The escalating environmental heat-stress associated with global warming is a societal challenge with large and potential harmful consequences for humans. Excess morbidity and mortality during heat waves provides strong evidence for fatal outcomes. However, it is unclear why some people are particularly vulnerable and get sick from hyperthermia, while others adapt and tolerate exposure.

The Icarus project aims to provide a psycho-physiological framework for improved mitigation of the health threats associated with global warming. Combining expertise in integrative thermal physiology, pharmacology, photobiology, psychology and machine learning, we will collaborate on comprehensive cross-scientific studies using controlled lab-exposure combined with investigations in ecological settings including vulnerable and highly tolerant people across populations from northern to southern Europe.

Advanced algorithms will be developed to generate personalized alerts and advising based on behavioral patterns, psychological profiling, predicted vulnerability and willingness to adopt resilience-building strategies.

Global warming is projected to continue towards the end of the 21st century and constitutes an increasing threat to human health unless we as individuals and collectively become better in preventing acute effects, as well as devise sustainable strategies to limit further anthropogenic warming of the climate system. Acutely, improved guidance is important for both individual and public health, where Icarus aims at providing a highly improved basis for preventing heat-related disease, advising or nudging people towards pro-health behavior, including smarter use of technologies to mitigate heat stress, or adjusting medication to reduce adverse effects during heat events. In support of the sustainability agenda, our framework also forms a novel basis for developing advising algorithms relevant for optimization of climate change mitigation policy-making.

Warming of the climate system is ongoing and there is strong evidence for detrimental effects of environmental heat stress on human with impact on public health and quality of life for billions of people globally - with the most damaging effects on societies in the hottest parts of the world. However, recent heatwaves in Canada, USA, and Northern Europe saw temperatures surpassing 40°C. Documented impacts on mortality show how climate change and the associated geographical spread of heatwaves also have health consequences in regions previously spared from high temperatures. At the same time, cutaneous melanoma already is a documented and increasing public health concern and characterized by high incidence in fair-skinned populations of European descent, particularly in Central and North European countries. The incidence of 29.7 per 100,000 person-years in Denmark is the 3rd highest globally, compared to the world average of 3.4. Alarmingly, the World Health Organization (WHO) projects that the number of new cases of melanoma per year will increase by more than 50% from 2020 to 2040.

It is abundantly clear that certain populations are more vulnerable to global warming and that certain individuals within each population are more susceptible to heat-stress than others. In the Icarus project, we will find ways to identify these people and at a large scale protect using predictive algorithms. Achieving this ambition may save lives, reduce the burden on healthcare systems, support the global sustainability agenda including UN defined sustainability goals such as the prevention of poverty via improved productivity. Thus, public health, sustainability and economic benefits from this ambitious project are clear should it succeed.

The fatal outcome of exposure to extreme heat and sunlight, as described in the myth about Icarus and scientifically documented with epidemiological evidence for excess death rates during heatwaves is, however, only the tip of the iceberg in terms of public health problems and societal impact imposed by global warming. We have documented the occupational health burden, productivity losses and economic costs associated with elevated environmental heat and we have shed light on the interaction between heat stress and exposure to solar radiation. The later with major isolated health effects of ultraviolet radiation (UVR) on the skin. Our pilot observations from combined heat-radiation exposure studies indicate that some individuals, both before and after acclimatization, are very tolerant and show almost no detrimental effects on motor-cognitive performance; while others (healthy; matched for fitness and age) show drastic changes in clinical outcomes and major declines in physical and mental performance. It is well known that sunlight exposure, and in particular certain UVR wavelengths, has direct damaging effects on the skin, but there is a large knowledge gap on its interaction with thermal physiological effects. Also, there is no research on acclimatization effects and very limited understanding of the interaction between impacts on cognitive function and psychological/behavioral factors. This is central for understanding heat vulnerability at the individual level and how it subsequently affects public health - as those at highest risk become ill, hospitalized, or add to the mortality statistics. Furthermore, these interactions are fundamental for the development of a psychophysical framework and improve the ability to understand and subsequently influence collective behavior, which is highly relevant for the implementation of policies and climate change mitigation strategies.

Differences in heat vulnerability are also observed at the population-level with markedly lower temperature thresholds for excess mortality in North compared to South European countries, but it is largely unknown if this pronounced difference in heat resilience relates to a superior "physiological defense system" in South Europeans orprimarily relates to different social experiences of heat and thus different behaviors i.e., more appropriate thermoregulatory behavior in South Europeans. Higher risk taking (e.g., inappropriate "sun-bathing culture") is also a highly relevant factor in terms of skin damage (DNA mutation and photocarcinogenesis) and the associated risk for developing skin cancer. For instance, in a recent pilot study, we observed a 10-fold higher excretion of cyclobutane thymine dimers in the urine (as a marker of skin DNA damage) of Danish volunteers after a winter vacation to a sunny region, compared to their peers who freely chose to be less exposed.

Analogous to the mythical Icarus, who flew too close to the sun, our recent pilot data individual data from papers by our consortium show that vulnerable people, collectively translating into differences at the population level, arenot able to sense and comprehend the danger associated with exposure to solar radiation. If we - unlike Icarus' father - are to become better at protecting individuals atrisk and advise humanity at large, we need an improved and interdisciplinary approach to mitigate and understand the risks imposed by escalating environmental heat exposure.

The Icarus project will generate a psycho-physical framework for improved ability tomitigate the threats associated with increased exposure aggravated by global warming: from individual vulnerability to heat and sun exposure, to public health and collective behavior. The developed framework shall allow us to identify patterns and develop algorithms for early detection of those susceptible to becoming sick from heat and sun exposure. This may directly benefit public health as well as bridge the gap from individual to collective behavior which has relevance for policy-making and climate change mitigation. To achieve the ambitious overall aim, we have composed a consortium led by experts in thermal physiology, psychology, dermatology, pharmacological prevention of adverse effects from sunlight exposure, as well as artificial intelligence and machine learning - allowing us to complete the inter-disciplinary studies and sub-tasks.

Study Population

Healthy adult volunteers residing in Denmark (Northern Europe) or Greece (Southern Europe).

Inclusion Criteria

• Age 18-65 years (or your protocol-specific age range)
• Healthy as determined by medical history screening questionnaire
• Able to provide written informed consent
• Able to complete heat exposure and light exercise protocol
• No heat acclimatization or extensive sun exposure in the previous 4 weeks
• Fitzpatrick skin type I-IV (if applicable for UV testing)
• Willing to undergo blood sampling, urine collection, and skin biopsy

Exclusion Criteria

• History of cardiovascular, metabolic, neurological, or dermatological disease
• History of heat-related illness (e.g., heat stroke)
• Use of medications affecting thermoregulation or cardiovascular function
• Smoking or substance abuse
• Pregnancy or breastfeeding
• Abnormal ECG or uncontrolled hypertension
• Recent severe sunburn or UV treatment
• Contraindications to skin biopsy
• Inability to tolerate heat exposure during screening