Human physiology at the upper limit of extreme heat exposure

Human physiology at the upper limit of extreme heat exposure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Human physiology at the upper limit of extreme heat exposure Ollie Jay, Jem Cheng, Jake McCahon, Lee Jin, Jennifer Vanos This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9227989/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Assessments of future human survivability under extreme heat with climate change have recently been anchored to a theoretical physiological tipping point: 6 hours of exposure to a wet-bulb temperature (Twet) of 35°C1. This framework broadly treats a fixed Twet as imposing equivalent physiological strain irrespective of the temperature-humidity combinations that produce it. In contrast, human thermoregulation models predict greater physiological strain with increasing ambient temperature under constant Twet conditions2. Here we show that multi-system physiological heat strain differs profoundly in heat-acclimated humans studied under controlled climate-chamber conditions when the canonical 35°C Twet survival limit is imposed across a range of ambient temperatures (38°C with 81% relative humidity (RH), 46°C with 46%RH, 54°C with 26%RH). At 54°C, projected times to heat exhaustion and heat stroke were reduced by ~45% compared with 38°C, driven by an accelerated rise in rectal temperature and accompanied by greater cardiovascular strain and disruption of acid-base balance. These findings demonstrate that the physiological tipping point for human heat tolerance at 35°C Twet is state-dependent, and that utilising a universal Twet survival limit may substantially over-estimate survivability in hot, dry environments projected to expand most rapidly with climate change. Biological sciences/Physiology Health sciences/Risk factors Earth and environmental sciences/Climate sciences physiological tipping point wet-bulb temperature extreme heat exposure human thermoregulation climate change impact Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1.0 Introduction The year 2024 was the hottest globally in 175 years of recorded history 1 . As the climate warms, bouts of extreme heat, often compounded by humidity, will intensify and become more frequent. Extreme heat is already the deadliest weather-related hazard for humans due to the risk of heat stroke 2 . If Earth remains on its current warming trajectory, the health risk from extreme heat will increase, occasionally becoming severe enough to threaten human life across more extensive spatial and temporal scales by mid-century 3 . However, the specific ambient temperature-humidity thresholds at which human mortality becomes unavoidable (i.e., the limits of “survivability” or “habitability”) have not yet been empirically established and remain a subject of theoretical modelling 4-6 . In 2010, Sherwood and Huber proposed the 35˚C wet-bulb temperature (T wet ) limit for human survival due to heat stress 4 . This model assumes that fatal heat stroke is unavoidable – even in young, healthy, fully heat acclimatised people – after 6 hours of exposure to any ambient temperature-humidity combination yielding a T wet of 35˚C. This assumption is grounded in the notion that, under such climatic conditions, both the temperature and water vapour pressure gradients between the skin and surrounding air that are required for heat dissipation are eliminated, resulting in critical internal body heat storage 7 . Elegant in its simplicity and widely cited, this model is frequently used as a common benchmark for projecting heat stress risk under climate change 8 . However, because physiological ceilings on sweating and cardiovascular stability were excluded, concerns have emerged that human survivability at a T wet of 35˚C may be over-estimated, and that the potential heat stress impacts of present-day extremes as well as those with future climate change are consequently under-estimated. In 2023, our group proposed a physiologically constrained model incorporating key thermoregulation limits, predicting that human heat strain at a T wet of 35˚C should vary substantially depending on the temperature-humidity combination that produces it 5 . Specifically, the model indicated that the physiologically attainable T wet limit increasingly diverges from 35°C as air temperature rises, due to escalating evaporative demands that accelerate the rise in core body temperature 5 . Controlled environmental exposures of humans in climate chambers have, to date, been restricted to examining the limits of “liveability” – the environmental boundaries at which thermoregulatory equilibrium can no longer be physiologically maintained and core body temperature begins to rise, which reside around T wet of ~30-32˚C 5,9-11 . However, for human health to be threatened, human core body temperature must rise to around 39˚C (heat exhaustion) and ≥40-40.5˚C (heat stroke) 12,13 . The time required to reach these thresholds depends on the rate of core temperature rise and may take many hours. Beyond core temperature alone, the risk of heat illnesses and death is also driven by integrative physiological strain, including the increased cardiac work required to defend central blood pressure in the face of extreme heat, and disturbances in blood pH arising from heat-induced hyperventilation 14 . Here we report a first-in-human study that directly interrogates the canonical 35˚C wet-bulb temperature survival limit across a range of ambient temperatures. We show that three distinct temperature-humidity combinations, each yielding an identical wet-bulb temperature of 35˚C, impose substantially different multi-system physiological strain in young, healthy, fully heat-acclimated adults, with the magnitude of strain strongly influenced by ambient temperature. The projected exposure time to a core temperature indicative of heatstroke was ~45% shorter at the highest (54˚C) than at the lowest (38˚C) temperature tested, despite the same T wet of 35˚C. Compared to the 6-h survival time assumed by the 35˚C T wet model, the median times to heat exhaustion were 4.6 hours at 38˚C and 2.5 hours at 54˚C, while median times to heat stroke were 7.2 hours at 38˚C and 3.8 hours at 54˚C, indicating that the physiological strain, and potentially the associated health impacts of extreme heat under climate change may be presently under-estimated. 2.0 Results Different responses at a fixed T wet of 35°C We exposed twenty-six young, healthy adults (Extended Data Table 1) to three different environmental conditions at rest, each with an equivalent T wet of 35°C. Prior to testing, participants completed 7 consecutive days of climate chamber-based heat acclimation (Extended Data Table 2) to minimise seasonal variability and ensure that results would be generalisable to fully heat acclimatised populations in the future. The environmental conditions tested were: (1) 38°C and 81.1% RH (38/81), (2) 46°C and 45.8% RH (46/46), and (3) 54°C and 26.2% RH (54/26). Participants were monitored during a maximum 3-hour seated exposure in a climate chamber, and their physiological heat strain responses were compared across conditions (Figure 1) . We hypothesised that for the same T wet of 35°C, multi-system physiological heat strain would be greater at higher ambient temperatures. To answer our main research question, we calculated the slope of the final 60 minutes of core temperature data from each trial and extrapolated further to determine the amount of time it would have required participants to remain in the chamber until they reached core temperatures indicative of the onset of heat exhaustion (39.0°C) and heat stroke (40.5°C). Our linear mixed-model analysis revealed an effect of condition (P<0.001) such that projected times to reach both critical core temperatures decreased as ambient temperature increased (P<0.001 for all pairwise comparisons), with no sex-based differences observed for either a core temperature of 39.0°C (P=0.489) or 40.5°C (P=0.473) (Figure 2A and B and Extended Data Table 3) . Corresponding survival analyses with a Logrank (Mantel-Cox) test confirmed that the Kaplan-Meier curves differed across conditions (P<0.001). Median exposure time [95% CI] to heat exhaustion was 4.6 hours [4.0, 5.0] in 38/81, 3.1 hours [2.8, 3.5] in 46/46, and 2.5 hours [2.3, 2.7] in 54/26; median exposure time to heat stroke was 8.6 [7.6, 8.8] hours in 38/81, 5.5 hours [5.0, 6.4] in 46/46, and 4.6 hours [4.2, 4.9] in 54/26 (Figure 2C and D) . Exacerbated cardiovascular strain A fundamental part of the theoretical basis for the 35°C wet-bulb temperature threshold for heat stress survival is that vasodilation of the skin will increase the average skin temperature across the body surface to ~35˚C 4 . We observed end-trial mean skin temperatures exceeding 35°C for all three conditions, which were progressively higher with increasing ambient temperature (37.6 [37.4, 37.8] vs. 38.6 [38.4, 38.8] vs. 39.4 [39.2, 39.6] °C, P<0.001 for all pairwise comparisons) (Figure 3A and Extended Data Table 4A) . While these skin temperatures support higher heat dissipation potential than previously assumed, large associated increases in cardiovascular strain were observed. After adjusting for trial duration as a covariate (P=0.036), there was an effect of condition (P=0.010) for heart rate, with significantly higher end-trial increases from baseline reported in 54/26 compared to 38/81 (41 [36, 46] vs. 32 [27, 37] bpm, P=0.010) (Figure 3B and Extended Data Table 4B) . Mean skin temperature (P=0.661) and heart rate responses (P=0.907) were not different between males and females. Differences in sweat losses Whole-body sweat rates were greater at higher ambient temperatures (P<0.001) and greater in males vs. females (P=0.036) even when expressed relative to body surface area (Figure 3C and Extended Data Table 4C ). Water consumption throughout the trials was similar between conditions (Figure 3D and Extended Data Table 4D ) . A greater sweat rate was observed from 38/81 (0.24 [0.20, 0.28] L/h/m 2 ) to 46/46 (0.31 [0.27, 0.35] L/h/m 2 ) to 54/26 (0.41 [0.36, 0.45] L/h/m 2 ); P<0.001 for all pairwise comparisons. Greater sweating was also observed in males (0.36 [0.30, 0.42] L/h/m 2 ) compared to females (0.28 [0.22, 0.33] L/h/m 2 ). Disrupted acid-base balance Significant condition-by-time interactions were observed for both blood pH and pCO 2 (P=0.020 and P=0.009, respectively). After adjusting for trial duration, pH increased and pCO 2 decreased from the start to the end of the trial in all three conditions (P<0.001 for all pairwise comparisons). Importantly, end-trial pH was higher and pCO2 was lower in the hotter conditions (46/46 and 54/26) compared with 38/81, indicating more pronounced respiratory alkalosis at higher ambient temperatures. Specifically, pH reached 7.51 [7.49, 7.54] and 7.52 [7.50, 7.54] in 46/46 and 54/26, respectively, versus 7.48 [7.46, 7.51] in 38/81, while pCO 2 fell to 27.7 [25.6, 29.9] and 27.3 [25.0, 29.6] mmHg in 46/46 and 54/26, compared with 30.7 [28.5, 32.9] mmHg in 38/81 ( Figure 4 and Extended Data Table 5 ). There was no effect of sex for blood pH (start-trial: P=0.738, end-trial: P=0.633); however, baseline pCO 2 was greater in males compared to females (40.0 [38.3, 41.7] vs. 37.4 [35.8, 38.9] mmHg, P=0.027). Worsened heat distress symptoms To assess symptoms of heat distress, we administered a modified version (Supplemental Table S1) of the 68-item Environmental Symptoms Questionnaire originally developed by the US Army Research Institute of Environmental Medicine 15 . From a subset of 22 items that inform the Subjective Heat Illness index, we clustered similar items to generate 8 prompts that broadly classify common heat distress symptoms: (1) feeling lightheaded, dizzy, or faint (items 1, 4, 5), (2) headache (item 2), (3) difficulty breathing (items 8, 9), (4) muscle or stomach cramping (items 16, 17), (5) numbness and tingling (item 38), (6) tiredness and weakness (items 19, 56), (7) nausea (item 53), (8) blurry vision (item 41). As with many of the physiological variables, symptoms became more pervasive as ambient temperature increased with T wet held constant at 35˚C, with 65%, 73%, and 96% of participants reporting any symptom across the trial period in 38/81, 46/46, and 54/26, respectively (Figure 5) . Trial termination For the safety of our participants, we employed the following conservative trial termination criteria: (i) T rec ≥39.0 °C, (ii) 50>HR>80% HR max bpm, (iii) 90>SBP>200 mmHg, (iv) severe and/or escalating signs and symptoms of heat distress, (v) volitional termination for any reason. Trial completions dropped precipitously from 38/81 to 46/46 to 54/26 (Figure 6A, inset) . In a survival curve depicting the proportion of participants that remained in each trial up to a total duration of 3 hours, we observed the conditions diverge after 80 minutes (P<0.001) such that while 85% of participants were able to complete 3 hours in 38/81, only 50%, and 12% were able to do so in 46/46 and 54/26, respectively (Figure 6A) . We compared the reasons for trial termination across conditions and found that the proportion of participants terminating due to reaching the core temperature safety threshold increased progressively with increasing ambient temperature (4% vs. 27% vs. 65%) (Figure 6B) . Furthermore, terminations due to severe symptoms increased 6-fold between 38/81 and 46/46 or 54/26 (Figure 6B) . 3.0 Discussion The widely cited 35°C wet-bulb temperature (T wet ) limit for human survivability under extreme heat associated with climate change has been framed as a physiological tipping point, beyond which irreversible heat trauma (heat stroke) becomes unavoidable after six hours of exposure, irrespective of the temperature–humidity combination that produces it 4 . By replicating these modelled conditions in a controlled climate chamber, we empirically demonstrate for the first time in young, healthy, fully heat-acclimatised humans that exposure to a wet-bulb temperature of 35°C does not impose equivalent physiological strain across different environments. Moreover, our integrated assessment across multiple physiological systems indicates that identifying the physiological ‘tipping point’ requires moving beyond core temperature alone, which has largely underpinned climate-based survivability models to date. Across all outcome variables, we observed a consistent intensification of physiological strain as ambient temperature increased and relative humidity decreased, despite T wet being held constant. All conditions were physiologically uncompensable, as evidenced by a constantly rising core temperature throughout all trials. But the rate of core temperature rise increased from 0.39±0.11°C/h in 38/81 to 0.62±0.15°C/h in 46/46 and 0.75±0.24 °C/h in 54/26, leading to projected times to heat exhaustion (38/81: 4.7 h; 46/46: 3.3 h; 54/26: 2.5 h) and heat stroke (38/81: 8.8 h; 46/46: 5.8 h; 54/26: 4.8 h) decreasing by approximately 1.5- to 2-fold as conditions became hotter and drier. The difference in the core temperature response between conditions, nor the projected times to heat exhaustion or heat stroke, were altered by sex. The observed differences in core temperature across conditions reflect fundamental constraints on thermoregulatory capacity that differ between humid and dry environments, even when T wet is matched. In warm but extremely humid conditions, evaporative cooling is limited by the environment. The air is near-saturated with water vapour, so any sweat produced struggles to evaporate and instead is absorbed into clothing or drips off the skin without contributing to latent cooling 16 . While the environment is uncompensable, physiological heat strain builds gradually because the addition of heat to the body from the environment via sensible heat transfer pathways of convection and radiation is relatively modest 17 . In contrast, in extremely hot but drier conditions, evaporative cooling is limited not by the environment but by the person’s physiological capacity to produce sweat 5,18 . Since the air can accept virtually unlimited moisture, sweat produced readily evaporates. At a certain point, however, the maximum rate of sweat secretion is reached, which limits this system as a mechanism for heat loss. If air temperature is simultaneously very high relative to skin temperature, sensible heat gain by the body is substantial and physiological heat strain accelerates dramatically 19,20 . A similar phenomenon has been previously reported at lower air temperatures (45˚C) but with sensible heat gain accelerated by high air movement from the use of electric fans 21,22 . Higher core temperatures at 54˚C drove higher whole-body sweat rates, increasing the risk of dehydration relative to the same T wet at lower ambient temperatures. Measures of serum creatinine or urinalysis were not included in the present study; therefore, it cannot be determined whether