioRxiv. 2022. doi:10.1101/2022.06.08.495285
  25. Patel CJ and Ioannidis JPA. Studying the elusive environment in large scale. JAMA. 2014;311(21):2173–4. doi:10.1001/jama.2014.4129
  26. Chen CHS, Yuan TH, Shie RH et al. Linking sources to early effects by profiling urine metabolome of residents living near oil refineries and coal-fired power plants. Environ Int. 2017;102:87–96. doi:10.1016/j.envint.2017.02.003
  27. Chen CHS, Kuo TC, Kuo HC et al. Metabolomics of children and adolescents exposed to industrial carcinogenic pollutants. Environ Sci Technol. 2019;53:5454–5465. doi:10.1021/acs.est.9b00392
  28. Gaskins AJ, Tang Z, Hood RB et al. Periconception air pollution, metabolomic biomarkers, and fertility among women undergoing assisted reproduction. Environ Int. 2021;155:106666. doi:10.1016/j.envint.2021.106666
  29. Wu Y, Ding R, Zhang X et al. Meet-in-metabolite analysis: a novel strategy to identify connections between arsenic exposure and male infertility. Environ Int. 2021;147:106360. doi:10.1016/j.envint.2020.106360
  30. Rattray NJ, Deziel NC, Wallach JD et al. Beyond genomics: understanding exposotypes through metabolomics. Hum Genomics. 2018;12(1):4. doi:10.1186/s40246-018-0134-x

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