MODIFYING THE EXPOSOME – INTERVENTIONS/SOLUTIONS
Non-Pharmacological Health Intervention Portfolio (2016–2026)
Over the past decade (2016–2026), the CLOTHO research group has led and contributed to a diverse portfolio of non-pharmacological intervention studies grounded in the human exposome paradigm. These interventions address environmental, dietary, behavioral, and urban determinants of health, with a focus on mechanistic understanding, biomonitoring and translational public health impact.
These interventions are classified into the following main groups:
1. School System Interventions
2. Chrono-Interventions Exploiting the Circadian Clock System
3. Dietary Interventions
4. Climate and Urban Health Interventions
5. Precision Nutrition Interventions
1. Chrono-Interventions Exploiting the Circadian Clock System
1.1. Reducing body burden of food contaminants by choosing the time of food consumption (fruits and vegetables) in the 24-h day period (CIRCA-CHEM)
This randomized crossover trial evaluated the impact of time-restricted eating (TRE) on internal exposure to foodborne contaminants. Healthy adults consumed fruits and vegetables either during the light or dark phase of the 24-h period, over 14 days.
Key findings:
– Significant time-dependent variation in 125 biomarkers of exposure.
– Evidence of chrono-modulated metabolism for pesticides, VOCs, phytoestrogens, parabens, and flame retardants.
– Associations between selected contaminants (e.g., pesticides, VOCs) and
lipid oxidative stress.
These findings support the concept of chronotoxicity windows and highlight the importance of temporal exposome profiling in precision prevention.
References:
Kunde H, Ioannou EI, Chovatiya J, Jagani R, Charisiadis P, Arora M, Andra SS, Makris KC. An exposomics analysis of 125 biomarkers of exposure to food contaminants and biomarkers of oxidative stress: a randomized cross-over chrononutrition trial of healthy adults. Environ Int. 2025;202:109682. doi:10.1016/j.envint.2025.109682
Ioannou E, Oikonomou S, Efthymiou N, Constantinou A, Delplancke T, Charisiadis P, Makris KC. A time differentiated dietary intervention effect on the biomarkers of exposure to pyrethroids and neonicotinoids pesticides. iScience. 2022 Dec 22;26(2):105847. doi: 10.1016/j.isci.2022.105847.
1.2. Reducing the body burden of chemicals during disinfection cleaning activities by choosing the time of cleaning in the 24-h day period.
Three time-series panel intervention trials demonstrated that the timing of chlorine-based cleaning activities significantly influences internal exposure to disinfection by-products (e.g., trihalomethanes, THMs).
Key findings:
– Higher urinary THM levels observed following afternoon/evening exposures compared to morning.
– Findings are consistent with circadian variation in CYP2E1 activity.
Implication: Incorporation of time-resolved biomarker of exposure to chemicals data is critical for better understanding the temporal disease process dynamics in population studies.
References:
Gängler S, Charisiadis P, Seth R, Chatterjee S, Makris KC. Time of the day dictates the
variability of biomarkers of exposure to disinfection byproducts. Environ Int.
2018;112:33–40. doi:10.1016/j.envint.2017.12.013
2. Dietary Interventions
2.1 Organic Diet Intervention in Children Protects DNA and Lipids (ORGANIKO LIFE+)
A randomized crossover intervention assessed the impact of an organic diet on pesticide exposure and health biomarkers in children.
Key findings:
– Significant reductions in pyrethroid and neonicotinoid exposure.
– Decrease in oxidative stress and genotoxicity biomarkers (e.g., 8-OHdG, 8-iso-PGF2a, MDA).
– Evidence of reduced BMI z-scores, with noted confounding factors (e.g., caloric intake).
– Reduction in lead (Pb) exposure, but not cadmium (Cd).
– Suggestive anti-inflammatory effects (by monitoring c-reactive protein, CRP levels).
– Metabolomics analyses revealed mechanistic shifts in metabolic pathways.
This intervention study in primary school children provides evidence linking dietary exposure reduction to measurable biological effects on improving DNA and lipids protection, supporting exposome-informed dietary guidelines.
References:
Abimbola SO, Konstantinou C, Xeni C, Charisiadis P, Makris KC. An anti-inflammatory response of an organic food intervention by reducing pesticide exposures in children of Cyprus: a cluster-randomized crossover trial. Environ Res. 2024;252(Pt 1):118710. doi:10.1016/j.envres.2024.118710.