the risks of acute kidney injury or renal dysfunction were also different. Of all the variables measured, a discernible sex difference was only observed for whole-body sweat rate. Even after controlling for body size, males produced more sweat than females. However, since there was no corresponding sex-specific impact on the rate of rise of core temperature, these differences – likely arising from a lower sensitivity to acetylcholine 23 , the neurotransmitter primarily responsible for the sweating mechanism – did not translate into physiologically significant differences in body heat storage. Exacerbations in cardiovascular strain with increasing ambient temperature despite a fixed T wet are also noteworthy. While the cause of death resulting from extreme heat events is multifactorial, emerging evidence suggests that cardiovascular strain is a key contributor 24,25 . High skin temperatures dilate blood vessels and direct a greater flow to the cutaneous circulation, which decreases vascular resistance and central blood volume, followed by increased heart rate and cardiac contractility to match 26 . If cadiac function is impaired because of chronic disease, the body may be unable to meet the increased myocardial oxygen demand required to sustain this volume of perfusion, leading to increased risk of cardiac ischemia 27 . In parallel, the redistribution of blood flow away from the splanchnic (abdominal) region triggers a systemic inflammatory response, creating a hypercoagulant environment that encourages the formation of thromboses 27 . Both pathways can lead to adverse cardiovascular outcomes. Beyond the classical indicators of physiological heat strain, we also observed the likely consequecnes of substantial respiratory distress, which worsened with increasing ambient temperature. Respiratory responses were not measured but hyperventilation is a well-documented physiological response to extreme heat 28 , and signs of respiratory alkalosis were evidenced by a lower end-trial pCO 2 coupled with higher end-trial pH compared to rest measured from capillary blood samples. In isolation, hypocapnic alkalosis is non-life threatening. However, its associated signs and symptoms and the potential deleterious effects on critical organ systems are worth noting. Due to a leftward shift in the oxyhemoglobin dissociation curve in these conditions, less oxygen is unbound at the tissue level potentially resulting in reduced oxygen supply; compounding this issue, hypocapnia also stimulates systemic vasoconstriction 29 . In comparatively mild cases, a person may exhibit paraesthesias, palpitations, and cramps; but if sufficiently severe, further central nervous system consequences such as seizures and convulsions may transpire due to increased axonal excitability secondary to the resultant hypocalcemia 27,30 . There is no universal safety threshold for pCO 2 and pH because individual tolerance to excursions from the normative range varies. However, several observational studies have identified the pCO 2 and pH values when specific adverse events such as dizziness, light-headedness, and paraesthesiae 31 ; syncope 32 ; seizures 33,34 , and alkalemia-associated morbidity and mortality occur 35 . As a result, clinical care guidelines 36 indicate critical limits of ≤20 mmHg for pCO 2 and ≥7.60 for pH to signal conditions approaching incompatibility with life. It is therefore of particular concern that these thresholds were approached in the current study, with more participants lying within this danger zone in the higher temperature conditions 46/46 and 54/26 compared to 38/81. Vulnerability to the effects of hypocapnic alkalosis is further heightened in those with panic disorder and cardiovascular conditions. Because there is significant overlap in the manifestation of panic attacks and hypocapnia-induced cerebral hypoxia (e.g., lightheadedness, dizziness, confusion, syncope), an alkalotic environment will almost always induce panic in those with this psychological disorder 37,38 . While we did not medically screen for psychological disorders in the current study, there were instances of self-termination due to panic and presyncopal symptoms in the absence of substantial physiological heat strain assessed through core temperature that align with this evidence. In terms of cardiovascular consequences, hypocapnia can exacerbate ischemic conditions by increasing coronary and cerebrovascular resistance and susceptibility to thrombosis (via increased platelet levels and platelet aggregation) 39,40 . The inherent ion imbalances with alkalosis – specifically the shift of potassium from the extracellular to intracellular compartment – is thought to result in a global misfiring of action potentials, which can trigger arrhythmias to occur 38,41 . Compared to the 6-hour benchmark for heat stroke set forth by Sherwood & Huber, the present data indicate that, if core temperature is treated as the only biomarker of physiological heat strain, the original model potentially under-estimated survival time in warm and very humid conditions (38/81) but likely over-estimated it in very hot but drier conditions (54/26). Skin temperatures higher than 35˚C permit better heat dissipation potential than originally modelled; however, this comes at the cost of higher levels of skin blood perfusion, which drive greater cardiovascular and respiratory strain and could escalate to cause severe and debilitating symptoms. Even with a core temperature stop-threshold of 39.0˚C in the present study, approximately one-quarter of participants stopped their trials at 46/46 and 54/26 due to heat-related symptoms. While heat stress survival models currently assume that the cause of death is a critical core temperature 4,5 , the substantial physiological strain across multiple organ systems could manifest lethal outcomes before core temperature reaches heat stroke levels. Critical core temperature thresholds for heatstroke range from 42-43˚C to 40.5˚C 12,13,42 . By choosing the more conservative threshold in the present analysis, extreme body temperatures linked with irreversible health outcomes such as coma, delirium, or serious brain damage are avoided 12,13 . Analogous to the aging-related discourse on lifespan vs. healthspan, we should aim not only to survive extreme heat on a clinical level, but to emerge with full function and health. Moreover, all human physiology studies in climate chambers on this topic to date have assessed the critical environmental limits at which thermal compensability is breached, which, by definition, are the conditions that cause any continuous rise in core temperature from a low steady-state level 9-11,43 . It is important to recognise that the present findings do not constitute evidence of population-level heat survivability outcomes. All data supporting survivability thresholds to date have been based on theoretical modeling 4,5 , and the present study provides empirical physiological data that fundamentally tests for the first time in humans the validity of the 35˚C T wet limit for heat stress survivability across a range of temperature-humidity combinations, but only in a controlled, small-scale setting. Liveability thresholds, typically defined as the limit of thermal compensability 5 are increasingly supported by physiological evidence using similar-scale studies 10,11,43 , albeit in non-heat-acclimated individuals. The present findings also support recent modeling approaches that estimate heat-related health risk after accounting for human physiology such as ASU/USYD HEAT-Lim model reported by Vanos et al 5 , which predicts different physiological heat strain between dry and humid conditions at a fixed T wet . To maximise survivability, we deliberately adopted experimental conditions that favoured physiological tolerance to extreme heat. All participants were healthy, young, and completed 7 consecutive days of exercise heat acclimation to controlled hyperthermia in a climate-controlled chamber directly prior to their experimental trials. All participants remained quietly seated throughout, wearing minimal clothing, without any additional radiative heat load (equivalent of fully shaded). Real-world heat exposure typically involves sustained metabolic activity (∼1.5-3.0 METs for daily living and 3.5-12 METs during physical activity) across dynamic indoor and outdoor (often sun-exposed) environments, indicating that the physiological strain observed here likely represents a conservative estimate of heat stress under future climate extremes. 4.0 Conclusion Our findings show that treating 35°C wet-bulb temperature as a universal survivability threshold fails to capture large, condition-dependent differences in physiological strain. They further underscore the need to approach human survivability holistically, recognising that multiple, interacting physiological processes govern tolerance to extreme heat. Declarations Data Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Code Availability No specific code was used to generate data for this paper. Acknowledgements O.J. is funded by the National Health and Medical Research Council (Investigator Grant No. 2021/GNT2009507). J.L.C. is funded by the Canadian Institutes of Health Research (Postdoctoral Fellowship Award). The authors acknowledge the technical assistance of Dr. Alexandra Green and the Sydney Informatics Hub, a Core Research Facility of the University of Sydney. Author contributions J.L.C., J.V., and O.J. conceived of the work and designed the study. J.L.C., J.A.M, and L.Y.J. conducted the experimental trials and acquired and analyzed the data. J.L.C. performed statistical analyses and generated figures. J.L.C. and O.J. interpreted the findings. J.L.C. and O.J. drafted the manuscript. All authors read, revised, and contributed significantly to the final version of the manuscript. Competing interests The authors have no competing interests to declare. References United Nations. Degrees of change: 1.5 °C — What it means and why it matters. United Nations (2025). 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J Appl Physiol (1985) 116 , 844-851 (2014). https://doi.org:10.1152/japplphysiol.00637.2013 Salvati, K. A. et al. Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats. Elife 11 (2022). https://doi.org:10.7554/eLife.72898 Wissler, E. H. & Havenith, G. A simple theoretical model of heat and moisture transport in multi-layer garments in cool ambient air. Eur J Appl Physiol 105 , 797-808 (2009). https://doi.org:10.1007/s00421-008-0966-5 Anderson, L. E. & Henrich, W. L. Alkalemia-associated morbidity and mortality in medical and surgical patients. South Med J 80 , 729-733 (1987). https://doi.org:10.1097/00007611-198706000-00016 Toffaletti, J. in Contemporary Practice in Clinical Chemistry 629-649 (Elsevier, 2020). Coplan, J. D. et al. Plasma cortisol concentrations preceding lactate-induced panic. Psychological, biochemical, and physiological correlates. Arch Gen Psychiatry 55 , 130-136 (1998). https://doi.org:10.1001/archpsyc.55.2.130 Hanashiro, P. K. Hyperventilation. Benign symptom or harbinger of catastrophe? Postgrad Med 88 , 191-193, 196 (1990). https://doi.org:10.1080/00325481.1990.11716371 Kazmaier, S. et al. Effects of respiratory alkalosis and acidosis on myocardial blood flow and metabolism in patients with coronary artery disease. Anesthesiology 89 , 831-837 (1998). https://doi.org:10.1097/00000542-199810000-00006 Staubli, M., Vogel, F., Bartsch, P., Fluckiger, G. & Ziegler, W. H. Hyperventilation-induced changes of blood cell counts depend on hypocapnia. Eur J Appl Physiol Occup Physiol 69 , 402-407 (1994). https://doi.org:10.1007/BF00865403 Lawson, N. W., Butler, G. H., 3rd & Ray, C. T. Alkalosis and cardiac arrhythmias. Anesth Analg 52 , 951-964 (1973). Bouchama, A. et al. Classic and exertional heatstroke. Nat Rev Dis Primers 8 , 8 (2022). https://doi.org:10.1038/s41572-021-00334-6 Meade, R. D. et al. Validating new limits for human thermoregulation. Proc Natl Acad Sci U S A 122 , e2421281122 (2025). https://doi.org:10.1073/pnas.2421281122 Methods Trial Design This study used a randomized crossover design in which all participants completed seven consecutive days of exercise heat acclimation, followed by a day of rest, and then three experimental trials in varying temperature-humidity combinations equivalent to a wet-bulb temperature of 35°C. These trials were spaced exactly 48 hours apart to balance adequate recovery from heat stress with the maintenance of heat acclimation status. The same participants were measured repeatedly across conditions and timepoints. The complete study timeline and experimental protocols are outlined in Figure 1 . The manuscript was reported according to the Consolidated Standards of Reporting Trials (CONSORT) extension guidelines 1 . Participants To be eligible, participants had to be between 18 and 40 years old, generally healthy, and able to read and understand English to provide informed written consent to participate in the study. Exclusion criteria included any contraindications to the use of a rectal thermistor (i.e., haemorrhoids, heterotopic ossification, rectal bleeding or bleeding disorders, fissures or active infections, anticoagulant therapy, colitis), smoking, pregnancy, a current diagnosis or history of hypertension, cardiovascular, respiratory, and/or metabolic disorders or any medication use associated with the aforementioned conditions, and the inability to participate in physical activity according to the Physical Activity Readiness Questionnaire 2 . All study visits were completed in the Thermal Ergonomics Laboratory located on level 9 of the Susan Wakil Health Building at the University of Sydney in Camperdown, NSW, Australia. This study was approved by the University of Sydney Human Research Ethics Committee (Project Number: 2023/884) and prospectively registered in the Australian New Zealand Clinical Trials Registry (ACTRN: 12624000258550) before the first participant commenced the study. Participants provided informed written consent prior to completing any portion of the study. Familiarization and V̇O 2 peak Test No more than 14 days and no less than 48 hours before the initiation of the study protocol, participants were invited to the laboratory to be familiarized with the testing environment. Basic anthropometric measures (height and body mass) were collected before participants performed a cardiorespiratory fitness test to exhaustion (V̇O 2 peak test) on a commercially-available treadmill. Our step-wise protocol involved a 3-minute warm-up at a sustainable, self-selected running pace and 1% incline followed by alternating increases in treadmill speed (by 0.8 km/h) and grade (by 2%) every minute until volitional failure 3 . Protocol parameters were chosen to be appropriately challenging to target a test duration between ~8 to 12 minutes, and alternating speed and grade increases were chosen to encourage participants to terminate the test at peak cardiorespiratory capacity rather than as a result of the inability to match pace or continue due to muscular fatigue. A test was deemed successful if a V̇O 2 plateau was observed in the final 30 seconds (i.e., 3 x 10-s bins within 0.1 L/min in value) or if two out of the following three criteria were met: (1) rating of perceived exertion ≥ 17, (2) respiratory exchange ratio ≥ 1.13, or (3) heart rate (HR) ≥ 93% age-predicted maximum (208-0.7*age)*0.93) 4 . Heat Acclimation Participants completed seven consecutive days of exercise heat acclimation on a treadmill using the controlled hyperthermia approach 5–7 . Each session was 90 minutes in total. In a climate chamber set to 40°C and 50% relative humidity (T wet = 30.9 °C), participants were instructed to walk, jog, or run at an intensity sufficient to reach a core temperature of 38.5 °C within the first 30 minutes, and then to adjust intensity thereafter to maintain their core temperature for the remainder of the session. Experimental Trials In a randomized order, participants completed three experimental trials in which they were exposed to temperature-humidity combinations equivalent to a wet-bulb temperature of 35°C for up to a maximum of 3 hours. The conditions were: (1) 38°C and 81.1% RH (38/81), (2) 46°C and 45.8% RH (46/46), and (3) 54°C and 26.2% RH (54/26). Upon arrival, participants self-inserted a rectal thermistor and provided a urine sample to assess hydration status via measurement of urine specific gravity (USG). If USG ≥ 1.02, they were given ~250 ml of water to drink. Nude body mass was measured in triplicate followed by instrumentation with a heart rate monitor and skin thermistors. Participants were asked to wear clothing as minimal as they were comfortable with, and to wear the same clothing for each trial. For males, we recommended no shirt and athletic shorts or swim briefs/trunks; for females, we recommended a sports bra and athletic shorts or swimwear. Participants completed 15 minutes of quiet, seated