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Dear Dr Kim E. Barrett, Editor-in-Chief of The Journal of Physiology, We would like to comment on the insightful opinion article from Dr Abderrezak Bouchama published in The Journal of Physiology, who opened an important debate regarding the development of a new and comprehensive model of human thermal limits (Bouchama, 2025). We fully agree with the main point of the article, i.e. classical models based only on thermodynamics fail to provide an adequate explanation of the vulnerability to heat, highlighting the need to integrate physiological and molecular dimensions. Nevertheless, through this letter, we would like to provide several comments and propose an alternative approach. Although the buffer concept is an attractive framework, we propose to dissociate two complementary yet distinct notions to describe individual vulnerability more informatively: heat tolerance and thermotolerance (IUPS, 2001). The former refers to the ability of an individual to maintain thermal balance (or comfort) in given environmental and activity conditions. It reflects the limits of whole-body physiological compensability and is governed by the thermodynamic principles of heat exchange. In contrast, the latter refers to the resilience of the body to a given load of hyperthermia and is based on the cellular sensitivity to heat. Thermal balance can be evaluated by comparing the evaporative requirement (Ereq), obtained from a rearrangement of the heat balance equation, with the maximal evaporative capacity (Emax), which depends on both environmental conditions and the anthropometric and physiological status of the individual (Ravanelli et al., 2018). If Ereq exceeds Emax, heat storage becomes inevitable and core temperature rises, potentially leading to heatstroke. Most of the six elements added to the buffer by Bouchama are already included in the classical equation, influencing one or more aspects of the thermal balance. Mitochondrial function largely determines Hprod (Chrétien et al., 2018). Heat acclimation or acclimatization increases Emax, primarily by enhancing sweat production. Both Hprod and Emax differ amongst demographic groups according to body surface-to-mass ratio, ovarian cycle or age, health conditions (hyperthyroidism, diabetes, burns, etc.) and medications (β-agonists, anticholinergics, etc.). We refer to the review by Cramer et al. (2022) for a comprehensive discussion of the factors influencing heat balance. Although the impact of several factors (sweat efficiency, genetic variants such as mitochondrial haplotypes, etc.) still requires more extensive investigation, most components of the buffer proposed by Bouchama are already incorporated into the conventional thermal balance model. Thus, its added value in accounting for physiological compensability appears limited. However, we agree with the author that the concept of heat tolerance, based only on the ability to reach thermal balance, is not sufficient to explain heat vulnerability fully. Indeed, some individuals develop heatstroke at a core temperature of 40°C, whereas others tolerate temperatures exceeding 41°C or even 43°C (Singh et al., 2023). In our view, the relevance of the buffer concept lies in accounting for determinants that modulate thermotolerance. Molecular defences, identified in the buffer proposed by Bouchama, play a key role in the individual thermotolerance, notably through the heat shock response. Heat shock proteins (HSPs) are widely recognized to play a critical role in the evolutionary molecular resilience during hyperthermia, although their role in the pathogenesis of human heatstroke is still debated (Bouchama et al., 2023; Sonna et al, 2004). Some other components of the buffer listed previously are also involved in the heat shock response. Independently of Hprod, mitochondrial function might be responsible for a small amount of HSP expression (Zeng et al., 2013). Heat acclimation or acclimatization increases the basal HSP level (Amorim et al., 2015) and induces epigenetic alterations that promote faster reinduction after a new exposure (Horowitz, 2014), both of which modify the depletion dynamics of molecular defences. Demographic characteristics, such as age (Gomez et al., 2025), in addition to medications or dietary supplements, such as glutamine or quercetin (Kuennen et al., 2011; Zuhl et al., 2024), are also known to modulate HSP responses. In addition, elements of the heat shock response other than HSPs might also contribute to thermotolerance. Gastrointestinal barrier permeability, gut microbiota diversity and abundance (Armstrong et al., 2018; Garcia et al., 2022), metabolic reprogramming and the immune response to heat stress (Bouchama et al., 2025; Ren et al., 2019) display high individual variability, and their role in buffering capacity to heat strain should be explored further. Few studies have highlighted the connection between the two concepts. In their elegant study, Kuennen et al. (2011) revealed that the molecular basis of thermotolerance could also influence physiological responses to heat acclimation and, consequently, thermal balance. Likewise, Malgoyre et al. (2020) showed that prolonged acclimatization can further improve thermal balance, even after physiological responses have disappeared, supporting a potential link between epigenetic modifications and thermal balance. Nevertheless, a unique and comprehensive concept of heat vulnerability unifying physiological thermal balance and cellular thermotolerance has not yet been established. To conclude, in our opinion, thermal balance and thermotolerance should be considered as distinct concepts. We also regret the current knowledge gap between well-described factors influencing heat tolerance and the relatively unexplored determinants of thermotolerance. This highlights the need to define biomarkers of thermotolerance better, in addition to the influence of ethnicity and acquired adaptations, in order to achieve a more comprehensive understanding of human heat limits. Finally, behavioural thermoregulation should also be considered in understanding interindividual heat vulnerability (Verdonk et al., 2025), an aspect too often neglected by physiologists. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare no conflicts of interest. All the authors contributed to the conception or design of the work, drafting the work or revising it critically for important intellectual content. All authors gave final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.