Agboola SA, Konstantinou C, Charisiadis P, Delplancke T, Efthymiou N, Makris KC. The
effect of an organic food intervention treatment on biomarkers of exposure to lead and
cadmium in primary school children of Cyprus: a cluster-randomized crossover trial.
Environ Res. 2023;216(Pt 3):114675.
Konstantinou C, Gaengler S, Oikonomou S, Delplancke T, Charisiadis P, Makris KC. Use of metabolomics in refining the effect of an organic food intervention on biomarkers of exposure to pesticides and biomarkers of oxidative damage in primary school children in Cyprus: a cluster-randomized cross-over trial. Environ Int. 2022;158:107008. doi:10.1016/j.envint.2021.107008
Makris KC, Konstantinou C, Andrianou XD, Charisiadis P, Kyriacou A, et al. (2019) A cluster-randomized crossover trial of organic diet impact on biomarkers of exposure to pesticides and biomarkers of oxidative stress/inflammation in primary school children. PLOS ONE 14(9):e0219420. doi:10.1371/journal.pone.0219420
2.2 Food Packaging and Plasticizer Exposure (BIOFOODPACK)
This intervention examined whether substituting conventional food packaging with bio-based food packaging materials reduces plasticizer exposure.
Key findings:
– No significant reduction in urinary bisphenols (BPA, BPF) over a short- term (5-day) intervention.
Implication: Highlights the complexity of exposure sources and the need for longer-term and covering more components of the exposome in such interventions.
2.3 Reforming the European Health Claims Framework
Emerging evidence supports a shift toward holistic evaluation of foods, integrating:
– Nutrient–contaminant interactions
– Mixture toxicity
– Cumulative risk-benefit assessment
This work advocates for updating regulatory frameworks to reflect exposome- based evidence.
Reference:
Makris KC, Chourdakis M. The need for an alternative health claim process for foods based on both nutrient and contaminant profiles. Curr Dev Nutr. 2024;8(6):103764. doi:10.1016/j.cdnut.2024.103764.
3. Climate and Urban Health Interventions
3.1 Climate Relocation and Metabolic Health
A short-term relocation intervention from urban to nearby (1-h driving) cooler mountainous environments demonstrated:
– Significant reductions in leptin levels
– Associations between ambient/skin temperature and metabolic biomarkers
Implication: Climate-sensitive interventions may mitigate metabolic risks in urban populations.
References:
Makris KC, Konstantinou C, Perikkou A, Zdravic AB, Christophi CA. Contrasting short- term temperature effects on the profiling of metabolic and stress hormones in non-obese healthy adults: a randomized cross-over trial. Environ Res. 2020;182:109065. doi:10.1016/j.envres.2019.109065.
Makris KC, Charisiadis P, Delplancke T, Efthymiou N, Giuliani A. Diurnal Nonlinear Recurrence Metrics of Skin Temperature and Their Association with Metabolic Hormones in Contrasting Climate Settings: A Randomized Cross-Over Trial. International Journal of Environmental Research and Public Health. 2022;
19(22):15195. doi:10.3390/ijerph192215195
3.2 Urban Exposome and Infectious Disease Control
Conceptual and methodological work highlights the integration of:
– Built environment
– Socioeconomic factors
– Individual susceptibility
into exposome-based intervention frameworks for infectious disease modeling and response.
References:
Andrianou XD, Pronk A, Galea KS, Stierum R, Loh M, Riccardo F, Pezzotti P, Makris KC. Exposome-based public health interventions for infectious diseases in urban settings. Environ Int. 2021;146:106246. doi:10.1016/j.envint.2020.106246.
3.3 HEAL Micro-Mobility Intervention
An ongoing intervention in Limassol city integrates:
– Behavioral science (COM-B model)
– Exposome profiling
– Urban infrastructure (cycling networks)
Limassol is selected by the European Commission as one of 100 EU cities that are part of the EU Mission for 100 climate-neutral and smart cities by 2030. Our intervention will be carried out through a network of local public and private- commercial partners.
References:
The HEAL project is funded to run in the Limassol Municipality.
4. Precision Nutrition Interventions
4.1 Weight Loss and Endocrine Disruptors (LOWER Study)
The LOWER intervention on obese individuals subject to a dietary treatment showed:
– Reduction in phthalate exposure following weight loss
– Higher baseline EDC exposure associated with reduced weight loss
Implication: Supports the role of environmental chemicals in metabolic regulation and obesity.
