Effect on Markers of Cardiovascular, Reproductive and Cancer Risk From Firefighting Training

Oxidative Stress Clinical Trial

— BIOBRAND3  

Official title:

Effect on Markers of Cardiovascular, Reproductive and Cancer Risk From Firefighting Activities - a Study Under Different Training Methods

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05753254
• Other study ID #: 72403
• Secondary ID: FFIKA WP4.3AMFF
• Status: Recruiting
• Phase: N/A
• Start date: March 10, 2023
• Est. completion date: June 2024

Study information

• Verified date: August 2023
• Source: National Research Centre for the Working Environment, Denmark
• Contact: Maria Helena G Andersen, PhD
• Phone: +45 2020 9222
• Email: mga[@]nfa.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Epidemiological studies based on Danish registries have observed that Danish male firefighters have more cardiovascular disease, infertility diagnose and a trend to increased risk of cancer than other Danish employed males. Firefighting activities include a combination of stressors such as strenuous work under heat, smoke and soot known to be able to affect cardiovascular and reproductive health, with smoke and soot also being known to increase the risk of cancer. The training facilities of real-fire extinguishing exercises in Denmark operate using wood or natural gas fire, which will have differential gradients of smoke, soot and possibly heat. The investigators will use different training conditions to create gradients of the different stressors and investigate health effects thereof. With this approach, the investigators expect to be able to evaluate the individual contribution of the different stressors in markers of cardiovascular, cancer and reproductive health risk. The project will include approx. 35 young conscript participants on a firefighting course, followed in four sessions, three firefighting training sessions under different fire conditions (no fire, wood fire and gas fire) and one control scenario.

Description:

The study methodology is based on a crossover design on firefighting training under different conditions, with characterization of exposure and assessment of cardiovascular, cancer and reproductive effect biomarkers. The study will be performed in cooperation with the Danish Emergency Management Agency. The study will have one baseline session, while conscripts are in a classroom, and three sessions of firefighting-related exercises under different fire conditions, used currently in firefighting training programs in Denmark. The three firefighting training sessions will be controlled for equivalent work exercise using full protective gear and under different ambient conditions of firefighting training: - Firefighting equivalent work (no fire), with exercises performed in a clean environment, without fire (no ambient temperature, soot or smoke). This type of exercise precedes or complements the training under real fire conditions. - Firefighting under wood fire (wood fire), with exposure to ambient heat, smoke and soot. This is the most common training scenario used by Danish Emergency Management Agency training centres. - Firefighting under gas fire (gas fire), with exposure to ambient heat, and expectably less smoke and soot than with wood fire. These conditions are used in some Danish training centres, with logistical advantages (ease of turning or putting out the fire and managing the fire fuel) and unknown effect relating to exposure prevention (smoke and soot). The order of the firefighting sessions will be as randomized as possible, and according to a selection of three sequence order options (no-wood-gas; wood-gas-no and gas-wood-no). Each campaign (corresponding to each rescue course) would desirably have one of these session sequences. It is not possible to blind the participants to the different scenarios, neither the field staff, but all the samples will be blinded for the subsequent laboratory analysis. The training sessions will have 1-3 weeks in between (accordingly with programmatic educational course schemes).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 35
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

The participants will be volunteers (both males and females) recruited among conscripts in training in a desirable involved group up to 35 individuals.

Inclusion Criteria:

• legally competent,
• conscript subjects following a Rescue Specialist Educational course

Exclusion Criteria:

• current smoking status,
• pregnancy,
• on prescribed medication,
• body mass index (BMI) bellow 19 or over 30,
• alcohol or drug abuse.

Related Conditions & MeSH terms

• Heart Rate Variability
• Heat Stress
• Hyperemia
• Oxidative Stress

Intervention

Other:
• Firefighting training exercises with no fire
The participants will be performing firefighting equivalent work in a clean environment, without fire (no ambient temperature, soot or smoke).
• Firefighting training exercises under wood fire
The participants will be in teams performing pre-defined tasks (knocking down the fire, moving heavy objects, and searching and rescuing metal stand in models), under wood fire conditions.
• Firefighting training exercises under gas fire
The participants will be in teams performing pre-defined tasks (knocking down the fire, moving heavy objects, and searching and rescuing metal stand in models), under gas fire conditions.