rest in a thermoneutral environment for baseline recordings of physiological outcomes. Afterwards, they were transferred to the climate chamber where they remained seated for the remainder of the trial. Participants were allowed to drink room temperature water ad libitum, and the volume was recorded for the calculation of whole-body sweat loss. Trials were terminated if any of the following criteria were met: (i) participants reached a core temperature of 39.0 °C, (ii) HR >80% HR max or 200 mmHg or <90 mmHg, (iv) exposure time reached 3 hours, (v) participants showed any severe and/or escalating signs or symptoms of heat distress (self-reported according to the modified Environmental Symptoms Questionnaire) that progressively worsened over 3 x 5-minute periods from when they were initially observed or recorded, (vi) volitional termination for any reason. Outcome Measures Projected time to reach critical core temperatures Core temperature (T rec ) was monitored continuously via a rectal thermometer self-inserted to a depth of 20 cm (Mon-a-therm 400TM, Covidien; PowerLab C, AD Instruments). To determine the projected times to reach a T rec of 39.0 and 40.5°C indicative of heat exhaustion and heat stroke, respectively, we calculated the rate of change in T rec in the final 60 minutes of each trial and used this information to extrapolate T rec from the final measured value to the target values. The additional time was summed with the elapsed trial time to yield the total predicted time to reach critical core temperatures. Change in heart rate Heart rate was measured continuously using a Bluetooth-enabled sensor and chest strap (Polar, AD Instruments). The change in heart rate was calculated as the difference between 5-minute averages at baseline and at the end of each trial. End-trial mean skin temperature Mean skin temperature (T skin ) was measured continuously using skin thermistors (MLT422/D, AD Instruments). Probes were attached to the chest (T chest ), shoulder (T shoulder ), thigh (T thigh ), and calf (T calf ) with a perforated plastic medical tape (Transpore, 3M), and mean T skin was calculated as a weighted average using the Ramanathan equation 8 : (1) End-trial mean T skin was given as the average of the final 5 minutes of trial data. Whole-body sweat rate To quantify whole-body sweat rate (WBSR) per unit body surface area, the following variables were measured and subsequently inputted into the equation below: (1) participant nude body mass (NBM) in triplicate on a platform scale (Model No. KW-4050-150+, @Weigh) before and after each exposure, (2) total amount of water consumed during each trial, (3) trial duration, and body surface area (BSA) calculated using the Dubois & Dubois formula 9 ( . (2) Blood pH and pCO 2 Blood pH and gases were measured at the start and end of each trial using a standard finger-prick capillary blood sample and a point-of-care analysis system (CG8+ cartridges and iSTAT-1 device, Abbott). For each measurement, a lancet (Safe-T-Pro Plus, Accu-Chek) was used to pierce the fingertip and a 200 µl lithium heparin Minivette (Minivette® POCT Lithium heparin LH, 200 µl, Sarstedt) was used to collect a blood sample. From the Minivette, 95 µl of blood was dispensed into the well of a CG8+ cartridge, which was subsequently inserted into the iSTAT-1 device for immediate analysis. Symptoms of heat distress Signs and symptoms of heat distress were monitored throughout each trial using a modified version of the 68-item Environmental Symptoms Questionnaire 10 . From the 22-item subset that comprised the Subjective Heat Illness Index 11 , we identified 8 major themes, which were used as prompts for this study (Supplemental Table S1) . Every 20 minutes, participants rated each symptom on a scale of 0 - Not at all to 5 - Extreme. The measurement frequency was increased to every 5 minutes once a rating of 2+ was reported for any symptom, and trials were terminated if participants’ ratings further increased over three successive 5-minute time points. For data analysis, symptoms of heat distress were classified as categorical and coded as either (1) Yes (value: 1, symptom reported during trial) or (2) No (value: 0, symptom not reported during trial). Trial duration Trial duration was quantified as the number of minutes of the study protocol completed, defined by the presence of T rec data. The maximum value of this outcome was 180 minutes (3 hours). Trial completion Trial completion was a categorical outcome coded as either (1) Yes (value: 1, trial duration = 180 minutes) or (2) No (value: 0, trial duration <180 minutes). Reasons for trial termination Reasons for trial termination was a categorical outcome coded as either (1) Symptoms (value: 1, severe or escalating symptoms of heat distress either self-reported or based on the modified ESQ), (2) Core temperature (value: 2, T rec ≥ 39.0 °C), or (3) Trial duration (value: 3, trial duration = 180 minutes). Participants did not terminate the trial for any other reason; therefore, no other termination criteria were coded. Sample Size Calculation Sample size was determined a priori based on an expected difference across conditions and the minimally clinically important difference between sexes in the rates of core temperature change in response to the experimental conditions. A fourth condition at 54°C and 13.1% RH (54/13) was included in the sample size calculation and trial randomization to allow for the investigation of an exploratory research question. This condition is not relevant to the current manuscript. Using a simulation-based R package 12 , we entered the following information: anticipated rates of change (°C/h) of 0.49 and 0.57 for 38/81, 0.67 and 0.75 for 46/46, and 0.86 and 0.93 for 54/26 and 54/13 in males and females, respectively; (2) a common standard deviation of 0.05°C/h based on typical measurement error; (3) α level set at 0.05; and (4) N = 12 per group. These parameters yielded >80% power to detect differences between all relevant comparisons. As there is no prior empirical work in this area, the estimates for each condition were based on pilot data collected during protocol development, and the estimates for potential sex-based differences were based on the minimum difference between males and females that we deemed meaningful (i.e., a difference in survival time of 30 minutes). We aimed to recruit 30 participants in anticipation of subject attrition, for a minimum target sample size of 24 (12 per sex). Randomisation Experimental trial conditions were administered in a randomised order, and participants completed the study in male-female pairs so that any potential order effects would be matched between sexes. The randomization sequence and order was generated by selecting for 24 sets of 4 unique numbers (range 1 to 4) from randomizer.org. Each set was assigned to a pair of participants as they were enrolled, and additional sets were available in case of dropout. Statistical Analysis Demographic and experimental data were presented as means and standard deviations or 95% confidence intervals for continuous, normally distributed data. Frequencies and percentages were used to describe categorical data. All analyses were determined a priori and documented in a Statistical Analysis Plan (Supplementary Information) . Analyses were conducted using R and RStudio (Version 2025.05.1+513, Posit Software, PBC, Boston, MA, USA). All statistical tests were two-sided with the accepted significance level set to p<0.05. Linear mixed-effects models were fitted to examine the responses of the following outcome variables: projected times to reach critical T rec (39.0 and 40.5°C), change in HR, end-trial mean T skin , WBSR relative to BSA, rate of water consumption, and blood pH, pO 2 , and pCO 2 levels. Condition (three levels: 38/81, 46/46, 54/26), sex (two levels: male and female), and trial duration (where appropriate as a covariate for time-dependent outcomes) were included as fixed effects, and Participant ID was included as a random intercept to model the within-subject dependence of the data. The compound symmetry covariance structure was selected based on an assessment of the Akaike’s and Bayesian Information Criteria (AIC/BIC) and log likelihood ratio tests to identify the best fitting model while also considering model parsimony. Models were estimated using the Restricted Maximum Likelihood estimation. Model residuals were examined for normality, homoscedasticity, and influential points. Significant main effects and interactions were probed using Tukey’s honest significant difference-adjusted post-hoc pairwise comparisons to control the family-wise error rate. These analyses were conducted using the lme4 and emmeans packages. Model fit statistics were generated using the lmerTest and car packages. Model outputs were extracted using the broom.mixed and sjPlot packages. Model diagnostics and goodness-of-fit tests were run using the ggResidpanel and DHARMa packages. Supplemental Figure S1 and S3 summarizes the results of the diagnostics tests performed for these analyses. Sensitivity analyses were conducted to ensure the robustness of the final models for these numerical outcome measures. In separate analyses, Trial order (four levels: first, second, third, fourth) and Previous trial (five levels: none, 38/81, 46/46, 54/26, 54/13) were included as fixed effect covariates to examine potential order and carryover effects, respectively (Supplemental Table S2) . Any significant effect of these design variables was probed further using Tukey’s honest significant difference-adjusted posthoc pairwise comparisons. Estimates and significance levels from the final and adjusted models were compared to determine whether the interpretation of the findings are impacted by trial order and carryover (Supplemental Table S3) . For survival analyses, Kaplan-Meier curves were generated and Logrank (Mantel-Cox) tests were used to compare the curves across conditions for the following outcome variables: trial duration and projected times to reach critical core temperature. These analyses were conducted using the survival package on R. Generalized linear mixed models were used to examine proportional differences across conditions for trial completion and symptom prevalence. Condition was included as a fixed effect, Participant ID was included as a random intercept, and the compound symmetry covariance structure was selected. Models were fit using the maximum likelihood (Laplace Approximation). Model dispersion, residual patterns, and random effects distribution were examined to evaluate model assumptions and goodness-of-fit. These analyses were conducted using the lme4 , emmeans , and DHARMa packages on R. Supplemental Figure S2 and S4 summarizes the results of the diagnostic tests performed for these analyses. A multinomial logistic regression was performed to examine proportional differences across conditions for the reasons for trial termination. Condition was included as a fixed effect, Participant ID was included as a random intercept, and the compound symmetry covariance structure was selected. As the model failed to converge, its assumptions and goodness-of-fit were not examined further. This analysis was conducted using the mclogit package on R. For exploratory analyses (i.e., generalized linear mixed model and multinomial logistic regression), results were presented descriptively where models failed to converge or satisfy all assumptions and goodness-of-fit tests. 1. Dwan, K., Li, T., Altman, D. G. & Elbourne, D. CONSORT 2010 statement: extension to randomised crossover trials. BMJ l4378 (2019) doi:10.1136/bmj.l4378. 2. Warburton, D., Jamnik, V., Bredin, S. & Gledhill, N. The Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) and Electronic Physical Activity Readiness Medical Examination (ePARmed-X+). Health Fit. J. Can. 4 , 3–23 (2011). 3. Beltz, N. M. et al. Graded Exercise Testing Protocols for the Determination of VO 2 max: Historical Perspectives, Progress, and Future Considerations. J. Sports Med. 2016 , 1–12 (2016). 4. Wagner, J. et al. New Data-based Cutoffs for Maximal Exercise Criteria across the Lifespan. Med. Sci. Sports Exerc. 52 , 1915–1923 (2020). 5. Fox, R. H., Goldsmith, R., Hampton, I. F. & Hunt, T. J. Heat acclimatization by controlled hyperthermia in hot-dry and hot-wet climates. J. Appl. Physiol. 22 , 39–46 (1967). 6. Garrett, A. T., Goosens, N. G., Rehrer, N. G., Patterson, M. J. & Cotter, J. D. Induction and decay of short-term heat acclimation. Eur. J. Appl. Physiol. 107 , 659–670 (2009). 7. Périard, J. D., Racinais, S. & Sawka, M. N. Adaptations and mechanisms of human heat acclimation: Applications for competitive athletes and sports. Scand. J. Med. Sci. Sports 25 , 20–38 (2015). 8. Ramanathan, N. L. A new weighting system for mean surface temperature of the human body. J. Appl. Physiol. 19 , 531–533 (1964). 9. Burton, R. F. Estimating body surface area from mass and height: Theory and the formula of Du Bois and Du Bois. Ann. Hum. Biol. 35 , 170–184 (2008). 10. Sampson, J. B., Kobrick, J. L. & Johnson, R. F. The Environmental Symptoms Questionnaire (ESQ): Development and Application: http://www.dtic.mil/docs/citations/ADA264127 (1993) doi:10.21236/ADA264127. 11. Richard F. Johnson & Donna J. Merullo. Subjective Reports of Heat Illness. in Nutritional Needs in Hot Environments: Applications for Military Personnel in Field Operations 277–293 (National Academies Press, Washington, D.C., 1993). 12. Lakens, D. & Caldwell, A. R. Simulation-Based Power Analysis for Factorial Analysis of Variance Designs. Adv. Methods Pract. Psychol. Sci. 4 , 2515245920951503 (2021). Additional Declarations There is NO Competing Interest. Supplementary Files 35CTWExtendedDataTable105Mar2026.jpg Extended Data Table Legends Extended Data Table 1. Participant characteristics. Data are expressed as mean ± standard deviation or as count data. Abbreviations: BMI = body mass index, SBP = systolic blood pressure, DBP = diastolic blood pressure, MAP = mean arterial pressure, HR = heart rate, VO 2 peak = peak oxygen uptake. 35CTWExtendedDataTable205Mar2026.jpg Extended Data Table 2. Magnitude of heat acclimation. Data are expressed as mean ± standard deviation. 35CTWExtendedDataTable305Mar2026.jpg Extended Data Table 3. Linear mixed model analysis on projected times to reach critical core temperatures in response to 35 °C wet-bulb temperature exposures. Abbreviation: CI = confidence interval. 35CTWExtendedDataTable405Mar2026.jpg Extended Data Table 4. Linear mixed model analysis on indicators of physiological heat strain in response to 35 °C wet-bulb temperature exposures. Abbreviation: CI = confidence interval. 35CTWExtendedDataTable505Mar2026.jpg Extended Data Table 5. Linear mixed model analysis of blood pH and pCO 2 responses to 35 °C wet-bulb temperature exposures. Abbreviation: CI = confidence interval. 35CTWsupplementaryinformation05Mar2026.docx Additional information Supplementary information is available for this paper online. Correspondence and requests for materials should be addressed to Ollie Jay ( [email protected] ). Peer review information Reprints and permissions information is available at www.nature.com/reprints. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9227989","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":626739802,"identity":"94a47c44-b80a-4393-9013-b4a86a0c8127","order_by":0,"name":"Ollie Jay","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYDACduaGAwwMbEBGAwMDD0TMAL8WZkaoFp4DJGiBMCQSiNTCz8zYeOADA5+8wc3nzyTe7rBJbGBv3ibBUHMYpxbJZsaGgzMY2Aw33M4xk5x7Ji2xgedYmQTDMdxaDA4zNhzmYWBjBGphk+ZtO5zYIJFjJsHARkDLHwY2+w03jz8Davmf2CD/BqjlHwEtwBBL3HCDwQyo5QDQFh4zCcY2An7pMWBLnnkmx9hybluycRtPWrFFYl86Ti387M2HP/yoOGbbd/z4wxtv2+xk+9kPb7zx4Zs1Ti1Q5x1jUDjAwCIBZDq2gQQSCGgAghoG+QYG5g9Alj1hxaNgFIyCUTDSAAA7JVaQEddhPgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-6076-6337","institution":"University of Sydney","correspondingAuthor":true,"prefix":"","firstName":"Ollie","middleName":"","lastName":"Jay","suffix":""},{"id":626739803,"identity":"387d35ad-bc87-4cc5-bc98-bc06f5cd3aa3","order_by":1,"name":"Jem Cheng","email":"","orcid":"","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Jem","middleName":"","lastName":"Cheng","suffix":""},{"id":626739804,"identity":"3045166a-38de-4dbd-8426-6b3fc968dde6","order_by":2,"name":"Jake McCahon","email":"","orcid":"","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Jake","middleName":"","lastName":"McCahon","suffix":""},{"id":626739805,"identity":"1d1cc352-856d-4142-b67a-64e927b5b4e1","order_by":3,"name":"Lee Jin","email":"","orcid":"","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Lee","middleName":"","lastName":"Jin","suffix":""},{"id":626739806,"identity":"bb167d95-7709-472b-9fb2-d965b4964dd2","order_by":4,"name":"Jennifer Vanos","email":"","orcid":"https://orcid.org/0000-0003-1854-9096","institution":"Arizona State University","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Vanos","suffix":""}],"badges":[],"createdAt":"2026-03-26 01:45:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9227989/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9227989/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107528375,"identity":"e9bc0ff0-52ac-46c8-a71e-bea7ebb852cc","added_by":"auto","created_at":"2026-04-22 09:58:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":117884,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy timeline and experimental protocols. \u003c/strong\u003eTwenty-six human participants (12 male, 14 female) completed the study protocol which consisted of (1) a familiarization visit (gray), (2) seven consecutive days of exercise heat acclimation (orange), and (3) three maximum 3-hour exposure trials to different temperature-humidity combinations equivalent to a wet-bulb temperature of 35°C (purple). Rest days (pink) were interspersed across the study period to ensure adequate recovery between heat exposures. Abbreviations: T\u003csub\u003erec\u003c/sub\u003e = rectal temperature, VO\u003csub\u003e2\u003c/sub\u003epeak = peak oxygen uptake, HR = heart rate, T\u003csub\u003eskin\u003c/sub\u003e = skin temperature, BP = blood pressure, pCO\u003csub\u003e2\u003c/sub\u003e = partial pressure of carbon dioxide.