- Editorial
- Open access
- Published:
New approach methodologies to address population variability and susceptibility
Human Genomics volume 17, Article number: 56 (2023)
Human health risk assessment aims to characterize the potential harmful effects of chemical exposures to ensure the safety of broad populations. Among these broad populations are those with higher susceptibility to adverse effects from chemical exposures. Characterizing population-level variability and the interplay of factors that influence heterogeneity of response will help to build a comprehensive understanding of chemical risk that is inclusive, and protective, of susceptible populations. Variation in response to chemicals is determined by a myriad of aspects such as life stage, sex, genomics, epigenomics, nutrition, microbiome, comorbidities, psychosocial stressors, co- and cumulative exposures [1,2,3]. Genetic variations, such as single nucleotide variants (SNVs), copy number variations (CNVs), or structural variations, can impact how an individual metabolizes and responds to different environmental exposures. Historically, inter-individual differences with respect to potential hazardous effects are addressed by applying default uncertainty factors that include contributions from species extrapolation, sensitive subgroups, toxico-kinetics and -dynamics [4]. However, there are concerns that this may not provide sufficient protection for some populations, and data that inform on chemical-specific adjustment factors would be preferred [5, 6]. Currently, the traditional animal-based toxicology approach is insufficient to inform quantitative assessments of population variability and susceptibility.
Considerable progress has been made in the development and application of new approach methods (NAMs) that are human-relevant and suitable for testing high numbers of chemicals in terms of cost and time. Furthermore, NAMs have the potential to experimentally incorporate variability and susceptibility to derive toxicity predictions that better protect broad populations. Several recent case studies have demonstrated that NAMs can be applied to generate such data informing hazard and risk assessment [7]. For instance, variability of response across multiple donors due to genetics and chronic exposure was demonstrated in a human primary bronchial epithelial cell air–liquid model [8]. Genetic variability and environmental exposures have also been evaluated using cell lines [9], induced pluripotent stem cells (iPSCs) [10, 11], in silico models [12], and small model organisms, e.g., Zebrafish [13], Elegans [14] and Drosophila [15]. NAMs have been applied to assess additional factors that contribute to variability and susceptibility such as sex [16, 17], life stage [16, 18, 19], and comorbidities [20], including rare diseases [21]. Moreover, NAMs have the potential to incorporate complex mixtures and cumulative exposures [22,23,24]. Probabilistic methods can incorporate variability into predictions and have been used to derive reference dose estimates [25] and points of departure [23]. Understanding how variability and susceptibility factors are associated with exposure responses will help to identify susceptible populations and support NAMs-based risk assessment paradigms by quantifying and controlling for known sources of variability [3].
Certain populations who are more susceptible to chemical exposures encounter health disparities resulting from various factors that may include cumulative impacts, psychosocial stressors, or complex mixtures, among others. NAMs have the potential to elucidate the mechanisms underlying long-term exposure; however, community engagement is imperative to conducting meaningful, impactful research. In this collection, we welcome cutting-edge research on developing, applying, and validating NAMs that are designed to represent population variability and susceptibility and ensure better human health protection for the most vulnerable and sensitive individuals among us.
References
Birnbaum LS, Burke TA, Jones JJ. Informing 21st-century risk assessments with 21st-century science. Environ Health Perspect. 2016;124(4):A60–3.
Zeise L, Bois FY, Chiu WA, Hattis D, Rusyn I, Guyton KZ. Addressing human variability in next-generation human health risk assessments of environmental chemicals. Environ Health Perspect. 2013;121(1):23–31.
Varshavsky JR, Rayasam SDG, Sass JB, Axelrad DA, Cranor CF, Hattis D, et al. Current practice and recommendations for advancing how human variability and susceptibility are considered in chemical risk assessment. Environ Health. 2023;21(Suppl 1):133.
WHO. Chemical-specific adjustment factors for interspecies differences and human variability: guidance document for use of data in dose/concentration–response assessment. https://apps.who.int/iris/bitstream/handle/10665/43294/9241546786_eng.pdf;sequence=1 (2005).
Dilger M, Schneider K, Drossard C, Ott H, Kaiser E. Distributions for time, interspecies and intraspecies extrapolation for deriving occupational exposure limits. J Appl Toxicol. 2022;42(5):898–912.
Dorne JL, Walton K, Renwick AG. Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review. Food Chem Toxicol. 2005;43(2):203–16.
Rusyn I, Chiu WA, Wright FA. Model systems and organisms for addressing inter- and intra-species variability in risk assessment. Regul Toxicol Pharmacol. 2022;132: 105197.