Locations

Country	Name	City	State
Denmark	The National Research Centre for the Working Environment	Copenhagen
Denmark	Maria Helena Guerra Andersen	København Ø

Sponsors (4)

Lead Sponsor	Collaborator
National Research Centre for the Working Environment, Denmark	Rigshospitalet, Denmark, University Hospital Bispebjerg and Frederiksberg, University of Copenhagen

Country where clinical trial is conducted

Denmark, 

References & Publications (18)

Alhamdow A, Lindh C, Albin M, Gustavsson P, Tinnerberg H, Broberg K. Early markers of cardiovascular disease are associated with occupational exposure to polycyclic aromatic hydrocarbons. Sci Rep. 2017 Aug 25;7(1):9426. doi: 10.1038/s41598-017-09956-x. — View Citation

Andersen MHG, Saber AT, Clausen PA, Pedersen JE, Lohr M, Kermanizadeh A, Loft S, Ebbehoj N, Hansen AM, Pedersen PB, Koponen IK, Norskov EC, Moller P, Vogel U. Association between polycyclic aromatic hydrocarbon exposure and peripheral blood mononuclear cell DNA damage in human volunteers during fire extinction exercises. Mutagenesis. 2018 Feb 24;33(1):105-115. doi: 10.1093/mutage/gex021. — View Citation

Andersen MHG, Saber AT, Frederiksen M, Clausen PA, Sejbaek CS, Hemmingsen CH, Ebbehoj NE, Catalan J, Aimonen K, Koivisto J, Loft S, Moller P, Vogel U. Occupational exposure and markers of genetic damage, systemic inflammation and lung function: a Danish cross-sectional study among air force personnel. Sci Rep. 2021 Sep 9;11(1):17998. doi: 10.1038/s41598-021-97382-5. — View Citation

Andersen MHG, Saber AT, Pedersen JE, Pedersen PB, Clausen PA, Lohr M, Kermanizadeh A, Loft S, Ebbehoj NE, Hansen AM, Kalevi Koponen I, Norskov EC, Vogel U, Moller P. Assessment of polycyclic aromatic hydrocarbon exposure, lung function, systemic inflammation, and genotoxicity in peripheral blood mononuclear cells from firefighters before and after a work shift. Environ Mol Mutagen. 2018 Jul;59(6):539-548. doi: 10.1002/em.22193. Epub 2018 May 15. — View Citation

Andersen MHG, Saber AT, Pedersen PB, Loft S, Hansen AM, Koponen IK, Pedersen JE, Ebbehoj N, Norskov EC, Clausen PA, Garde AH, Vogel U, Moller P. Cardiovascular health effects following exposure of human volunteers during fire extinction exercises. Environ Health. 2017 Sep 6;16(1):96. doi: 10.1186/s12940-017-0303-8. — View Citation

Beitel SC, Flahr LM, Hoppe-Jones C, Burgess JL, Littau SR, Gulotta J, Moore P, Wallentine D, Snyder SA. Assessment of the toxicity of firefighter exposures using the PAH CALUX bioassay. Environ Int. 2020 Feb;135:105207. doi: 10.1016/j.envint.2019.105207. Epub 2019 Dec 4. — View Citation

Henriksen T, Weimann A, Larsen EL, Poulsen HE. Quantification of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydro-guanosine concentrations in urine and plasma for estimating 24-h urinary output. Free Radic Biol Med. 2021 Aug 20;172:350-357. doi: 10.1016/j.freeradbiomed.2021.06.014. Epub 2021 Jun 22. — View Citation

Hjollund NH, Storgaard L, Ernst E, Bonde JP, Olsen J. Impact of diurnal scrotal temperature on semen quality. Reprod Toxicol. 2002 May-Jun;16(3):215-21. doi: 10.1016/s0890-6238(02)00025-4. — View Citation

Jung A, Schuppe HC. Influence of genital heat stress on semen quality in humans. Andrologia. 2007 Dec;39(6):203-15. doi: 10.1111/j.1439-0272.2007.00794.x. — View Citation

Kales SN, Soteriades ES, Christophi CA, Christiani DC. Emergency duties and deaths from heart disease among firefighters in the United States. N Engl J Med. 2007 Mar 22;356(12):1207-15. doi: 10.1056/NEJMoa060357. — View Citation