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/d15224fa1d4af77c9fca4ee1.png"},{"id":107528383,"identity":"b6020ccc-530b-43eb-a53a-9305345ffe8e","added_by":"auto","created_at":"2026-04-22 09:58:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":146325,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProjected times to reach clinically-diagnosed heat exhaustion (T\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003erec\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e = 39.0 °C, A and C) and heat stroke (T\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003erec\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e = 40.5 °C, B and D) following exposure to environmental conditions equivalent to a wet-bulb temperature of 35 °C in 26 human participants. A-B:\u003c/strong\u003e Linear mixed-model analyses comparing projected times across conditions and between sexes. The symbols depict the model-estimated means and 95% CIs and the lines show the sample-derived individual responses. P values indicate a significant difference between conditions after conducting Tukey’s honest significant difference-adjusted post-hoc pairwise comparisons. The tables summarize all fixed effects (condition, sex) included in the final models, with significant omnibus effects in bold text. \u003cstrong\u003eC-D:\u003c/strong\u003e Survival analyses comparing Kaplan-Meier curves across conditions. P values indicates the result of the Logrank (Mantel-Cox) test, and the tables summarize the time in hours yielding 50% and 25% survival in our participant cohort for each of the conditions. Conditions are abbreviated as 38/81 (grey): 38°C and 81% relative humidity (RH), 46/46 (teal): 46°C and 45.8% RH, and 54/26 (orange): 54°C and 26.2% RH.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/cbc2562cc4869fac0f384e5b.png"},{"id":107528376,"identity":"1c0d8791-930e-4184-8b8b-4b3db6f4cd9c","added_by":"auto","created_at":"2026-04-22 09:58:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":148879,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePhysiological heat strain responses to environmental conditions equivalent to a wet-bulb temperature of 35 °C in 26 human participants.\u003c/strong\u003e Linear mixed-model analyses comparing end-trial mean skin temperature \u003cstrong\u003e(A)\u003c/strong\u003e, change in heart rate \u003cstrong\u003e(B)\u003c/strong\u003e, whole-body sweat rate \u003cstrong\u003e(C)\u003c/strong\u003e, and rate of water consumption \u003cstrong\u003e(D)\u003c/strong\u003e across conditions and between sexes. The symbols depict the model-estimated means and 95% CIs and the lines show the sample-derived individual responses. P values indicate a significant difference between conditions after conducting Tukey’s honest significant difference-adjusted post-hoc pairwise comparisons. The tables summarize all fixed effects (condition, sex) and covariates (trial duration) included in the final models, with significant omnibus effects in bold text. Conditions are abbreviated as 38/81 (grey): 38°C and 81% relative humidity (RH), 46/46 (teal): 46°C and 45.8% RH, and 54/26 (orange): 54°C and 26.2% RH.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/ce5e000a4ac9a18101404f2b.png"},{"id":107528379,"identity":"e48fda30-b005-46b7-baaf-0479d691247d","added_by":"auto","created_at":"2026-04-22 09:58:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":156350,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBlood pH and pCO\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e responses to environmental conditions equivalent to a wet-bulb temperature of 35 °C in 26 human participants.\u003c/strong\u003e Linear mixed-model analyses comparing blood pH \u003cstrong\u003e(A)\u003c/strong\u003e and blood pCO\u003csub\u003e2\u003c/sub\u003e \u003cstrong\u003e(B)\u003c/strong\u003e across conditions and between timepoints. The large circles depict the model-estimated means and 95% CIs and the small circles show the sample-derived individual responses. Solid large circles represent the start timepoint and dotted large circles represent the end timepoint. The gray shaded areas indicate the normal range and the yellow shaded areas represent the danger zone for each variable. P values indicate a significant difference between data points after conducting Tukey’s honest significant difference-adjusted post-hoc pairwise comparisons. The tables summarize all fixed effects (condition, time), interaction effects (condition*time), and covariates (trial duration) included in the final models, with significant effects in bold text. Conditions are abbreviated as 38/81 (grey): 38°C and 81% relative humidity (RH), 46/46 (teal): 46°C and 45.8% RH, and 54/26 (orange): 54°C and 26.2% RH.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/f990ba1af02b40e19ca1892b.png"},{"id":107528385,"identity":"743e8655-104f-4102-9d07-b36087b45d4f","added_by":"auto","created_at":"2026-04-22 09:58:37","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":97815,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePercentage of total participants reporting common signs and symptoms of heat distress at any point during each trial. \u003c/strong\u003ePrompts were based on the USARIEM Environmental Symptoms Questionnaire version IV, Subjective Heat Illness Index. Conditions are abbreviated as 38/81 (grey): 38°C and 81% relative humidity (RH), 46/46 (teal): 46°C and 45.8% RH, and 54/26 (orange): 54°C and 26.2% RH.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/eef65fd2c8df5912a5e9962c.png"},{"id":107528377,"identity":"ed00207b-eb7d-4666-9c66-c9b7190da075","added_by":"auto","created_at":"2026-04-22 09:58:35","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":119739,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTrial completion and termination statistics across conditions. A: \u003c/strong\u003eSurvival curve depicting the proportion of participants that remained in each trial up to the maximum trial duration of 180 minutes. Inset: Rate of trial completion for each condition. \u003cstrong\u003eB:\u003c/strong\u003e Percentage distribution of reasons for trial termination for each condition. Conditions are abbreviated as 38/81 (grey): 38°C and 81% relative humidity (RH), 46/46 (teal): 46°C and 45.8% RH, and 54/26 (orange): 54°C and 26.2% RH.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/0bd2b1a7415977844ef04e04.png"},{"id":107706382,"identity":"65457567-4fec-4fbb-881f-095dcf5e4a8d","added_by":"auto","created_at":"2026-04-24 09:17:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1093247,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/3880d127-7e4e-4df3-90c5-268b76095c5e.pdf"},{"id":107528382,"identity":"57b94edc-e0cf-4adc-8191-cf8e58b6f050","added_by":"auto","created_at":"2026-04-22 09:58:36","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":218217,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExtended Data Table Legends\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Table 1. Participant characteristics.\u003c/strong\u003e Data are expressed as mean ± standard deviation or as count data. Abbreviations: BMI = body mass index, SBP = systolic blood pressure, DBP = diastolic blood pressure, MAP = mean arterial pressure, HR = heart rate, VO\u003csub\u003e2\u003c/sub\u003epeak = peak oxygen uptake.\u003c/p\u003e","description":"","filename":"35CTWExtendedDataTable105Mar2026.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/63bb334fa2b3c6212f92efac.jpg"},{"id":107528381,"identity":"34ef4eb0-a042-4e3a-9656-04a91ffd97fd","added_by":"auto","created_at":"2026-04-22 09:58:36","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":137888,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExtended Data Table 2. Magnitude of heat acclimation. \u003c/strong\u003eData are expressed as mean ± standard deviation.\u003c/p\u003e","description":"","filename":"35CTWExtendedDataTable205Mar2026.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/7ea2984c72ecb29bfef3098c.jpg"},{"id":107528374,"identity":"54881d64-e619-4efc-8c42-c23260a88327","added_by":"auto","created_at":"2026-04-22 09:58:35","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":190003,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExtended Data Table 3. Linear mixed model analysis on projected times to reach critical core temperatures in response to 35 °C wet-bulb temperature exposures. \u003c/strong\u003eAbbreviation: CI = confidence interval.\u003c/p\u003e","description":"","filename":"35CTWExtendedDataTable305Mar2026.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/7d64a4db64a24a674c824169.jpg"},{"id":107528384,"identity":"380359fe-ff74-4eee-b75b-6a7c12fb4f11","added_by":"auto","created_at":"2026-04-22 09:58:36","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":421624,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExtended Data Table 4. Linear mixed model analysis on indicators of physiological heat strain in response to 35 °C wet-bulb temperature exposures. \u003c/strong\u003eAbbreviation: CI = confidence interval.\u003c/p\u003e","description":"","filename":"35CTWExtendedDataTable405Mar2026.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/691320d3a67d479d62ebbdd4.jpg"},{"id":107528380,"identity":"7b90401b-6b6f-4370-ac27-532d91fa8d34","added_by":"auto","created_at":"2026-04-22 09:58:36","extension":"jpg","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":654685,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExtended Data Table 5. Linear mixed model analysis of blood pH and pCO\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e responses to 35 °C wet-bulb temperature exposures.\u003c/strong\u003e Abbreviation: CI = confidence interval.\u003c/p\u003e","description":"","filename":"35CTWExtendedDataTable505Mar2026.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/abb309a6b282b042ad65afb9.jpg"},{"id":107528378,"identity":"b8dae0ae-ad09-4cf6-8243-01b061397191","added_by":"auto","created_at":"2026-04-22 09:58:35","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":3080145,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary information is available for this paper online.\u003c/p\u003e\n\u003cp\u003eCorrespondence and requests for materials should be addressed to Ollie Jay ([email protected]).\u003c/p\u003e\n\u003cp\u003ePeer review information\u003c/p\u003e\n\u003cp\u003eReprints and permissions information is available at www.nature.com/reprints.\u003c/p\u003e","description":"","filename":"35CTWsupplementaryinformation05Mar2026.docx","url":"https://assets-eu.researchsquare.com/files/rs-9227989/v1/e1abde6bbf85d1d6218ba79c.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Human physiology at the upper limit of extreme heat exposure","fulltext":[{"header":"1.0 Introduction ","content":"\u003cp\u003eThe year 2024 was the hottest globally in 175 years of recorded history\u003csup\u003e1\u003c/sup\u003e. As the climate warms, bouts of extreme heat, often compounded by humidity, will intensify and become more frequent. Extreme heat is already the deadliest weather-related hazard for humans due to the risk of heat stroke\u003csup\u003e2\u003c/sup\u003e. If Earth remains on its current warming trajectory, the health risk from extreme heat will increase, occasionally becoming severe enough to threaten human life across more extensive spatial and temporal scales by mid-century\u003csup\u003e3\u003c/sup\u003e. However, the specific ambient temperature-humidity thresholds at which human mortality becomes unavoidable (i.e., the limits of \u0026ldquo;survivability\u0026rdquo; or \u0026ldquo;habitability\u0026rdquo;) have not yet been empirically established and remain a subject of theoretical modelling\u003csup\u003e4-6\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn 2010, Sherwood and Huber proposed the 35˚C wet-bulb temperature (T\u003csub\u003ewet\u003c/sub\u003e) limit for human survival due to heat stress\u003csup\u003e4\u003c/sup\u003e. This model assumes that fatal heat stroke is unavoidable \u0026ndash; even in young, healthy, fully heat acclimatised people \u0026ndash; after 6 hours of exposure to any ambient temperature-humidity combination yielding a T\u003csub\u003ewet\u003c/sub\u003e of 35˚C. This assumption is grounded in the notion that, under such climatic conditions, both the temperature and water vapour pressure gradients between the skin and surrounding air that are required for heat dissipation are eliminated, resulting in critical internal body heat storage\u003csup\u003e7\u003c/sup\u003e. Elegant in its simplicity and widely cited, this model is frequently used as a common benchmark for projecting heat stress risk under climate change\u003csup\u003e8\u003c/sup\u003e. However, because physiological ceilings on sweating and cardiovascular stability were excluded, concerns have emerged that human survivability at a T\u003csub\u003ewet\u003c/sub\u003e of 35˚C may be over-estimated, and that the potential heat stress impacts of present-day extremes as well as those with future climate change are consequently under-estimated. In 2023, our group proposed a physiologically constrained model incorporating key thermoregulation limits, predicting that human heat strain at a T\u003csub\u003ewet\u003c/sub\u003e of 35˚C should vary substantially depending on the temperature-humidity combination that produces it\u003csup\u003e5\u003c/sup\u003e. Specifically, the model indicated that the physiologically attainable T\u003csub\u003ewet\u003c/sub\u003e limit increasingly diverges from\u0026nbsp;35\u0026deg;C as air temperature rises, due to escalating evaporative demands that accelerate the rise in core body temperature\u003csup\u003e5\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eControlled environmental exposures of humans in climate chambers have, to date, been restricted to examining the limits of \u0026ldquo;liveability\u0026rdquo; \u0026ndash; the environmental boundaries at which thermoregulatory equilibrium can no longer be physiologically maintained and core body temperature begins to rise, which reside around T\u003csub\u003ewet\u003c/sub\u003e of ~30-32˚C\u003csup\u003e5,9-11\u003c/sup\u003e. However, for human health to be threatened, human core body temperature must rise to around 39˚C (heat exhaustion) and\u0026nbsp;\u0026ge;40-40.5˚C (heat stroke)\u003csup\u003e\u0026nbsp;12,13\u003c/sup\u003e. The time required to reach these thresholds depends on the rate of core temperature rise and may take many hours. Beyond core temperature alone, the risk of heat illnesses and death is also driven by integrative physiological strain, including the increased cardiac work required to defend central blood pressure in the face of extreme heat, and disturbances in blood pH arising from heat-induced hyperventilation\u003csup\u003e14\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHere we report a first-in-human study that directly interrogates the canonical 35˚C wet-bulb temperature survival limit across a range of ambient temperatures. We show that three distinct temperature-humidity combinations, each yielding an identical wet-bulb temperature of 35˚C, impose substantially different multi-system physiological strain in young, healthy, fully heat-acclimated adults, with the magnitude of strain strongly influenced by ambient temperature. The projected exposure time to a core temperature indicative of heatstroke was ~45% shorter at the highest (54˚C) than at the lowest (38˚C) temperature tested, despite the same T\u003csub\u003ewet\u003c/sub\u003e of 35˚C. Compared to the 6-h survival time assumed by the 35˚C T\u003csub\u003ewet\u003c/sub\u003e model, the median times to heat exhaustion were 4.6 hours at 38˚C and 2.5 hours at 54˚C, while median times to heat stroke were 7.2 hours at 38˚C and 3.8 hours at 54˚C, indicating that the physiological strain, and potentially the associated health impacts of extreme heat under climate change may be presently under-estimated. \u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"2.0 Results ","content":"\u003cp\u003e\u003cstrong\u003eDifferent responses at a fixed T\u003csub\u003ewet\u003c/sub\u003e of 35\u0026deg;C\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe exposed twenty-six young, healthy adults \u003cstrong\u003e(Extended Data Table 1)\u0026nbsp;\u003c/strong\u003eto three different environmental conditions at rest, each with an equivalent T\u003csub\u003ewet\u003c/sub\u003e of 35\u0026deg;C. Prior to testing, participants completed 7 consecutive days of climate chamber-based heat acclimation \u003cstrong\u003e(Extended Data Table 2)\u003c/strong\u003e to minimise seasonal variability and ensure that results would be generalisable to fully heat acclimatised populations in the future. The environmental conditions tested were: (1) 38\u0026deg;C and 81.1% RH (38/81), (2) 46\u0026deg;C and 45.8% RH (46/46), and (3) 54\u0026deg;C and 26.2% RH (54/26). Participants were monitored during a maximum 3-hour seated exposure in a climate chamber, and their physiological heat strain responses were compared across conditions \u003cstrong\u003e(Figure 1)\u003c/strong\u003e. We hypothesised that for the same T\u003csub\u003ewet\u003c/sub\u003e of 35\u0026deg;C, multi-system physiological heat strain would be greater at higher ambient temperatures.