References:
van der Meer TP, Thio CHL, van Faassen M, van Beek AP, Snieder H, van Berkum FNR, Kema IP, Makris KC, Wolffenbuttel BHR, van Vliet-Ostaptchouk JV. Endocrine disrupting chemicals during diet-induced weight loss – a post-hoc analysis of the LOWER study. Environ Res. 2021;192:110262. doi:10.1016/j.envres.2020.110262.
4.2 Time-Restricted Eating (TRE) in MASLD Patients
An ongoing randomized controlled trial evaluates:
– TRE combined with controlled timing of fruit and vegetable intake
– Effects on body weight and fat, liver health, pesticide metabolism, and toxicity
This parallel-arm, randomized controlled trial (RCT) will study the effects of an ad libitum TRE dietary pattern (8 hours eating, 16 hours fasting) with an additional restriction regarding the fruit and vegetable consumption on health parameters, pesticide metabolism and concomitant toxicity in MASLD patients compared with the Standard of Care (SoC) approach, that will serve as the control group. Participants will be asked to consume all meals/snacks during the 8 hours daily period that they will select for themselves without any further dietary advice regarding caloric or other macronutrient intake.
References:
Makris KC, Ioannou EI. Chrononutrition/chronotoxicity intervention in people with metabolic-associated steatotic liver disease (MASLD) (CHRONOMASLD). ClinicalTrials.gov [Internet]. 2024 Nov 26. Available from: https://clinicaltrials.gov/study/NCT06705868
5. School System Interventions
5.1 Micronutrient Awareness (Iodine Intervention)
A multi-country school-based intervention across six countries (Bangladesh, Pakistan, Slovenia, Cyprus, Germany and the UK) demonstrated improved awareness and behavioral outcomes related to iodine intake across diverse populations.
References:
Christensen BJ, Cecon-Stabel N, Sleire SN, et al. Enhancing iodine health awareness among adolescents: a study protocol for a multi-country intervention study in educational settings across the UK, Slovenia, Cyprus, Bangladesh, Germany and Pakistan. BMC Public Health. 2026;26:27121. doi:10.1186/s12889-026-27121-w.
Völzke H, Henck V, Ittermann T, Pendt P, Khan Khattak MN, Makris KC, JV, Bath SC, Henderson L, Bokor A, Dahl L, Sleire SN, Heering T, De Bock F. EUthyroid2: the next step towards the elimination of iodine deficiency and preventable iodine-related disorders in Europe and beyond. Eur Thyroid J. 2026;15(1):ETJ250335. doi:10.1530/ETJ-25-0335.
5.2 Health-Promoting Schools and the Exposome
This work proposes integrating exposome methodologies into the WHO/UNICEF Health Promoting Schools framework to:
– Holistically address multiple exposures and outcomes
– Enhance student health and wellbeing
References:
Makris KC, Philippou C, Vasileiou C, et al. Reforming schools into health promoting schools: perspective based on expert consensus from a European multistakeholder consultation. Eur J Pediatr. 2026;185:126. doi:10.1007/s00431-025-06736-y.
5.3 Cost-Effectiveness of Organic School Meals
Economic analyses indicate:
– Potential cost-effectiveness in preventing obesity and type 2 diabetes
– Positive return on investment under multiple scenarios
Two separate analyses were performed to determine the cost-effectiveness of an organic treatment intervention (ORGANIKO LIFE+) in school children of Cyprus against the no action scenario. The first analysis was performed to determine the cost of preventing one case of adult obesity and compare that to the lifetime societal and public health cost of obesity per person. The second analysis determined the cost to avert the loss of one type 2 diabetes-associated DALY using this intervention. Obesity outcome results: if organic diet treatment was administered for the 12 years of school, the cost would be €23,112/child over the
12-year period. This would eliminate the 9.3:1 return on investment value (ROI) based on the calculated 4.38 children fed to prevent one case of adult obesity as the cost of feeding 4.38 children for 12 years equals €101,230 (€78,288 saved for one case of obesity prevented). However, if we use the mean total lifetime cost of a child or adolescent with obesity of €149,206, the ROI is much lower (1.47:1) but still remains. Type II diabetes outcome: the organic diet was proven to be a highly cost-effective intervention based on the criteria set by the WHO- CHANGE program.
Reference:
McKinney A, Makris KC. Ecosystem function restoration study: cost-effectiveness analysis of an organic food intervention in primary school children in Cyprus. 2019.
Available from: http://organikolife.com/wp-content/uploads/2019/10/Ecosystem-function-
restoration-study.pdf