Keir JLA, Akhtar US, Matschke DMJ, Kirkham TL, Chan HM, Ayotte P, White PA, Blais JM. Elevated Exposures to Polycyclic Aromatic Hydrocarbons and Other Organic Mutagens in Ottawa Firefighters Participating in Emergency, On-Shift Fire Suppression. Environ Sci Technol. 2017 Nov 7;51(21):12745-12755. doi: 10.1021/acs.est.7b02850. Epub 2017 Oct 18. — View Citation

Kirstine Ugelvig Petersen K, Pedersen JE, Bonde JP, Ebbehoej NE, Hansen J. Long-term follow-up for cancer incidence in a cohort of Danish firefighters. Occup Environ Med. 2018 Apr;75(4):263-269. doi: 10.1136/oemed-2017-104660. Epub 2017 Oct 21. — View Citation

Kumar K, Trzybulska D, Tsatsanis C, Giwercman A, Almstrup K. Identification of circulating small non-coding RNAs in relation to male subfertility and reproductive hormones. Mol Cell Endocrinol. 2019 Jul 15;492:110443. doi: 10.1016/j.mce.2019.05.002. Epub 2019 May 8. — View Citation

Morup N, Rajpert-De Meyts E, Juul A, Daugaard G, Almstrup K. Evaluation of Circulating miRNA Biomarkers of Testicular Germ Cell Tumors during Therapy and Follow-up-A Copenhagen Experience. Cancers (Basel). 2020 Mar 23;12(3):759. doi: 10.3390/cancers12030759. — View Citation

Pedersen JE, Ugelvig Petersen K, Ebbehoj NE, Bonde JP, Hansen J. Incidence of cardiovascular disease in a historical cohort of Danish firefighters. Occup Environ Med. 2018 May;75(5):337-343. doi: 10.1136/oemed-2017-104734. Epub 2018 Jan 26. — View Citation

Petersen KU, Hansen J, Ebbehoej NE, Bonde JP. Infertility in a Cohort of Male Danish Firefighters: A Register-Based Study. Am J Epidemiol. 2019 Feb 1;188(2):339-346. doi: 10.1093/aje/kwy235. — View Citation

Pieterse B, Felzel E, Winter R, van der Burg B, Brouwer A. PAH-CALUX, an optimized bioassay for AhR-mediated hazard identification of polycyclic aromatic hydrocarbons (PAHs) as individual compounds and in complex mixtures. Environ Sci Technol. 2013 Oct 15;47(20):11651-9. doi: 10.1021/es403810w. Epub 2013 Sep 25. — View Citation