\u003c/p\u003e\n\u003cp\u003eTo answer our main research question, we calculated the slope of the final 60 minutes of core temperature data from each trial and extrapolated further to determine the amount of time it would have required participants to remain in the chamber until they reached core temperatures indicative of the onset of heat exhaustion (39.0\u0026deg;C) and heat stroke (40.5\u0026deg;C). Our linear mixed-model analysis revealed an effect of condition (P\u0026lt;0.001) such that projected times to reach both critical core temperatures decreased as ambient temperature increased (P\u0026lt;0.001 for all pairwise comparisons), with no sex-based differences observed for either a core temperature of 39.0\u0026deg;C (P=0.489) or 40.5\u0026deg;C (P=0.473) \u003cstrong\u003e(Figure 2A and B and Extended Data Table 3)\u003c/strong\u003e. Corresponding survival analyses with a Logrank (Mantel-Cox) test confirmed that the Kaplan-Meier curves differed across conditions (P\u0026lt;0.001). Median exposure time [95% CI] to heat exhaustion was 4.6 hours [4.0, 5.0] in 38/81, 3.1 hours [2.8, 3.5] in 46/46, and 2.5 hours [2.3, 2.7] in 54/26; median exposure time to heat stroke was 8.6 [7.6, 8.8] hours in 38/81, 5.5 hours [5.0, 6.4] in 46/46, and 4.6 hours [4.2, 4.9] in 54/26 \u003cstrong\u003e(Figure 2C and D)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExacerbated cardiovascular strain\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA fundamental part of the theoretical basis for the 35\u0026deg;C wet-bulb temperature threshold for heat stress survival is that vasodilation of the skin will increase the average skin temperature across the body surface to ~35˚C \u003csup\u003e4\u003c/sup\u003e. We observed end-trial mean skin temperatures exceeding 35\u0026deg;C for all three conditions, which were progressively higher with increasing ambient temperature (37.6 [37.4, 37.8] vs. 38.6 [38.4, 38.8] vs. 39.4 [39.2, 39.6] \u0026deg;C, P\u0026lt;0.001 for all pairwise comparisons) \u003cstrong\u003e(Figure 3A and Extended Data Table 4A)\u003c/strong\u003e. While these skin temperatures support higher heat dissipation potential than previously assumed, large associated increases in cardiovascular strain were observed. After adjusting for trial duration as a covariate (P=0.036), there was an effect of condition (P=0.010) for heart rate, with significantly higher end-trial increases from baseline reported in 54/26 compared to 38/81 (41 [36, 46] vs. 32 [27, 37] bpm, P=0.010) \u003cstrong\u003e(Figure 3B and Extended Data Table 4B)\u003c/strong\u003e. Mean skin temperature (P=0.661) and heart rate responses (P=0.907) were not different between males and females.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDifferences in sweat losses\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhole-body sweat rates were greater at higher ambient temperatures (P\u0026lt;0.001) and greater in males vs. females (P=0.036) even when expressed relative to body surface area \u003cstrong\u003e(Figure 3C and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eExtended Data Table 4C\u003c/strong\u003e\u003cstrong\u003e).\u003c/strong\u003e Water consumption throughout the trials was similar between conditions \u003cstrong\u003e(Figure 3D and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eExtended Data Table 4D\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e. A greater sweat rate was observed from 38/81 (0.24 [0.20, 0.28] L/h/m\u003csup\u003e2\u003c/sup\u003e) to 46/46 (0.31 [0.27, 0.35] L/h/m\u003csup\u003e2\u003c/sup\u003e) to 54/26 (0.41 [0.36, 0.45] L/h/m\u003csup\u003e2\u003c/sup\u003e); P\u0026lt;0.001 for all pairwise comparisons. Greater sweating was also observed in males (0.36 [0.30, 0.42] L/h/m\u003csup\u003e2\u003c/sup\u003e) compared to females (0.28 [0.22, 0.33] L/h/m\u003csup\u003e2\u003c/sup\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisrupted acid-base balance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificant condition-by-time interactions were observed for both blood pH and pCO\u003csub\u003e2\u003c/sub\u003e (P=0.020 and P=0.009, respectively). After adjusting for trial duration, pH increased and pCO\u003csub\u003e2\u003c/sub\u003e decreased from the start to the end of the trial in all three conditions (P\u0026lt;0.001 for all pairwise comparisons). Importantly, end-trial pH was higher and pCO2 was lower in the hotter conditions (46/46 and 54/26) compared with 38/81, indicating more pronounced respiratory alkalosis at higher ambient temperatures. Specifically, pH reached 7.51 [7.49, 7.54] and 7.52 [7.50, 7.54] in 46/46 and 54/26, respectively, versus 7.48 [7.46, 7.51] in 38/81, while pCO\u003csub\u003e2\u003c/sub\u003e fell to 27.7 [25.6, 29.9] and 27.3 [25.0, 29.6] mmHg in 46/46 and 54/26, compared with 30.7 [28.5, 32.9] mmHg in 38/81 (\u003cstrong\u003eFigure 4 and Extended Data Table 5\u003c/strong\u003e). There was no effect of sex for blood pH (start-trial: P=0.738, end-trial: P=0.633); however, baseline pCO\u003csub\u003e2\u003c/sub\u003e was greater in males compared to females (40.0 [38.3, 41.7] vs. 37.4 [35.8, 38.9] mmHg, P=0.027).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWorsened heat distress symptoms\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo assess symptoms of heat distress, we administered a modified version \u003cstrong\u003e(Supplemental Table S1)\u003c/strong\u003e of the 68-item Environmental Symptoms Questionnaire originally developed by the US Army Research Institute of Environmental Medicine\u003csup\u003e15\u003c/sup\u003e. From a subset of 22 items that inform the Subjective Heat Illness index, we clustered similar items to generate 8 prompts that broadly classify common heat distress symptoms: (1) feeling lightheaded, dizzy, or faint (items 1, 4, 5), (2) headache (item 2), (3) difficulty breathing (items 8, 9), (4) muscle or stomach cramping (items 16, 17), (5) numbness and tingling (item 38), (6) tiredness and weakness (items 19, 56), (7) nausea (item 53), (8) blurry vision (item 41). As with many of the physiological variables, symptoms became more pervasive as ambient temperature increased with T\u003csub\u003ewet\u003c/sub\u003e held constant at 35˚C, with 65%, 73%, and 96% of participants reporting any symptom across the trial period in 38/81, 46/46, and 54/26, respectively \u003cstrong\u003e(Figure 5)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial termination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the safety of our participants, we employed the following conservative trial termination criteria: (i) T\u003csub\u003erec\u003c/sub\u003e \u0026ge;39.0 \u0026deg;C, (ii) 50\u0026gt;HR\u0026gt;80% HR\u003csub\u003emax\u003c/sub\u003e bpm, (iii) 90\u0026gt;SBP\u0026gt;200 mmHg, (iv) severe and/or escalating signs and symptoms of heat distress, (v) volitional termination for any reason.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTrial completions dropped precipitously from 38/81 to 46/46 to 54/26 \u003cstrong\u003e(Figure 6A, inset)\u003c/strong\u003e. In a survival curve depicting the proportion of participants that remained in each trial up to a total duration of 3 hours, we observed the conditions diverge after 80 minutes (P\u0026lt;0.001) such that while 85% of participants were able to complete 3 hours in 38/81, only 50%, and 12% were able to do so in 46/46 and 54/26, respectively \u003cstrong\u003e(Figure 6A)\u003c/strong\u003e. We compared the reasons for trial termination across conditions and found that the proportion of participants terminating due to reaching the core temperature safety threshold increased progressively with increasing ambient temperature (4% vs. 27% vs. 65%) \u003cstrong\u003e(Figure 6B)\u003c/strong\u003e. Furthermore, terminations due to severe symptoms increased 6-fold between 38/81 and 46/46 or 54/26 \u003cstrong\u003e(Figure 6B)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e"},{"header":"3.0 Discussion ","content":"\u003cp\u003eThe widely cited 35\u0026deg;C wet-bulb temperature (T\u003csub\u003ewet\u003c/sub\u003e) limit for human survivability under extreme heat associated with climate change has been framed as a physiological tipping point, beyond which irreversible heat trauma (heat stroke) becomes unavoidable after six hours of exposure, irrespective of the temperature\u0026ndash;humidity combination that produces it\u003csup\u003e4\u003c/sup\u003e. By replicating these modelled conditions in a controlled climate chamber, we empirically demonstrate for the first time in young, healthy, fully heat-acclimatised humans that exposure to a wet-bulb temperature of 35\u0026deg;C does not impose equivalent physiological strain across different environments. Moreover, our integrated assessment across multiple physiological systems indicates that identifying the physiological \u0026lsquo;tipping point\u0026rsquo; requires moving beyond core temperature alone, which has largely underpinned climate-based survivability models to date.\u003c/p\u003e\n\u003cp\u003eAcross all outcome variables, we observed a consistent intensification of physiological strain as ambient temperature increased and relative humidity decreased, despite T\u003csub\u003ewet\u003c/sub\u003e being held constant. All conditions were physiologically uncompensable, as evidenced by a constantly rising core temperature throughout all trials. But the rate of core temperature rise increased from 0.39\u0026plusmn;0.11\u0026deg;C/h in 38/81 to 0.62\u0026plusmn;0.15\u0026deg;C/h in 46/46 and 0.75\u0026plusmn;0.24 \u0026deg;C/h in 54/26, leading to projected times to heat exhaustion (38/81: 4.7 h; 46/46: 3.3 h; 54/26: 2.5 h) and heat stroke (38/81: 8.8 h; 46/46: 5.8 h; 54/26: 4.8 h) decreasing by approximately 1.5- to 2-fold as conditions became hotter and drier. The difference in the core temperature response between conditions, nor the projected times to heat exhaustion or heat stroke, were altered by sex.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe observed differences in core temperature across conditions reflect fundamental constraints on thermoregulatory capacity that differ between humid and dry environments, even when T\u003csub\u003ewet\u003c/sub\u003e is matched. In warm but extremely humid conditions, evaporative cooling is limited by the environment. The air is near-saturated with water vapour, so any sweat produced struggles to evaporate and instead is absorbed into clothing or drips off the skin without contributing to latent cooling\u003csup\u003e16\u003c/sup\u003e. While the environment is uncompensable, physiological heat strain builds gradually because the addition of heat to the body from the environment via sensible heat transfer pathways of convection and radiation is relatively modest\u003csup\u003e17\u003c/sup\u003e. In contrast, in extremely hot but drier conditions, evaporative cooling is limited not by the environment but by the person\u0026rsquo;s physiological capacity to produce sweat\u003csup\u003e5,18\u003c/sup\u003e. Since the air can accept virtually unlimited moisture, sweat produced readily evaporates. At a certain point, however, the maximum rate of sweat secretion is reached, which limits this system as a mechanism for heat loss. If air temperature is simultaneously very high relative to skin temperature, sensible heat gain by the body is substantial and physiological heat strain accelerates dramatically\u003csup\u003e19,20\u003c/sup\u003e. A similar phenomenon has been previously reported at lower air temperatures (45˚C) but with sensible heat gain accelerated by high air movement from the use of electric fans\u003csup\u003e21,22\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eHigher core temperatures at 54˚C drove higher whole-body sweat rates, increasing the risk of dehydration relative to the same T\u003csub\u003ewet\u003c/sub\u003e at lower ambient temperatures. Measures of serum creatinine or urinalysis were not included in the present study; therefore, it cannot be determined whether the risks of acute kidney injury or renal dysfunction were also different. Of all the variables measured, a discernible sex difference was only observed for whole-body sweat rate. Even after controlling for body size, males produced more sweat than females. However, since there was no corresponding sex-specific impact on the rate of rise of core temperature, these differences \u0026ndash; likely arising from a lower sensitivity to acetylcholine\u003csup\u003e23\u003c/sup\u003e, the neurotransmitter primarily responsible for the sweating mechanism \u0026ndash; did not translate into physiologically significant differences in body heat storage.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExacerbations in cardiovascular strain with increasing ambient temperature despite a fixed T\u003csub\u003ewet\u003c/sub\u003e are also noteworthy. While the cause of death resulting from extreme heat events is multifactorial, emerging evidence suggests that cardiovascular strain is a key contributor\u003csup\u003e24,25\u003c/sup\u003e. High skin temperatures dilate blood vessels and direct a greater flow to the cutaneous circulation, which decreases vascular resistance and central blood volume, followed by increased heart rate and cardiac contractility to match\u003csup\u003e26\u003c/sup\u003e. If cadiac function is impaired because of chronic disease, the body may be unable to meet the increased myocardial oxygen demand required to sustain this volume of perfusion, leading to increased risk of cardiac ischemia\u003csup\u003e27\u003c/sup\u003e. In parallel, the redistribution of blood flow away from the splanchnic (abdominal) region triggers a systemic inflammatory response, creating a hypercoagulant environment that encourages the formation of thromboses\u003csup\u003e27\u003c/sup\u003e. Both pathways can lead to adverse cardiovascular outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBeyond the classical indicators of physiological heat strain, we also observed the likely consequecnes of substantial respiratory distress, which worsened with increasing ambient temperature. Respiratory responses were not measured but hyperventilation is a well-documented physiological response to extreme heat\u003csup\u003e28\u003c/sup\u003e, and signs of respiratory alkalosis were evidenced by a lower end-trial pCO\u003csub\u003e2\u003c/sub\u003e coupled with higher end-trial pH compared to rest measured from capillary blood samples. In isolation, hypocapnic alkalosis is non-life threatening. However, its associated signs and symptoms and the potential deleterious effects on critical organ systems are worth noting. Due to a leftward shift in the oxyhemoglobin dissociation curve in these conditions, less oxygen is unbound at the tissue level potentially resulting in reduced oxygen supply; compounding this issue, hypocapnia also stimulates systemic vasoconstriction\u003csup\u003e29\u003c/sup\u003e. In comparatively mild cases, a person may exhibit paraesthesias, palpitations, and cramps; but if sufficiently severe, further central nervous system consequences such as seizures and convulsions may transpire due to increased axonal excitability secondary to the resultant hypocalcemia\u003csup\u003e27,30\u003c/sup\u003e. There is no universal safety threshold for pCO\u003csub\u003e2\u003c/sub\u003e and pH because individual tolerance to excursions from the