Bowers EC, Martin EM, Jarabek AM, Morgan DS, Smith HJ, Dailey LA, et al. Ozone responsive gene expression as a model for describing repeat exposure response trajectories and interindividual toxicodynamic variability in vitro. Toxicol Sci. 2021;185(1):38–49.
Abdo N, Wetmore BA, Chappell GA, Shea D, Wright FA, Rusyn I. In vitro screening for population variability in toxicity of pesticide-containing mixtures. Environ Int. 2015;85:147–55.
Burnett SD, Blanchette AD, Grimm FA, House JS, Reif DM, Wright FA, et al. Population-based toxicity screening in human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019;381: 114711.
Modafferi S, Zhong X, Kleensang A, Murata Y, Fagiani F, Pamies D, et al. Gene-environment interactions in developmental neurotoxicity: a case study of synergy between chlorpyrifos and chd8 knockout in human brainspheres. Environ Health Perspect. 2021;129(7):77001.
Kosnik MB, Enroth S, Karlsson O. Distinct genetic regions are associated with differential population susceptibility to chemical exposures. Environ Int. 2021;152: 106488.
Thunga P, Truong L, Rericha Y, Du J, Morshead M, Tanguay RL, et al. Utilizing a population-genetic framework to test for gene-environment interactions between zebrafish behavior and chemical exposure. Toxics. 2022;10(12):769.
Widmayer SJ, Crombie TA, Nyaanga JN, Evans KS, Andersen ECC. elegans toxicant responses vary among genetically diverse individuals. Toxicology. 2022;479: 153292.
Saha S, Spinelli L, Castro Mondragon JA, Kervadec A, Lynott M, Kremmer L, et al. Genetic architecture of natural variation of cardiac performance from flies to humans. Elife. 2022;11:e82459.
Sefiani A, Rusyn I, Geoffroy CG. Novel adult cortical neuron processing and screening method illustrates sex- and age-dependent effects of pharmaceutical compounds. Sci Rep. 2022;12(1):13125.
Fogli Iseppe A, Ni H, Zhu S, Zhang X, Coppini R, Yang PC, et al. Sex-specific classification of drug-induced torsade de pointes susceptibility using cardiac simulations and machine learning. Clin Pharmacol Ther. 2021;110(2):380–91.
Ke T, Santamaria A, Barbosa F Jr, Rocha JBT, Skalny AV, Tinkov AA, et al. Developmental methylmercury exposure induced and age-dependent glutamatergic neurotoxicity in Caenorhabditis elegans. Neurochem Res. 2023;48(3):920–8.
Ali Nasser R, Harel Y, Stern S. Early-life experience reorganizes neuromodulatory regulation of stage-specific behavioral responses and individuality dimensions during development. Elife. 2023;12:e84312.
Babich R, Ulrich JC, Ekanayake E, Massarsky A, De Silva P, Manage PM, et al. Kidney developmental effects of metal-herbicide mixtures: implications for chronic kidney disease of unknown etiology. Environ Int. 2020;144: 106019.
Blumenrath SH, Lee BY, Low L, Prithviraj R, Tagle D. Tackling rare diseases: clinical trials on chips. Exp Biol Med (Maywood). 2020;245(13):1155–62.
Jang S, Ford LC, Rusyn I, Chiu WA. Cumulative risk meets inter-individual variability: probabilistic concentration addition of complex mixture exposures in a population-based human in vitro model. Toxics. 2022;10(10):549.
Ford LC, Jang S, Chen Z, Zhou YH, Gallins PJ, Wright FA, et al. A population-based human in vitro approach to quantify inter-individual variability in responses to chemical mixtures. Toxics. 2022;10(8):441.
Babich R, Craig E, Muscat A, Disney J, Farrell A, Silka L, et al. Defining drinking water metal contaminant mixture risk by coupling zebrafish behavioral analysis with citizen science. Sci Rep. 2021;11(1):17303.
Chen Q, Chou WC, Lin Z. Integration of toxicogenomics and physiologically based pharmacokinetic modeling in human health risk assessment of perfluorooctane sulfonate. Environ Sci Technol. 2022;56(6):3623–33.
Author information
Authors and Affiliations
Contributions
All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The author Vasilis Vasiliou is Editor-in-Chief of this journal, Human Genomics.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
To, K.T., Kleinstreuer, N., Vasiliou, V. et al. New approach methodologies to address population variability and susceptibility. Hum Genomics 17, 56 (2023). https://0-doi-org.brum.beds.ac.uk/10.1186/s40246-023-00502-7
Received:
Accepted:
Published:
DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s40246-023-00502-7