Schwartz C, Bolling AK, Carlsten C. Controlled human exposures to wood smoke: a synthesis of the evidence. Part Fibre Toxicol. 2020 Oct 2;17(1):49. doi: 10.1186/s12989-020-00375-x. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in reactive hyperemia index - afternoon	Reactive hyperemia index (RHI) measured with the device EndoPAT 2000. A reactive hyperemia is induced by a blood cuff on the upper arm and the peripheral vasodilation response is assessed in the small digital vessels of a fingertip with a portable device connected to a computer, with RHI determined by an algorithm from the device, with lower index values corresponding to a worsen situation.	Baseline afternoon measurement, afternoon measurement immediately after firefighting without fire, afternoon measurement immediately after firefighting under wood fire and afternoon measurements immediately after firefighting under gas fire
Primary	Change in reactive hyperemia index - morning	Reactive hyperemia index (RHI) measured with the device EndoPAT 2000. A reactive hyperemia is induced by a blood cuff on the upper arm and the peripheral vasodilation response is assessed in the small digital vessels of a fingertip with a portable device connected to a computer, with RHI determined by an algorithm from the device, with lower index values corresponding to a worsen situation.	Baseline morning measurement, morning measurement in subsequent day after firefighting without fire, morning measurement in subsequent day after firefighting under wood fire and morning measurement in subsequent day after firefighting under gas fire
Primary	Change in Heart Rate Variability pNN50 at rest - afternoon	Heart rate variability (HRV) measured with the device EndoPAT 2000. The HRV is calculated using the initial 5.5 complete minutes before the cuff is applied. pNN50 is the proportion of successive NN intervals differing by more than 50 milliseconds divided by the total number of N intervals (given in percentage).	Baseline afternoon measurement, afternoon measurement immediately after firefighting without fire, afternoon measurement immediately after firefighting under wood fire and afternoon measurements immediately after firefighting under gas fire
Primary	Change in Heart Rate Variability pNN50 at rest - morning	Heart rate variability (HRV) measured with the device EndoPAT 2000. The HRV is calculated using the initial 5.5 complete minutes before the cuff is applied. pNN50 is the proportion of successive NN intervals differing by more than 50 milliseconds divided by the total number of N intervals (given in percentage).	Baseline morning measurement, morning measurement in subsequent day after firefighting without fire, morning measurement in subsequent day after firefighting under wood fire and morning measurement in subsequent day after firefighting under gas fire
Primary	Change in Heart Rate Variability RMSSD at rest - afternoon	Heart rate variability (HRV) measured with the device EndoPAT 2000. The HRV is calculated using the initial 5.5 complete minutes before the cuff is applied. RMSSD is the square root of the mean squared differences of successive NN intervals (given in milliseconds)	Baseline afternoon measurement, afternoon measurement immediately after firefighting without fire, afternoon measurement immediately after firefighting under wood fire and afternoon measurements immediately after firefighting under gas fire
Primary	Change in Heart Rate Variability RMSSD at rest - morning	Heart rate variability (HRV) measured with the device EndoPAT 2000. The HRV is calculated using the initial 5.5 complete minutes before the cuff is applied. RMSSD is the square root of the mean squared differences of successive NN intervals (given in milliseconds)	Baseline morning measurement, morning measurement in subsequent day after firefighting without fire, morning measurement in subsequent day after firefighting under wood fire and morning measurement in subsequent day after firefighting under gas fire
Primary	Change in Heart Rate Variability ratio LF/HF at rest - afternoon	Heart rate variability (HRV) measured with the device EndoPAT 2000. The HRV is calculated using the initial 5.5 complete minutes before the cuff is applied. Ratio of low frequency and high frequency bands	Baseline afternoon measurement, afternoon measurement immediately after firefighting without fire, afternoon measurement immediately after firefighting under wood fire and afternoon measurements immediately after firefighting under gas fire
Primary	Change in Heart Rate Variability ratio LF/HF at rest - morning	Heart rate variability (HRV) measured with the device EndoPAT 2000. The HRV is calculated using the initial 5.5 complete minutes before the cuff is applied. Ratio of low frequency and high frequency bands	Baseline morning measurement, morning measurement in subsequent day after firefighting without fire, morning measurement in subsequent day after firefighting under wood fire and morning measurement in subsequent day after firefighting under gas fire
Primary	Changes in levels of 8-oxodG excretion in first morning urine	Oxidized nucleobase 8-oxodG will be measured in urine samples by High-performance liquid chromatography (HPLC) as marker of oxidative stress, together with creatinine, for adjusting for urine concentration. Data will be reported as nanomol 8-oxodG per millimol creatinine.	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Primary	Changes in levels of DNA strand breaks in peripheral blood mononuclear cells	DNA strand breaks will be measured by comet assay, and reported as number of lesions per 10^6 base pairs, transformed from percentage of DNA in tail using the calibration curve from the well-establish relationship between ionizing radiation dose and yield of strand breaks in DNA.	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Primary	Changes in core temperature	Core body temperature will be assessed by an ingestible pill thermometer with data recorded and reported as time series during the period in transit.	Baseline day, during the day of firefighting without fire, during the day of firefighting under wood fire and during the day of firefighting under gas fire.