normative range varies. However, several observational studies have identified the pCO\u003csub\u003e2\u003c/sub\u003e and pH values when specific adverse events such as dizziness, light-headedness, and paraesthesiae\u003csup\u003e31\u003c/sup\u003e; syncope\u003csup\u003e32\u003c/sup\u003e; seizures\u003csup\u003e33,34\u003c/sup\u003e, and alkalemia-associated morbidity and mortality occur\u003csup\u003e35\u003c/sup\u003e. As a result, clinical care guidelines\u003csup\u003e36\u003c/sup\u003e indicate critical limits of \u0026le;20 mmHg for pCO\u003csub\u003e2\u003c/sub\u003e and \u0026ge;7.60 for pH to signal conditions approaching incompatibility with life. It is therefore of particular concern that these thresholds were approached in the current study, with more participants lying within this danger zone in the higher temperature conditions 46/46 and 54/26 compared to 38/81. Vulnerability to the effects of hypocapnic alkalosis is further heightened in those with panic disorder and cardiovascular conditions. Because there is significant overlap in the manifestation of panic attacks and hypocapnia-induced cerebral hypoxia (e.g., lightheadedness, dizziness, confusion, syncope), an alkalotic environment will almost always induce panic in those with this psychological disorder\u003csup\u003e37,38\u003c/sup\u003e. While we did not medically screen for psychological disorders in the current study, there were instances of self-termination due to panic and presyncopal symptoms in the absence of substantial physiological heat strain assessed through core temperature that align with this evidence. In terms of cardiovascular consequences, hypocapnia can exacerbate ischemic conditions by increasing coronary and cerebrovascular resistance and susceptibility to thrombosis (via increased platelet levels and platelet aggregation)\u003csup\u003e\u0026nbsp;39,40\u003c/sup\u003e. The inherent ion imbalances with alkalosis \u0026ndash; specifically the shift of potassium from the extracellular to intracellular compartment \u0026ndash; is thought to result in a global misfiring of action potentials, which can trigger arrhythmias to occur\u003csup\u003e38,41\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eCompared to the 6-hour benchmark for heat stroke set forth by Sherwood \u0026amp; Huber, the present data indicate that, if core temperature is treated as the only biomarker of physiological heat strain, the original model potentially under-estimated survival time in warm and very humid conditions (38/81) but likely over-estimated it in very hot but drier conditions (54/26). Skin temperatures higher than 35˚C permit better heat dissipation potential than originally modelled; however, this comes at the cost of higher levels of skin blood perfusion, which drive greater cardiovascular and respiratory strain and could escalate to cause severe and debilitating symptoms. Even with a core temperature stop-threshold of 39.0˚C in the present study, approximately one-quarter of participants stopped their trials at 46/46 and 54/26 due to heat-related symptoms. While heat stress survival models currently assume that the cause of death is a critical core temperature\u003csup\u003e4,5\u003c/sup\u003e, the substantial physiological strain across multiple organ systems could manifest lethal outcomes before core temperature reaches heat stroke levels.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCritical core temperature thresholds for heatstroke range from 42-43˚C to 40.5˚C\u003csup\u003e12,13,42\u003c/sup\u003e. By choosing the more conservative threshold in the present analysis, extreme body temperatures linked with irreversible health outcomes such as coma, delirium, or serious brain damage are avoided\u003csup\u003e12,13\u003c/sup\u003e. Analogous to the aging-related discourse on lifespan vs. healthspan, we should aim not only to survive extreme heat on a clinical level, but to emerge with full function and health. Moreover, all human physiology studies in climate chambers on this topic to date have assessed the critical environmental limits at which thermal compensability is breached, which, by definition, are the conditions that cause \u003cem\u003eany\u003c/em\u003e continuous rise in core temperature from a low steady-state level\u003csup\u003e9-11,43\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIt is important to recognise that the present findings do not constitute evidence of population-level heat survivability outcomes. All data supporting survivability thresholds to date have been based on theoretical modeling\u003csup\u003e4,5\u003c/sup\u003e, and the present study provides empirical physiological data that fundamentally tests for the first time in humans the validity of the 35˚C T\u003csub\u003ewet\u003c/sub\u003e limit for heat stress survivability across a range of temperature-humidity combinations, but only in a controlled, small-scale setting. Liveability thresholds, typically defined as the limit of thermal compensability\u003csup\u003e5\u003c/sup\u003e are increasingly supported by physiological evidence using similar-scale studies\u003csup\u003e10,11,43\u003c/sup\u003e, albeit in non-heat-acclimated individuals. The present findings also support recent modeling approaches that estimate heat-related health risk after accounting for human physiology such as ASU/USYD HEAT-Lim model reported by Vanos et al\u003csup\u003e5\u003c/sup\u003e, which predicts different physiological heat strain between dry and humid conditions at a fixed T\u003csub\u003ewet\u003c/sub\u003e.\u003c/p\u003e\n\u003cp\u003eTo maximise survivability, we deliberately adopted experimental conditions that favoured physiological tolerance to extreme heat. All participants were healthy, young, and completed 7 consecutive days of exercise heat acclimation to controlled hyperthermia in a climate-controlled chamber directly prior to their experimental trials. All participants remained quietly seated throughout, wearing minimal clothing, without any additional radiative heat load (equivalent of fully shaded). Real-world heat exposure typically involves sustained metabolic activity (\u0026sim;1.5-3.0 METs for daily living and 3.5-12 METs during physical activity) across dynamic indoor and outdoor (often sun-exposed) environments, indicating that the physiological strain observed here likely represents a conservative estimate of heat stress under future climate extremes.\u003c/p\u003e"},{"header":"4.0 Conclusion","content":"\u003cp\u003eOur findings show that treating 35\u0026deg;C wet-bulb temperature as a universal survivability threshold fails to capture large, condition-dependent differences in physiological strain. They further underscore the need to approach human survivability holistically, recognising that multiple, interacting physiological processes govern tolerance to extreme heat.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo specific code was used to generate data for this paper.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eO.J. is funded by the National Health and Medical Research Council (Investigator Grant No. 2021/GNT2009507). J.L.C. is funded by the Canadian Institutes of Health Research (Postdoctoral Fellowship Award). The authors acknowledge the technical assistance of Dr. Alexandra Green and the Sydney Informatics Hub, a Core Research Facility of the University of Sydney.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJ.L.C., J.V., and O.J. conceived of the work and designed the study. J.L.C., J.A.M, and L.Y.J. conducted the experimental trials and acquired and analyzed the data. J.L.C. performed statistical analyses and generated figures. J.L.C. and O.J. interpreted the findings. J.L.C. and O.J. drafted the manuscript. All authors read, revised, and contributed significantly to the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eUnited Nations. 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D.\u003cem\u003e et al.\u003c/em\u003e Validating new limits for human thermoregulation. \u003cem\u003eProc Natl Acad Sci U S A\u003c/em\u003e \u003cstrong\u003e122\u003c/strong\u003e, e2421281122 (2025). https://doi.org:10.1073/pnas.2421281122\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Methods ","content":"\u003cp\u003e\u003cstrong\u003eTrial Design\u003c/strong\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study used a randomized crossover design in which all participants completed seven consecutive days of exercise heat acclimation, followed by a day of rest, and then three experimental trials in varying temperature-humidity combinations equivalent to a wet-bulb temperature of 35\u0026deg;C. These trials were spaced exactly 48 hours apart to balance adequate recovery from heat stress with the maintenance of heat acclimation status. The same participants were measured repeatedly across conditions and timepoints. The complete study timeline and experimental protocols are outlined in \u003cstrong\u003eFigure 1\u003c/strong\u003e. The manuscript was reported according to the Consolidated Standards of Reporting Trials (CONSORT) extension guidelines\u003csup\u003e1\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo be eligible, participants had to be between 18 and 40 years old, generally healthy, and able to read and understand English to provide informed written consent to participate in the study. Exclusion criteria included any contraindications to the use of a rectal thermistor (i.e., haemorrhoids, heterotopic ossification, rectal bleeding or bleeding disorders, fissures or active infections, anticoagulant therapy, colitis), smoking, pregnancy, a current diagnosis or history of hypertension, cardiovascular, respiratory, and/or metabolic disorders or any medication use associated with the aforementioned conditions, and the inability to participate in physical activity according to the Physical Activity Readiness Questionnaire\u003csup\u003e2\u003c/sup\u003e. All study visits were completed in the Thermal Ergonomics Laboratory located on level 9 of the Susan Wakil Health Building at the University of Sydney in Camperdown, NSW, Australia. This study was approved by the University of Sydney Human Research Ethics Committee (Project Number: 2023/884) and prospectively registered in the Australian New Zealand Clinical Trials Registry (ACTRN: 12624000258550) before the first participant commenced the study. Participants provided informed written consent prior to completing any portion of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFamiliarization and V̇O\u003c/strong\u003e\u003cstrong\u003e\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003e\u003cstrong\u003epeak Test\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo more than 14 days and no less than 48 hours before the initiation of the study protocol, participants were invited to the laboratory to be familiarized with the testing environment. Basic anthropometric measures (height and body mass) were collected before participants performed a cardiorespiratory fitness test to exhaustion (V̇O\u003csub\u003e2\u003c/sub\u003epeak test) on a commercially-available treadmill. Our step-wise protocol involved a 3-minute warm-up at a sustainable, self-selected running pace and 1% incline followed by alternating increases in treadmill speed (by 0.8 km/h) and grade (by 2%) every minute until volitional failure\u003csup\u003e3\u003c/sup\u003e. Protocol parameters were chosen to be appropriately challenging to target a test duration between ~8 to 12 minutes, and alternating speed and grade increases were chosen to encourage participants to terminate the test at peak cardiorespiratory capacity rather than as a result of the inability to match pace or continue due to muscular fatigue. A test was deemed successful if a V̇O\u003csub\u003e2\u003c/sub\u003e plateau was observed in the final 30 seconds (i.e., 3 x 10-s bins within 0.1 L/min in value) or if two out of the following three criteria were met: (1) rating of perceived exertion \u0026ge; 17, (2) respiratory exchange ratio \u0026ge; 1.13, or (3) heart rate (HR) \u0026ge; 93% age-predicted maximum (208-0.7*age)*0.93)\u003csup\u003e4\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHeat Acclimation\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants completed seven consecutive days of exercise heat acclimation on a treadmill using the controlled hyperthermia approach\u003csup\u003e5\u0026ndash;7\u003c/sup\u003e. Each session was 90 minutes in total. In a climate chamber set to 40\u0026deg;C and 50% relative humidity (T\u003csub\u003ewet\u003c/sub\u003e = 30.9 \u0026deg;C), participants were instructed to walk, jog, or run at an intensity sufficient to reach a core temperature of 38.5 \u0026deg;C within the first 30 minutes, and then to adjust intensity thereafter to maintain their core temperature for the remainder of the session.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperimental Trials\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn a randomized order, participants completed three experimental trials in which they were exposed to temperature-humidity combinations equivalent to a wet-bulb temperature of 35\u0026deg;C for up to a maximum of 3 hours. The conditions were: (1) 38\u0026deg;C and 81.1% RH (38/81), (2) 46\u0026deg;C and 45.8% RH (46/46), and (3) 54\u0026deg;C and 26.2% RH (54/26). Upon arrival, participants self-inserted a rectal thermistor and provided a urine sample to assess hydration status via measurement of urine specific gravity (USG). If USG \u0026ge; 1.02, they were given ~250 ml of water to drink. Nude body mass was measured in triplicate followed by instrumentation with a heart rate monitor and skin thermistors. Participants were asked to wear clothing as minimal as they were comfortable with, and to wear the same clothing for each trial. For males, we recommended no shirt and athletic shorts or swim briefs/trunks; for females, we recommended a sports bra and athletic shorts or swimwear. Participants completed 15 minutes of quiet, seated rest in a thermoneutral environment for baseline recordings of physiological outcomes. Afterwards, they were transferred to the climate chamber where they remained seated for the remainder of the trial. Participants were allowed to drink room temperature water ad libitum, and the volume was recorded for the calculation of whole-body sweat loss.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTrials were terminated if any of the following criteria were met: (i) participants reached a core temperature of 39.0 \u0026deg;C, (ii) HR \u0026gt;80% HR\u003csub\u003emax\u0026nbsp;\u003c/sub\u003eor \u0026lt;50 bpm, (iii) systolic blood pressure \u0026gt;200 mmHg or \u0026lt;90 mmHg, (iv) exposure time reached 3 hours, (v) participants showed any severe and/or escalating signs or symptoms of heat distress (self-reported according to the modified Environmental Symptoms Questionnaire) that progressively worsened over 3 x 5-minute periods from when they were initially observed or recorded, (vi) volitional termination for any reason.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome Measures\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProjected time to reach critical core temperatures\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCore temperature (T\u003csub\u003erec\u003c/sub\u003e) was monitored continuously via a rectal thermometer self-inserted to a depth of 20 cm (Mon-a-therm 400TM, Covidien; PowerLab C, AD Instruments). To determine the projected times to reach a T\u003csub\u003erec\u003c/sub\u003e of 39.0 and 40.5\u0026deg;C indicative of heat exhaustion and heat stroke, respectively, we calculated the rate of change in T\u003csub\u003erec\u003c/sub\u003e in the final 60 minutes of each trial and used this information to extrapolate T\u003csub\u003erec\u003c/sub\u003e from the final measured value to the target values. The additional time was summed with the elapsed trial time to yield the total predicted time to reach critical core temperatures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eChange in heart rate\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHeart rate was measured continuously using a Bluetooth-enabled sensor and chest strap (Polar, AD Instruments). The change in heart rate was calculated as the difference between 5-minute averages at baseline and at the end of each trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEnd-trial mean skin temperature\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMean skin temperature (T\u003csub\u003eskin\u003c/sub\u003e) was measured continuously using skin thermistors (MLT422/D, AD Instruments). Probes were attached to the chest (T\u003csub\u003echest\u003c/sub\u003e), shoulder (T\u003csub\u003eshoulder\u003c/sub\u003e), thigh (T\u003csub\u003ethigh\u003c/sub\u003e), and calf (T\u003csub\u003ecalf\u003c/sub\u003e) with a perforated plastic medical tape (Transpore, 3M), and mean T\u003csub\u003eskin\u003c/sub\u003e was calculated as a weighted average using the Ramanathan equation\u003csup\u003e8\u003c/sup\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"438\" height=\"23\" 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\" v:shapes=\"_x0000_i1025\" alt=\"image\"\u003e\u0026nbsp;(1) \u003c/p\u003e\n\u003cp\u003eEnd-trial mean T\u003csub\u003eskin\u003c/sub\u003e was given as the average of the final 5 minutes of trial data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWhole-body sweat rate\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo quantify whole-body sweat rate (WBSR) per unit body surface area, the following variables were measured and subsequently inputted into the equation below: (1) participant nude body mass (NBM) in triplicate on a platform scale (Model No. KW-4050-150+, @Weigh) before and after each exposure, (2) total amount of water consumed during each trial, (3) trial duration, and body surface area (BSA) calculated using the Dubois \u0026amp; Dubois formula\u003csup\u003e9\u003c/sup\u003e (\u003cimg width=\"429\" height=\"22\" 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xZABcuG7LEgV/3XPON6vWqttO1isfr22SuPKIz64ey33J6+h/yp+LIGf1Q9M0ZxzZ9Kc3NY+79BXxgUQVk70P/arQvoh6KYKmp7Dmh1MguGWJXgkxTHwt7W4TriPgRvwnRP47q4Dvi30UbkKFyfa7Deu5WfvYSwHLMoM1HQv9eArVfXXW4SVLauJcr6LIM/nREASNHmDPDsE4IIrADnjCfEjpdRXEyIYTeH6s1vFEs+Uff3G22Pmw0i/ATJxxNCvceRm5U6vHgzCzdm+E1aPUtqRom0KhV6L7VfBtWzuSPxUmgECtcplkF/4+eJqeaO9Vyk5rKBToTpQqms0ckWpGRmhnXgocLqNgbEhDYRPseuohHge0ZBjiIYcaYUFBCkodB0Rj/vdil8QQYPQLBVJW8gFMYgJ7ykRIFFZ4YnV1fUojNvXtIbeSsON+yhKijvSDBAwrG91wC0e2SrmWCfmYNxcaxi3qwK3ivMdIt3GwOggLCPZceMoUoEbR4rWADcQwRIQwVAKEVzI3pPaDvwO+sY11JtT/zYJQgSc3ln0LDBnlYD2wAYCMtbpH9A2tJfS0dtw6/UcpC7hf+OHfJBKezV6DHLFuijLIkYgMPyOEbeIsa4SZOAUXgbAGRLPdPE5XHe4CYPwe1paJosIkT4EaZqD2Mbn9Qao4tgETZS7cB1IkJoEYTpFPkyYT4hBvE9gO21NIYUWWtmIGHyNeIFCq32uOKHMtAYSrkxV1avS57hXsMUx0fuXQte2taiLqq5p2saQkQ4l09rwQgtCBHILEvsV1nvJ1NSlzsvktIJ2GWSM9/bLTw3rVqiMxnEveFp8VA+LVyk+C4XMdnDhW/h6PAHaWX9f4PulQk4Quz+fGVMd5EFwjY3Ysbv1LuXWnwnymJcM5Anuzx95V0nQnvACQ8ein4QAc2QnLENPIUO8lUcrghxW9jJC8c+t9dvyaC10S9nmWOg4udrjzV1pyqjESnYRitxgl0uprf4IiMvyzrhvELD5dGhZCJzQkhkkzNKnFdbWU3XQR0FOgIbrmaYJM/Vnae5IM0CAH6RJh20O/rxwDQS7EQQjYGz82oJ0DWj7u5IJX7y/cMN4ENkJawe8oUzaKtd42AUkCDaIR2zgwQ3yR2DRQy6yWKebzuzfjVgHXntybjK4tpVmBEEIzzbc2n13Eu7KBd9j5p6224iJwK3OT3V1xtxpmjALt1R3pBkgkBm3BNFjoTN1ATdo1SAKVGuB29WuNMJnbEXMBdwsyxrjtjqBW/zhX1kWO9NyQglGIHoHOfFCdH7eEJ3HrWxl392I+c+a+d7QMQCXdGetQtcPuEn1G2J1KLp4yFjAzPmWZKGzRdkFH7tAfBYR/vGKm0pxxSMQ4bX3XKY1x27T408Uh3uNPot51cnv27W91EeDjz+Fq9FKjWFYxMC4qOgTw5VpuEYbcc9VCU2mpT9LPMQRyJLE5vgMB2pw5Atw35hIvRH0KVo0Chdn/B4w2/F8WchW+n1mkqzVyWdClZVatLBQxdAwC3FENI7SBBET64UVsQvgV0HPCAmaSTQzkDaQKnZlemDSDaIfE0/hMm1xq+/953JH972wo+POpFayoUgNfjZAXT/4jZcERIcLMgb/ptXPsOQl9GeJS5k+b5yMoX/BkGkrEyRYp3fh33wYNzFOCtJGcB8jUVncTRn0qXPA10H/jHMVRhv93YQr08iB1uSIxfYRAjgpQwBnCtxrxDX/YcFfdtlBELQyPBR9VlZMgQkiz5D13J5Y0548sxpJNwtseZ0sd5U9eszblkxYIETUFZHwKcsBN4AXWpkLR8qpO0e2daMgtU3HJJbLfXdS/ZHapCLV883pxcNi5yKJgIWHqwFYwXJhWYas3WWaOxW3vG4/EQmILe70J+XaQh4apVOf0kvgOsSzDxqirKGC80+TZY75Oy6+hUEK0R/WIM79ZY3EucGm6pn0urDvNn1Z17Z0IcIPq2QBeXJ6DHM3iKJDAo2M540Et4a7wiJofE0RLKCDQ4nrmaoJM/Rnye5IK0CA3Z71cNX4bCGfoj0CBCxPKQlCWUr9HeXk68Sv/fX9wnKR6eC+QzqsJegsmoBQ7Hc3Kjqi59hKER04SVd2XKDYjpOkNl+lmv1EO44M0lTJetqDXXGKi7irVG+lvkkdbpwBqlERVZiWFiP/+0jgxnuyRYQBN3V7QI8BN8WTQRMm+qS4I60AAR1uz2O1hXFBOK/EmsOS/xhEvJT6BG74p/i+ZAbOmItxM/aE6MNYDXDjqDhwNuMzYaHzKxE8GCc0CNOVKCFtBxXVuEnv9ImHdKjsu5h6s1TpRRSfzzVNsMIhmAO7BoEr75jU2kbcSnBNL7c3LJn3jlM4VWslrBwBOmoT7uePtNXS0LFRl596QJSGHn/iKADh2sWkFaTY7eEkvuWcQ81wfYnDZWjNRq9QX2enVj59g2pqJmh1FU6NsFUtStdrTmkrD30oIjmp/UZ8We9Er2sf3LxJ+rlb1EOqY3uVPhsZmVQnOmo1EbEZbZ+tWb9H1Y+eozf/2bxCIMWscmK3d66AgOS9Y1/YAnUhDclhn+avCDmi/YhGLdqjvjN+iyM4sZ9uxy9KYprCWrNDVpv9s0XbPldfr7oGTZoRYSrGNXVlAZC2Ny3SJkT9bDEspL+YrtHaVx6i+qlTNNQ1Rm8f3KKtxpxge4KE2smYfZ1vvxPVbh74R7qC77cO6s8/838xUKOdwVjvrXKJ/kwCk+bNQMamp0ZE5GUJzI7+6xvmTpX9nnb2qM69+2J/joxMOe7frp3jiM2fT7f/uWbDbof+/j/Qv8IRWkE/p9W4/sroVbp2u2PO981NOoBrWbwPn42wVW0aLwyn5lYe/A2uZXpxdJYK6J53cM0V4hiBRbwiLPyWzbNHqOz72RXbIs45+BAyHh5E1pYeo/OHffTNN8qKL74IszYv7QAnmd3767POQY4atoYSfXfSscPvkeMbNWtfa7BfrrwxW3LwrnPu3c+IXnWuaHr4hZhLELRhe8LMDORMDIIf5CQOZ1smu6su9FfrLpOAedv66QJ+9LptVwNFVJWpeBtoaPTO+INZCMjx9u2L4McqIs6JhJ12JOyEqBrk78Igjx9W2IK124e3C7DDSRA0+5FrTqtfEGsGcdLthHO+62uQCxAItmrpmYtjJ89taK8WMoe1BtYSWHmdZrqTV8ZuMUhE+P1bvLGnnp9vH/nMke8YC2lnXUuBXycIeTg5xrF7eEbpHAT5RDZ9lzK2fDVqpm7sMgTkmQiaRbh8VwZQJSCBkEHe+XVmiFz73UnnOHcVwjORWyg5XYaRUNaoIBA0osFiLPBuYF2Y+L6Vs0Eh7nZMtIcAHHNAAEUIIBB6r+HjYUQjIorTFzEqEuAcktTGGjibvhmNOAXtGq/PstDwPeaFdYqvF8+D+1svoG6KvjQSQ6SDsh2pBaBdVsMzm/RNEC5vwjzRMzeoDuRMZOGfjtJA+wmKsEbHnvF1ATeOSA7rZ4sS9lSDQcSejAEEbrBypeEW7wM+gYcu3GTigSpwa+2lc7X4zbFVVsg8R4HKui3Wwfk4itPfZVQxiPg5SS1wS7h7M+KGVA8TIF54NgrrWNl3DSB40GcBS+Ozbr2sRI9B1KVM6uVmuhDsZwjW16koCJpLHV7ViN8okDB8VfD7I1xsHAxhBqRmRFHokECq7IL81IYcqdm46RFBfJ9xjHD4t44ydvEOBdRjIKhItWEjYnhZOI8Et7Co2Wt+sug9dOy0dtlfp/rVrrh1UIFu72BXHRWtH0M/5Pwz02xUVO6kQE8dHSzC9YELs+88rHTmuVBnP1Vv8FOxo45/6DS2NB47lzjPixakGPfV2zndvWm/nY7QuWva2J5t6ja4GONj37+dpAfzdU5Rq7KHthU7OP2ERnjwBq5N0EafKympb7SPX2iwBvu97dtOAe9ZOli8nsZO1+NeKyRkAMEQXfiMNWIclIHxcB+erxUuW0MHxwlevQcpeLCIHJcDwOoWfehGxzFrrPP0HtJxMObR76+nzWuQMQQTgJhb8rBX/H9J3rogMMZaEMzx8Nynws1ZLvDdSsVO4KvTnCdwmur/Afh+iTQc45e0cHjcGTp6eq5n60HHNkcXrcX58x1BUv/uEzp49hCu5Tidhtv/5S9Bzi4mF0XH7zxcrWEHIZCgOEcgwQJ+Apa0aXh41Yrxa9WzxSBpmoY0JbMd5HSCTIXDc1j77PUDe51bO7dRUZc4N/valpA4Zy2C23zwRrGzqPE1evfUOH30exd9oyorCgfa//3dbQedd2B5nDz0q0S0RZbV4/s8e2BF2BmL4S4cRTqgjtrZYseWFfitmIu7OIUZn50QeKvnNz07F7AeqLnQKRTWBIzAZW/wsBC5nFKO+PcHqQWSLQcQjXde0NtGuLxNpoSdRu4hJohelLMpgCvRIn/8MDe0TJmj6bLNyf0GQRjZqpeUf2qeWyBOLliojbI5mfZpDZH4vUCuq/LCTLlKc85mWCbRpLo+rUwQdzTWwo/pHKkc5tvPPHMs6Tcivma+zkzEs+MXz6aPMkm+dSWJ/GBLvaAnGC+uG4Ow/4KVvyxlPPEDiD08sL0EMHkHWTJbJpPT+LnhcJx8cMPwFyAJ8T4pk0DElkpyk9tjjpS+4e6H6mawtc3WUDMXabO5JLbw7Idmy9Nm6KgSKSSS57GSv+rVx1hknZRqIn4Ob05uNRi3cvdN1RK+CurMIoIMgA2IkoUbzEVNCZNR/BwsSbaPQWjsfVJxu0cXU8xOueYQ16F7Rt0EtrbJGuoRcDNfRA3LGHAz9WcJjR7mOW6s1UqAC3MP+TmPHXCIf1Zq5rYT2LysIvVEbM/WIqXOUxXrA6GBkNxwfwr9GQgeYhiyHYi8E8L93rlUUrXwG94KLIgHDmAIQewaiR5dPC5SYaQe4eEZRwIniwBuooZGAzl7PxbNr9rUSOYpuocxrQMvOY5VG3FuYxzwpPP8KazujgZei5mWI98dhrvvYd6G+LwYQYxtN0QaEZabqNFaHA9+72JaZGj3zJa0NYTDGB+RpGLtj6x7YBVtwl43xW8g+zlj5WJOqx+fvnScGJHEWJdo3AQ907y/fbjZyXj84URzAsffPnRuxIcCxkeX6GVTHssVAX5qm4voT2n44lqib4PRF+cviQCSjdTQYH4C3DPlQBOuWri69yGQgEs9LcdAAn5GC6IiNHZE35qI4RqsCH14brZ1tNgZvNNFn13/DZU6U4JxwUnqYDV7/dQ5+s7xzYpLzZcEefuCaMX7+2Kz286ucbpegZAPpsMv8GG2Y2C/j7pe99DrQ5/T5ymN4gTNMOPbnZS2liJjOt6gvUOJFAkpAxmmfbj7LmR/6FqCwVR33XxfqAQRgRsHbyF4diUdglymkD6rQVykiB+/NDJlkUqUwIGXKr/DtCR6244kueYydY7PneLGy28i880QjeORfqkdzUz2qW7CfMfndsZ1yzHHQgabp61hKTXJ2VTCgpqtG1ugjrR59UgwSCcHajO7EZdwfYsZiuvNeXOsT7iip9pAtNdRydSgnlqPczFzPvU+7CJhtwnyLeVOIcHaH9w7GdJasH6IE8Ny+ShB8jYz6ZhhCULmnHBPfVPPYAJTKlAF6ye7eDO7cwzMPO+wC9s8zO9xqkWse+Zl9U5sUlQt2NqyI+7+jE7CoYccbdkMkYKc7e5R30GEpyXcfwa7l1NIBJIQ4GfL3bWn6CyiQWEczRgl+7whi05+bSQeroD29+9vrvCYrsX51mVYz8JOXd9HR3/lguWtiL4IJ1iY4CSeNUmkL9OYoV+unH2jZJ2z5ev36f6r2+l/pzTKK0hAhExDWAzZMgnPTMphuPxgyUGbXA8gEeqOg90Q6b/Sxg8Xu1LS5VTWucywsW6pafMME7C0BtacWUnOfFfCdj5hScxMFFOHsuZejD7MTkqtTAwZNid+5BczPo+V1xwLwGe+pkaqDdY3gpzl0Bnax7GE8wuxcs63jqU8L9z7IJEuexWAlAm4zeBUvd5+ch3dKLmgP41gkqXc08AVBD5A68bfw5yHIHLZXJYukSepEwK9yZgr5lIqoaPaQ82rj4GwlS/rxK6LxVLgBjxy4wZ9lpm2Y1IHLpVldAZZ74egUTtnWsS4UPseOq8M1rrUEAvV+d3ZJpMRblS9QiwzOlAT+x56pA60Zesap81Y/7cV6lF2AyLLv931uNh9yX4SgYUiAO/P3IZixdEy+h79Edq2j8PJ7s+Fjme1FwEKb3CR9n107VYHXLjpureFjD0lyotwHMgr9H/STF0c7ILTcF2vtpvXxATGuSxSVLbqrghBOvCxzYqZuq5Q6JcgeSXOwb2/o/8F+cV73OAu10vW6V/MxvMSNMPNxg9V/HqczLx1NtFByUX90FQMp+iJEsBa7rhMBMyIjBEhBFncecY4md2f2S5IgoBkmdO0HuVtgVqAxco+96L0YXlY6gwLnaE/q0Wp7faTzUYUHX+aEqSREaMccyQFY9giSMXncAtbEXltSNfApBxiaH3/btwHJsmu7h9MDiRh3ZXg8MnBJ0icqV/ZkRx0Yl9rQjifyLK/kC/gs2grip6XBnXWk011mqWaUiYOdw8rVLCZI32fxZIWPUflSzdi7gZL61aDvGGdMV+W1BBRaF0IgQScq4n5g/31SKTqOBaI9fj9ilvIKKsRmXuehjiH2szyzbq/WOCYVLkbjYjLOvd+cgO3TCk1BC7nW2Nje7YqRUjCobO2L0WjhuA/HgRiQ4qx+4V1VxOsVzMxLv8vAfKePSiSy3qhMTuPfHbWwa7HTQWGq04eEoHngQCeBXMHirc6Sq4iSOKPqrP046UhZ2Iv/FLIeQZjHB2vP1F1grgVjF4TBKwU/s2HNsBEtG6My4UdpYPBf1zR5DGE+8nHWVFK7dUU92deuA+00MGh16klUk6q8o8ZuyQImuXuS2lmWc82GxaPtHAHSyc1r8vPIjcpGjeENesDJ3eTqwEOUljgLmQQjduj2yK+dfyQz0/Ub82ZQaMlCIWL9Vsgn4gcnenOWIwnCQ3LHZiXxSrH3PlcvFzBAdzfbv1yUzut201UfwEh+50DtB+ap0hwN+2cx6WWbQ7Ud9N3X9kBXRUkyO3ryCVceH7a8eCGfrLsArRKBcoFToeB8NHgyR00teOBvu5kGdrr1ImoIk5AG/Htj4v77RrGiM/M0hAHgfHPUsvSbGPpIznLflwzNQ+I80XwZu+eHsGcz/XiNCJTZVf03euuUP1gepBLPmMshzbdDzdD65ZA+R4CCrIkYiejLYvnM7dhPdcmNLDkNkibQk3zf82WAwwLXgNIOvRxdtyStUz2AVnHZtdcAcG4Ro3b8VibMFZCppQs4g8Pv2zTwSX3XfDCZQeJwBIiwGWjNux54Hh/bJYeu5/MupVxWVxfdt1Z6tRYd40giCdZu5nORF9bISLTvzW1YuAks9dP7XUWN96l16o+Q1CEn8X/SS5McJIVb72rzXadJefZbW8gj93t2VdfC614mCXSM3WZVmDA6ydH6OZNx4q6Yv3f0SbNYJbTgma3nmUjMILAsYUlJWozDTeRcwjHUBB+2SD/S5C9Bq5VwyV/kNaD3V6pYmdrnHJE0xhBBEN4+CtM5nSDzKUHI8Tntua0acCYLEQH+kAifFg33upNC1A+1zm3izZlBGvuLNq4XPPFU1BkCNhI9LPcvhFq3o3ADDNgoRz7M+I9UHcxW/oHnM41R/dMgbK5wBCElz1gFZKXRpqZASasYnHNIiLpdsP5jfbi2vG4qWpGFtOzAt323E/aPixwOeG35hrChjZnzGeR3j1ZiJ/P1U20mW892Ubrhvh/M57RiEBe2ISytURAIiAR+BEggN9d50a8WdxD4MDTOERQw5sIvMDg9iCIRc01xVV2YY27exBRrAd5CM7tZ3ASJOy9dv/35ESKjEvNmdNrMCdpHS+mIMI1z25zkqfq2uy5zr+hbxHJaY/2zLS2KVjnzsbepd/9yg39GrcoRDoTGC/ujBICt8lRbPTKSdBSrGfmPAl3oWU9q+7PHc3IHeMBAimuN8tlhgTliIrMbnkwovqmdLdIx4FgBU7JMcLJWzO7lHhOw0KEA20BeYIQmrULLyCcLCfBsyE7n7s09SIsNiBCYGW6e6vrc+BqJt8ULs6MgRmZ3brWOvOZI7FnUGsk4s2cJgR6vByu7UV9cVI7WdbdkUmqzOJCXJJ55CASAYmAREAi8B8CgXiAAOqsrnR8Gw8QqER+tL1IvfHWHqLPbqen17DAEZGet+7PujgdBxJO3z27jYpHTxNyys3CUpGVpBmBAZ87X2v5iP7+NyrmDc9tCf0yI+ZZCdp81jPLbSXSakCelstDmEuPxVYHIbKGu8y3f0dSTqjUFQtLDHQ8U/2lhg6KrXEpeaSsPok5WfdkaJysNbMVjhlrvuRsoXerfe7MARHZR8xXuG+5W9M0e1lcyfYZ853DyOTNPdODIizym+baNiPZ8tb1LRTcZdIeb1lp7v5lsjS5DImAREAisBwRcCK9EBe6n/dgV6lza5dD49xgCzpQVxS57F4ucjiRRDjrXIkozLVUgUTCDvg3H5q5MLqRH+3cKc9s8cGzzm0H3iJED1BTWrkRY1FM0uinG+l+b8nsu9vOIvcZrHGco/FV9Mmy7oEWeB1jVXTFtJ59keRwuUtj0Na9+i9G5wRBK0RJD3xgBWlmtp7ZZhQCc9brzG89Szzos+Qqs1J85GkhYVJn5TBDEjNamVFrlSAXVhSksMLVV+ucnPbpRgXmikid527LMxAha3Sq5VrNlFbEmjrPOYyyNczPkrP95yLcccvhk1Q2WNAX8vk0xg9NWp6/57MSOatEQCIgEfhxIcCu0hAnc1vE8aePT2TOy5Y0lhWhiSCnDLnKCt2vomoHwjRHpoRF7Fskjs3ltgQnWXHrWhUqE5x1zp39NZPEWce3W9I0aSCesyvCqlOLnaVtK87yihJu1Qx7zWxBg9C7WaRDyCaej1I7yi3Nl1YjPp/1oF+EHivr9Sk/Qm1eiNSzpG4zyrHgSJ3TLL8TGXqKUYHx/aYn/Z3vfhPEWHAimCWHMyuqc1nALMtWrv75zMHrzB4UYRLQ1ICPeOLcJ6tsMB9G+Zx/1kEC+axJtpEISAQkAhKBZYAAlwcTCdCSE9Q+0crASU57P4ImLfMoVlqN2OstNH6rFtUxVFEtwGqNjAZIbpssO8tI0PrMvGdm5Gb6bH1sPeNM+tnTatg7xd1xWaw6ca1YynnDzTpG9bayUOmLyWyVy64BM/IQzSeiT51HlFUqhY5tHvG9ndgg4VtGNyqnlvBBWN8EYb19noRwv40QWJrdbRx3YyZXZMhHJ5f3HFhY1qAIi/ym7c+yHC6+skHGWzsfq2BKx+cRJPBEX27ZWSIgEZAISARyIrBUedCM8mAIECh1UfHWm2kpNAaudiKVB5aSch6cZPaN4nHn//h/vyGHWRYqfcFIUJvBKjfVvocODr5GnBvuJsjZZRs5s48xiiiB7xAlwF7VdIIGXZfhusxmPRuiIMxWnGcrtV5mNmRzJYuNlzPKkO7CInYodZh+5HDT5dKAJYgWrJdZaihm24eV7mG+fvnst7o/g4Us36LlWQlLHgQpzzniRA76s1RjXlY35lPSn/1HcZvK32aJgERAIiARyIHAEuVBsxLUBt7aAokZaJCtFpNBwlRnTH+dTh8qhz7NEdenGcQONTandXyesk4rbce+7bTtNyB9tqoE8Xqbr5+kcuRc4yDNfGL9bQTNsiyhZ85ksbyo/DLpc8vEgz45qtBId3ES6S4aRImo1ASm3NciOsHdyKl1ARGeZvZ5LnTOubY4TUam5Lg87mXL9ZmB3VkFqYeCJ9k6l1aYPdvtYZT1QQRpjnQP2fYrsBC515Deg/HLyM+yF0a3r2lewmK6dV2cVLa5JJ6Cg8eYL79afJ4cbul80o2Isk6oVdY8Vi9ScDzJj44x3/N3mz7JHmRfiYBEQCIgEXhCBJYgD5pBlhwgYMkJajlwYPr6KeeG4kYa1NZybjO6+a1jhceW28x69h3cW0PXznfOOgnRmjgPTgJShwLpr71Ln3X4yOlQk/KmiXqbsMjF1qDCCkpK2cmb4Aa/LJv9q30OlI7S6G7PAI3fdqNgemhFRhfnfGWRqvvnr6MYJyTruMoAH7C8cbkEW7oLr9dLpW1ITpuluLprRxuozGUaGUGEp0uMYqTKQL/q/ilEj6ZHYqZqjyJBF1v7ksvrxJPyYtx1I8hwjhqJiPKc99Yp9NNOL4hh5Ary9qcTO0HAsuxXrJvz4vKRoTbnfIXRrbXlEuiLhL5m7UqXchm54upBzhK54vKdQ8yVxUqXy7JGli4QaU0UaBir2zB/hsTD8+Jsa5BfTriFjCjbSgQkAi8aAvht1c60nFAvrz5Hg6tcjqbxMDug5j1Q4UHbM4bSV4drudi8A5qfvPrNO7Bs8FwQeNI8aLiPZg9s2Obs1DSQibt0sFhQoLhQ3+PxUGnLNfroPR8np00LDGBOElB66OuRj+it4rNcx9Poi35VqJxw1uemb5REPyNatNi5Fbo0EZCKVBye0+Ozd1/aItJrcF+DMG5zRuY0EjcnIkHfRSTouQ4/CKB5JCUTTa1GbrbhbOlNHDua5XzqFePyNgU5EpSK9jNGQtRMR/fwjFKAtBr8xwlAkw5kJc+U2iOj9iilvA7XRtyMjVhDgpzldbPZo0Cb24+kZbXPa79ipvT95lu03H6dMiVUHea6pPGMsMnY5jsHrzCBY/JamQQWADvjNkjGLS0hbY5rmxfgaJRPvrZ8x5LtJAKMADSgMX+kWumNdZBPUUQNS4lMbgSAmebvCqi9c530WEWNz2dIdPBiqW0oOqG+PX6Lat2q487A/llHY5caw9PR2zpBQwXurIQNVRkcd44o2oY9G9TJc7e01aHQM127vK+WFwJ4Rq/46cYQNW7Msa5Hf6BLzX/IxklW/HTVJuK/TYlSH0bbP3xMl1K6iTQcb4ao4U3bcH+6nDQ2VyX46d+gTdKn/4Q6nv+UO1Ht8oJ2mazGshIt0D2aa/X55yVbPAbPYo7Fry5zT8N6xpUm5gmaWOqJ5Xg/WgTwPYi1r29EKRJEb9H8RvNUILj/mfVuJcj1AL2tNHmnFpVR8id5uKdjNapfibBAeRH9n8eFCYV2aWfWN6rkQVASIPvyGS4CeGk1Dr9acm2OCr5SHeOXwrEwFTi0voC2wQ+Slsda8ELuuH2+AiTvgPr+bIeGGqnSkpYHbrLJ80dg3mLpz3+Jy2sFRkWDfn0M9S5960pyVjLIe+V5FEbPe6xsDZ/FHE+8yMQAVlLhCJzc/WYZqyUcXg71AiMgLGDUp+gRn9rUtDDrFxcrp02NKBXD9S3zs5zboRLFzu/0xcbW+5XONW4ULFcWtAa8Lasdsb4YgaR9XeEnN8hd0zKx4AkrGfWp+puPYZEaj3OfcPi3jgRmz7YIuyhYXdVLscefOgpsayLIVBbCr5mkvV8V0ZB4VI296c+aRPQF/lrIpf8IEZAEbREXld18nfqUXrLOhTfKy9TWfwEaNlQ5WOSRt3B/keNzt2cxxxMsL6mrCAJRXEYQSM4UK0s1oxznRUHAsEApiuc07g92TC6cYy3NVhG34n1nkWswA3C4ysjgc9yCHQjDUqWonlPY0zO1kWW/HMaaGtWqa1vozccqko8+2cX2ba8m2vYZ9X7o0/yqtKItzRdBjvI0EZAEbZHoWnqrqfqV+slmlHao1/XMtSpzT/AsRPDPYo5FwpjWTQR5ND8A6UVhdJBeWXh8qZB98ccpe3AjpioNihCM1bnxR7EGRPe2Tt6hrf0HaE9dJw3q1dTH2rLp61Szx0+dcEVSdR/X41Wn2tZp7rohhfNTVsOIFfElW6/wYhBrOVGniD44vNXVVDoyQiXn71Cty+bGFOlkUFLGnx/BssaNsFsU6/3uBkKmdA+B38WPypXfxfbUnVUG8TnvBwFVQhsH/VVsvbtO0U9DaxV0CWtbom0V9toZ36sYP4C9bkxYwHaVrdROnqhTjbmxp0CASkdHxZ5WfQktGcT2wFVT1QaVcRG4EmkWrv6BDVQUHGQxNAX6NAwNN6NNoJ8+fiud7xRuX+FGrFz5QNtT16UOerDWO51UPn2DDuxB4JjpIp6AixhWxMwuR06pADxOFWJFvKws/GzyJzXa3sYIrj0W6Q1Q7+1O8kMnlxYQ4NtOAdpGnw18SD/4F/0+/eJ/keQOXhgEJEF7wkslAhkQCJFv4ETqdAnR/QwntX3C1WTu/izmWKqFi+AERG/AIrlUQ8pxfiQIDBdsVifbKOauK1V6tYTAf2t/TewkHVFuT66mDe46utq+mq4qRXT4ziStXu+mse3lFOlE4ucw+rca/fER4aP4Mx/RfjG3fwiWuUmiOy4VOYC0GjfcmHqA+pgg2A4jzY2RjHm+wz6ubhuXvKcJ/E4cTLha3Lz+NWL941P40CJvU6OiskiVaW2LcluxV6Pt1fYSY6+3sdcN2OuOhLVpFyIYXf4hlfek137p0H/+k9kal1+N6FXU+wrRY54DPznA1THVSpqrrhRBAB3xIIBHF4/TRdpEU626OLdji4JzCdCs8at6J+njx186Knh8t18tApvSNz6mKZCzFjqs3p7AWouDxlrHea0addw4QA5fD/WjVOBXghNmOxhnzJvl9FDdXjrZd55qP+5w3PlZ++yGojp1a812kNTsbswRJAKN9Lilm3O+m1eef+4ISIL23C+BXIBEQCKQDwJxgb+nIkng3z1ToBZQNylTD2JDpCuD43jiR8rVghno06A3K7h3nJruGTOIPEYp/Q0r1V1BziwrFZIWioojyprtbI2J68yMIAEEGYgxch+5xiXWr8X1Zy+rq4YvQlL1HdbvUeyWtejkKCYJiGTRfHTPoC1okzLFbUkZHDP3yjo2sddmUYcwtGultt51V5CzoYIvDU1ZxS6jisqaHeT/9JO4ziwRBIA9ZQgCmLQws52zj98FcvYyxg+Pk2N7la5Fuq6ofR2d2j+rFY5VsKIp0QfaXZ1UsdaN/+YoOH4clrWvuZA1072sh0WEc6IcOEbG/Bexv0qq8B6kQawzc1iuW+xf1BeWh0TgBUBAErQX4CLJJUoEJAKCXtE486vTLK6nNHG98UCHy/NwOQVhHks1SCf0a8n9RW1auEZ7awvJhxEMO7ZRlcOTpjMzPxdryC3wH/hbrqsLl5t9XLMCSuBoeZIFj2cc+F0X/huIW+ZykUGDuMEdippwwfiaE3dJfO73CmH1chHSYuDkJI2h/rPYU5LOzPz8FPb0SYK48WgJbVryuUzjG0SvSUR7wugV90oa1wVrxXUpwIXjtTBR1s29ZrOO5XPPe0sKsZcU/ycKXE98qGtuqTPLB0LZZhkjIAnaMr44cmkSAYmADQGh/cJjHe4+q1CIdTZhXWPXYRZ9kU2cb/XPmnYjm84sxxrs1ypBrox6ufFDuCyT9WcGETItcwFYt0ziBwucqIhiENIEGUyMnXCTJs+dJS2GpemCbzX4JUib5eAVnxPtc79CQfg9k8T405M0gnOltnPZ024w0RMDUZFJ9LBWQdp0zykkijVIG5kBCVSVbMlLvdcL3aVLfPtjfcBTf3uJh5XDSQSeEgKSoD0lYOWwEgGJwNIiYFnIVuNBnx7AaVjX9ACnvoB1LUP6DSNRs0GOEv3T+xmWtkYEEySsWdZOjDVUU6qGLX2nZl3cqoQr0xqXoAFL06+ZljXDumUchpUqoT9LKFTTx06e37CIMVGyLGJWRKTOc9v0Z9xvGnvSgUtJBv/mdK+FWQbfZ2lifDEOp8SAUL8KOjgEE5hED2tNJW0gnsKmlsn6lQbkCE1GdWF5e+IjOkWj2GmpCwTVT7DkPfGIcgCJwFNFQBK0pwqvHFwiIBF4KghEB2IrbyIc8pwRYYmSE+KhX20GBGSK+BP6M7gy3YVRGqjZG3uw/TYe19O0mrVmI1epN1Ye802XUU0NBPcB/oyT2U5Te01LbOWhD8U8A/uROFlny44xxspDt5MjPOObNWsbj16hPh3jVibGpRG2qiWPy+u3jpgejV3//iZdUZAWArsqAaGMDtTEbq48RIO1LjVk7jUAYZo90CGBM7RWHvwfz93ZqYmIVt5TFQ/HyWanqb+mReM9cSQnfQ8czeOdnw1oH7TfJP3cbXFu8n9yfnMQ1VeipJzaq33/1m3q6VEcrjX6LLHW7HCn9pgUx89/sn/W5YfmraoPmrBPhSZNDGlaLQO24AUuI3eXozNhUjs/jQhM3lem8k1cd1HpovEoIUltyl2EMZhlD43ZToKAibK9a8fgoDatdfZuk2PC5fzX5QqBnz1h0o6nclfLQSUCSQhIgiZvCImAROCFQKDQv5Oqe+qQCUKlOuTI60OqCNRXFOkoEC2ZwTqWvK3yHdXk7YpA9D+CNBvnEUegqAXhbj10rDXW469TEN+I1BpIE9FRS8oHPVTXVUfu9ePUer4jkfYidQzMP5Mh0axIaItxL4txu5D9wUg/kRh3DON2JsZFUMJObx0FkeZC7Qng3G3qcF0nZbSLDrrX01jrebqDNBu816htr5kuHCeWxdwa5lZzzV1gptmo2GXgelDgiqhVzP3YPBcS++0iv2MUaTbOwzL2CdJsjMdCnVFqU3bT1iKVU3BohPrIgd4JnHc5NtvScLDVksnYO3ZRGhMvL/ZVxPs6Rueg0WPjXapmENHnIujAf/W6GnnzcTzq0ij91Kje4bQaXX7ylkxo9X/zMzrzRhFFYjHSh7po64YSmrhdm1Q1oP8q6jkj6e3WT5W8a3m+EF8MucgfLQKSoP1oL63cmETgx4UAssGrqxCp2GTWwLuHNBBmcCaiGzerjY1EnBoim+cKKVzUTY1NSByB497FeGRneHgGnzcan4sKA5wtfxM1Npqf2MbMNkZGorSQca0KB+beeB+8Ct6vWMaji3ECk99eZxzz7emRuejwb2cc8XkENIlqAdhvYhxgxhGifIjqAqhHaGEkPrSdt/DgWpgNfF0uHQeyVt/hxHyP7gFv6yqmo1je2U/VDj/p2+e01auNHGxcFWAjBo2XU3x0iZp5yRsbbDUWH6GeYmIfBqmrVq/NogIMYkefUkajH9cXTu7muSMgCdpzvwRyARIBiYBEQCKQkeTCitYx0Qpy9Ya6ehzFzisWXuxckLM9Perb92+JHG9pCWwl9BKBZYqAJGjL9MLIZUkEJAISAYkArF1c7HzimHam5Q21ffU5bXB1KG8XJVzf2vqTFepRaOrgDpfkTN5QLxQCkqC9UJdLLlYiIBGQCPzHQyDcPSxcqptmUNtgJv/9s4t1U8Ej4bbN7kjNfzzZUiLwLBGQBO1Zoi3nkghIBCQCEgGJgERAIpAHApKg5QGSbCIRkAhIBCQCEgGJgETgWSIgCdqzRFvOJRGQCEgEJAISAYmARCAPBP4/we9+AyuwrLcAAAAASUVORK5CYII=\" v:shapes=\"_x0000_i1025\" alt=\"image\"\u003e\u0026nbsp; (2) \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBlood pH and pCO\u003c/em\u003e\u003cem\u003e\u003csub\u003e2\u003c/sub\u003e\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBlood pH and gases were measured at the start and end of each trial using a standard finger-prick capillary blood sample and a point-of-care analysis system (CG8+ cartridges and iSTAT-1 device, Abbott). For each measurement, a lancet (Safe-T-Pro Plus, Accu-Chek) was used to pierce the fingertip and a 200 \u0026micro;l lithium heparin Minivette (Minivette\u0026reg; POCT Lithium heparin LH, 200 \u0026micro;l, Sarstedt) was used to collect a blood sample. From the Minivette, 95 \u0026micro;l of blood was dispensed into the well of a CG8+ cartridge, which was subsequently inserted into the iSTAT-1 device for immediate analysis.