Primary	Changes in scrotal temperature	Scrotal temperature will be assessed by skin sensor placed in the scrotum of male participants and reported as scrotal skin temperature time series.	Baseline day, during the day of firefighting without fire, during the day of firefighting under wood fire and during the day of firefighting under gas fire.
Primary	Changes in scrotal thermoregulation	Core body temperature will be assessed by an ingestible pill thermometer and scrotal temperature will be assessed by skin sensor placed in the scrotum of male participants, to assess the thermoregulation of the scrotum during firefighting exercises. Time series of core body temperature and scrotal skin temperature will be analysed for eventual thermoregulation disruption.	Baseline day, during the day of firefighting without fire, during the day of firefighting under wood fire and during the day of firefighting under gas fire.
Primary	Changes in levels of circulating micro RNA	Circulating micro RNA candidates will be measured by RNA extraction from serum samples, reverse transcribed into complementary DNA (cDNA) and analysed with quantitative polymerase chain reaction (qPCR).	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Primary	Changes in urinary potency of AhR activation	The aryl hydrocarbon receptor (AhR) activation will be assessed in vitro using urine samples on the PAH CALUX (Chemical Activated LUciferase gene eXpression bioassay) reporter assay. The smoke and soot exposures are complex mixtures of compounds with potential toxic effect. Routine measurements of PAHs are usually quantified for a target list of 16 common soot elements and even less chemical species for urinary metabolites, but many other compounds are present in both soot and metabolites mixtures. The toxicity of PAHs is primarily caused through the binding to AhR, and induction of AhR related genes and subsequent toxic pathways. The outcome will be measured in the form of benzo[a]pyrene equivalence.	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Primary	Changes in potency of AhR activation from skin deposits	The aryl hydrocarbon receptor (AhR) activation will be assessed in vitro using wipe samples on the PAH CALUX (Chemical Activated LUciferase gene eXpression bioassay) reporter assay. The smoke and soot exposures are complex mixtures of compounds with potential toxic effect. Routine measurements of PAHs are usually quantified for a target list of 16 common soot elements, but many other compounds are present in soot mixtures. The toxicity of PAHs is primarily caused through the binding to AhR, and induction of AhR related genes and subsequent toxic pathways. The outcome will be measured in the form of benzo[a]pyrene equivalence.	Baseline, before firefighting without fire, immediately after firefighting without fire, before firefighting under wood fire, immediately after firefighting under wood fire, before firefighting under gas fire, immediately after firefighting under gas
Secondary	Changes in levels of follicle-stimulating hormone in serum	Follicle-stimulating hormone (FSH) will be measured in serum samples	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Secondary	Changes in levels of serum inhibin B	Inhibin B hormone will be measured in serum samples	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Secondary	Changes in urinary levels of PAH metabolites excretion	The internal dose of polycyclic aromatic hydrocarbons (PAHs), that would have the contribution from different exposure routes, will be assessed in first morning urine samples and measured for 7 isomer hydroxyl-PAH compounds and 5 nitro-PAH compounds, measured by high-performance liquid chromatography (HPLC)	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Secondary	Changes in levels of PAHs in skin wipes from the neck	Skin wipes will be sampled to determine the PAH composition of deposited soot on the neck area. The wipes will be analysed for the 16 US Environmental Protection Agency priority list of PAH compounds by HPLC.	Baseline, before firefighting without fire, immediately after firefighting without fire, before firefighting under wood fire, immediately after firefighting under wood fire, before firefighting under gas fire, immediately after firefighting under gas
Secondary	Changes in FEV1 spirometric measurements	Lung function will be measured by spirometry using the Spirometer device EasyOne Air. Forced Expiratory Volume at 1 second (FEV1).	Baseline, immediately after firefighting without fire, immediately after firefighting under wood fire and immediately after firefighting under gas fire
Secondary	Changes in FVC spirometric measurements	Lung function will be measured by spirometry using the Spirometer device EasyOne Air. Forced Vital capacity (FVC).	Baseline, immediately after firefighting without fire, immediately after firefighting under wood fire and immediately after firefighting under gas fire
Secondary	Changes in PEF spirometric measurements	Lung function will be measured by spirometry using the Spirometer device EasyOne Air. Peak Expiratory Flow (PEF).	Baseline, immediately after firefighting without fire, immediately after firefighting under wood fire and immediately after firefighting under gas fire
Secondary	Changes in FEV1/FVC ratio from spirometric measurements	Lung function will be measured by spirometry using the Spirometer device EasyOne Air. Forced Expiratory Volume at 1 second (FEV1) and Forced Vital Capacity (FVC) ratio is calculated from device output.	Baseline, immediately after firefighting without fire, immediately after firefighting under wood fire and immediately after firefighting under gas fire
Secondary	Changes in blood troponin levels	Cardiac troponin levels using ELISA immunoassays will be assessed in serum samples.	Baseline, before firefighting without fire, day after firefighting without fire, before firefighting under wood fire, day after firefighting under wood fire, before firefighting under gas fire, day after firefighting under gas fire
Secondary	Changes in work load measured by muscle activity	Muscle activity will be assessed to control for body workload through electromyography (EMG) using the portable device Nexus10. Bipolar surface EMG electrodes are applied to the skin over the muscles in 3 relevant body regions (shoulder, leg and back). The signals are collected with a data logger and reported as work load during a working day.	Baseline day, firefighting without fire day, firefighting under wood fire day and firefighting under gas fire day