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSymptoms of heat distress\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSigns and symptoms of heat distress were monitored throughout each trial using a modified version of the 68-item Environmental Symptoms Questionnaire\u003csup\u003e10\u003c/sup\u003e. From the 22-item subset that comprised the Subjective Heat Illness Index\u003csup\u003e11\u003c/sup\u003e, we identified 8 major themes, which were used as prompts for this study \u003cstrong\u003e(Supplemental Table S1)\u003c/strong\u003e. Every 20 minutes, participants rated each symptom on a scale of 0 - Not at all to 5 - Extreme. The measurement frequency was increased to every 5 minutes once a rating of 2+ was reported for any symptom, and trials were terminated if participants\u0026rsquo; ratings further increased over three successive 5-minute time points.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor data analysis, symptoms of heat distress were classified as categorical and coded as either (1) Yes (value: 1, symptom reported during trial) or (2) No (value: 0, symptom not reported during trial).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTrial duration\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTrial duration was quantified as the number of minutes of the study protocol completed, defined by the presence of T\u003csub\u003erec\u003c/sub\u003e data. The maximum value of this outcome was 180 minutes (3 hours).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTrial completion\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTrial completion was a categorical outcome coded as either (1) Yes (value: 1, trial duration = 180 minutes) or (2) No (value: 0, trial duration \u0026lt;180 minutes).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eReasons for trial termination\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eReasons for trial termination was a categorical outcome coded as either (1) Symptoms (value: 1, severe or escalating symptoms of heat distress either self-reported or based on the modified ESQ), (2) Core temperature (value: 2, T\u003csub\u003erec\u003c/sub\u003e \u0026ge; 39.0 \u0026deg;C), or (3) Trial duration (value: 3, trial duration = 180 minutes). Participants did not terminate the trial for any other reason; therefore, no other termination criteria were coded.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size Calculation\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSample size was determined \u003cem\u003ea priori\u0026nbsp;\u003c/em\u003ebased on an expected difference across conditions and the minimally clinically important difference between sexes in the rates of core temperature change in response to the experimental conditions. A fourth condition at 54\u0026deg;C and 13.1% RH (54/13) was included in the sample size calculation and trial randomization to allow for the investigation of an exploratory research question. This condition is not relevant to the current manuscript. Using a simulation-based R package\u003csup\u003e12\u003c/sup\u003e, we entered the following information: anticipated rates of change (\u0026deg;C/h) of 0.49 and 0.57 for 38/81, 0.67 and 0.75 for 46/46, and 0.86 and 0.93 for 54/26 and 54/13 in males and females, respectively; (2) a common standard deviation of 0.05\u0026deg;C/h based on typical measurement error; (3) \u0026alpha; level set at 0.05; and (4) N = 12 per group. These parameters yielded \u0026gt;80% power to detect differences between all relevant comparisons. As there is no prior empirical work in this area, the estimates for each condition were based on pilot data collected during protocol development, and the estimates for potential sex-based differences were based on the minimum difference between males and females that we deemed meaningful (i.e., a difference in survival time of 30 minutes). We aimed to recruit 30 participants in anticipation of subject attrition, for a minimum target sample size of 24 (12 per sex).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomisation\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExperimental trial conditions were administered in a randomised order, and participants completed the study in male-female pairs so that any potential order effects would be matched between sexes. The randomization sequence and order was generated by selecting for 24 sets of 4 unique numbers (range 1 to 4) from randomizer.org. Each set was assigned to a pair of participants as they were enrolled, and additional sets were available in case of dropout.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDemographic and experimental data were presented as means and standard deviations or 95% confidence intervals for continuous, normally distributed data. Frequencies and percentages were used to describe categorical data. All analyses were determined \u003cem\u003ea priori\u0026nbsp;\u003c/em\u003eand documented in a Statistical Analysis Plan \u003cstrong\u003e(Supplementary Information)\u003c/strong\u003e. Analyses were conducted using R and RStudio (Version 2025.05.1+513, Posit Software, PBC, Boston, MA, USA). All statistical tests were two-sided with the accepted significance level set to p\u0026lt;0.05.\u003c/p\u003e\n\u003cp\u003eLinear mixed-effects models were fitted to examine the responses of the following outcome variables: projected times to reach critical T\u003csub\u003erec\u003c/sub\u003e (39.0 and 40.5\u0026deg;C), change in HR, end-trial mean T\u003csub\u003eskin\u003c/sub\u003e, WBSR relative to BSA, rate of water consumption, and blood pH, pO\u003csub\u003e2\u003c/sub\u003e, and pCO\u003csub\u003e2\u003c/sub\u003e levels. Condition (three levels: 38/81, 46/46, 54/26), sex (two levels: male and female), and trial duration (where appropriate as a covariate for time-dependent outcomes) were included as fixed effects, and Participant ID was included as a random intercept to model the within-subject dependence of the data. The compound symmetry covariance structure was selected based on an assessment of the Akaike\u0026rsquo;s and Bayesian Information Criteria (AIC/BIC) and log likelihood ratio tests to identify the best fitting model while also considering model parsimony. Models were estimated using the Restricted Maximum Likelihood estimation. Model residuals were examined for normality, homoscedasticity, and influential points. Significant main effects and interactions were probed using Tukey\u0026rsquo;s honest significant difference-adjusted post-hoc pairwise comparisons to control the family-wise error rate. These analyses were conducted using the \u003cem\u003elme4\u003c/em\u003e and \u003cem\u003eemmeans\u003c/em\u003e packages. Model fit statistics were generated using the \u003cem\u003elmerTest\u003c/em\u003e and \u003cem\u003ecar\u003c/em\u003e packages. Model outputs were extracted using the \u003cem\u003ebroom.mixed\u003c/em\u003e and \u003cem\u003esjPlot\u003c/em\u003e packages. Model diagnostics and goodness-of-fit tests were run using the \u003cem\u003eggResidpanel\u003c/em\u003e and \u003cem\u003eDHARMa\u003c/em\u003e packages. \u003cstrong\u003eSupplemental Figure S1 and S3\u003c/strong\u003e summarizes the results of the diagnostics tests performed for these analyses.\u003c/p\u003e\n\u003cp\u003eSensitivity analyses were conducted to ensure the robustness of the final models for these numerical outcome measures. In separate analyses, Trial order (four levels: first, second, third, fourth) and Previous trial (five levels: none, 38/81, 46/46, 54/26, 54/13) were included as fixed effect covariates to examine potential order and carryover effects, respectively \u003cstrong\u003e(Supplemental Table S2)\u003c/strong\u003e. Any significant effect of these design variables was probed further using Tukey\u0026rsquo;s honest significant difference-adjusted posthoc pairwise comparisons. Estimates and significance levels from the final and adjusted models were compared to determine whether the interpretation of the findings are impacted by trial order and carryover \u003cstrong\u003e(Supplemental Table S3)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eFor survival analyses, Kaplan-Meier curves were generated and Logrank (Mantel-Cox) tests were used to compare the curves across conditions for the following outcome variables: trial duration and projected times to reach critical core temperature. These analyses were conducted using the \u003cem\u003esurvival\u003c/em\u003e package on R.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGeneralized linear mixed models were used to examine proportional differences across conditions for trial completion and symptom prevalence. Condition was included as a fixed effect, Participant ID was included as a random intercept, and the compound symmetry covariance structure was selected. Models were fit using the maximum likelihood (Laplace Approximation). Model dispersion, residual patterns, and random effects distribution were examined to evaluate model assumptions and goodness-of-fit. These analyses were conducted using the \u003cem\u003elme4\u003c/em\u003e, \u003cem\u003eemmeans\u003c/em\u003e, and \u003cem\u003eDHARMa\u003c/em\u003e packages on R. \u003cstrong\u003eSupplemental Figure S2 and S4\u003c/strong\u003e summarizes the results of the diagnostic tests performed for these analyses.\u003c/p\u003e\n\u003cp\u003eA multinomial logistic regression was performed to examine proportional differences across conditions for the reasons for trial termination. Condition was included as a fixed effect, Participant ID was included as a random intercept, and the compound symmetry covariance structure was selected. As the model failed to converge, its assumptions and goodness-of-fit were not examined further. This analysis was conducted using the \u003cem\u003emclogit\u003c/em\u003e package on R.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor exploratory analyses (i.e., generalized linear mixed model and multinomial logistic regression), results were presented descriptively where models failed to converge or satisfy all assumptions and goodness-of-fit tests.\u003c/p\u003e\u003cp\u003e1.\u0026nbsp; \u0026nbsp;\u0026nbsp;Dwan, K., Li, T., Altman, D. G. \u0026amp; Elbourne, D. CONSORT 2010 statement: extension to randomised crossover trials. \u003cem\u003eBMJ\u003c/em\u003e l4378 (2019) doi:10.1136/bmj.l4378.\u003c/p\u003e\n\u003cp\u003e2.\u0026nbsp; \u0026nbsp;\u0026nbsp;Warburton, D., Jamnik, V., Bredin, S. \u0026amp; Gledhill, N. The Physical Activity Readiness Questionnaire for Everyone (PAR-Q+) and Electronic Physical Activity Readiness Medical Examination (ePARmed-X+). \u003cem\u003eHealth Fit. J. Can.\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 3\u0026ndash;23 (2011).\u003c/p\u003e\n\u003cp\u003e3.\u0026nbsp; \u0026nbsp;\u0026nbsp;Beltz, N. M. \u003cem\u003eet al.\u003c/em\u003e Graded Exercise Testing Protocols for the Determination of VO\u003csub\u003e2\u003c/sub\u003e max: Historical Perspectives, Progress, and Future Considerations. \u003cem\u003eJ. Sports Med.\u003c/em\u003e \u003cstrong\u003e2016\u003c/strong\u003e, 1\u0026ndash;12 (2016).\u003c/p\u003e\n\u003cp\u003e4.\u0026nbsp; \u0026nbsp;\u0026nbsp;Wagner, J. \u003cem\u003eet al.\u003c/em\u003e New Data-based Cutoffs for Maximal Exercise Criteria across the Lifespan. \u003cem\u003eMed. Sci. Sports Exerc.\u003c/em\u003e \u003cstrong\u003e52\u003c/strong\u003e, 1915\u0026ndash;1923 (2020).\u003c/p\u003e\n\u003cp\u003e5.\u0026nbsp; \u0026nbsp;\u0026nbsp;Fox, R. H., Goldsmith, R., Hampton, I. F. \u0026amp; Hunt, T. J. Heat acclimatization by controlled hyperthermia in hot-dry and hot-wet climates. \u003cem\u003eJ. Appl. Physiol.\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 39\u0026ndash;46 (1967).\u003c/p\u003e\n\u003cp\u003e6.\u0026nbsp; \u0026nbsp;\u0026nbsp;Garrett, A. T., Goosens, N. G., Rehrer, N. G., Patterson, M. J. \u0026amp; Cotter, J. D. Induction and decay of short-term heat acclimation. \u003cem\u003eEur. J. Appl. Physiol.\u003c/em\u003e \u003cstrong\u003e107\u003c/strong\u003e, 659\u0026ndash;670 (2009).\u003c/p\u003e\n\u003cp\u003e7.\u0026nbsp; \u0026nbsp;\u0026nbsp;P\u0026eacute;riard, J. D., Racinais, S. \u0026amp; Sawka, M. N. Adaptations and mechanisms of human heat acclimation: Applications for competitive athletes and sports. \u003cem\u003eScand. J. Med. Sci. Sports\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, 20\u0026ndash;38 (2015).\u003c/p\u003e\n\u003cp\u003e8.\u0026nbsp; \u0026nbsp;\u0026nbsp;Ramanathan, N. L. A new weighting system for mean surface temperature of the human body. \u003cem\u003eJ. Appl. Physiol.\u003c/em\u003e \u003cstrong\u003e19\u003c/strong\u003e, 531\u0026ndash;533 (1964).\u003c/p\u003e\n\u003cp\u003e9.\u0026nbsp; \u0026nbsp;\u0026nbsp;Burton, R. F. Estimating body surface area from mass and height: Theory and the formula of Du Bois and Du Bois. \u003cem\u003eAnn. Hum. Biol.\u003c/em\u003e \u003cstrong\u003e35\u003c/strong\u003e, 170\u0026ndash;184 (2008).\u003c/p\u003e\n\u003cp\u003e10.\u0026nbsp;\u0026nbsp;Sampson, J. B., Kobrick, J. L. \u0026amp; Johnson, R. F. \u003cem\u003eThe Environmental Symptoms Questionnaire (ESQ): Development and Application:\u003c/em\u003e http://www.dtic.mil/docs/citations/ADA264127 (1993) doi:10.21236/ADA264127.\u003c/p\u003e\n\u003cp\u003e11.\u0026nbsp;\u0026nbsp;Richard F. Johnson \u0026amp; Donna J. Merullo. Subjective Reports of Heat Illness. in \u003cem\u003eNutritional Needs in Hot Environments: Applications for Military Personnel in Field Operations\u003c/em\u003e 277\u0026ndash;293 (National Academies Press, Washington, D.C., 1993).\u003c/p\u003e\n\u003cp\u003e12.\u0026nbsp;\u0026nbsp;Lakens, D. \u0026amp; Caldwell, A. R. Simulation-Based Power Analysis for Factorial Analysis of Variance Designs. \u003cem\u003eAdv. Methods Pract. Psychol. Sci.\u003c/em\u003e \u003cstrong\u003e4\u003c/strong\u003e, 2515245920951503 (2021).\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"physiological tipping point, wet-bulb temperature, extreme heat exposure, human thermoregulation, climate change impact","lastPublishedDoi":"10.21203/rs.3.rs-9227989/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9227989/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Assessments of future human survivability under extreme heat with climate change have recently been anchored to a theoretical physiological tipping point: 6 hours of exposure to a wet-bulb temperature (Twet) of 35°C1. This framework broadly treats a fixed Twet as imposing equivalent physiological strain irrespective of the temperature-humidity combinations that produce it. In contrast, human thermoregulation models predict greater physiological strain with increasing ambient temperature under constant Twet conditions2. Here we show that multi-system physiological heat strain differs profoundly in heat-acclimated humans studied under controlled climate-chamber conditions when the canonical 35°C Twet survival limit is imposed across a range of ambient temperatures (38°C with 81% relative humidity (RH), 46°C with 46%RH, 54°C with 26%RH). At 54°C, projected times to heat exhaustion and heat stroke were reduced by ~45% compared with 38°C, driven by an accelerated rise in rectal temperature and accompanied by greater cardiovascular strain and disruption of acid-base balance. These findings demonstrate that the physiological tipping point for human heat tolerance at 35°C Twet is state-dependent, and that utilising a universal Twet survival limit may substantially over-estimate survivability in hot, dry environments projected to expand most rapidly with climate change.","manuscriptTitle":"Human physiology at the upper limit of extreme heat exposure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-22 09:58:25","doi":"10.21203/rs.3.rs-9227989/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0d35cf29-65f5-48a3-9e20-ee8c0898feed","owner":[],"postedDate":"April 22nd, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-08T15:40:14+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-07T06:52:30+00:00","index":2,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66699957,"name":"Biological sciences/Physiology"},{"id":66699958,"name":"Health sciences/Risk factors"},{"id":66699959,"name":"Earth and environmental sciences/Climate sciences"}],"tags":[],"updatedAt":"2026-04-22T09:58:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-22 09:58:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9227989","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9227989","identity":"rs-9227989","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}