Heat acclimation: Gold mines and genes

ABSTRACT

The underground gold mines of South Africa offer a unique historical setting to study heat acclimation. The early heat stress research was conducted and described by a young medical officer, Dr. Aldo Dreosti. He developed practical and specific protocols to first assess the heat tolerance of thousands of new mining recruits, and then used the screening results as the basis for assigning a heat acclimation protocol. The mines provide an interesting paradigm where the prevention of heat stroke evolved from genetic selection, where only Black natives were recruited due to a false assumption of their intrinsic tolerance to heat, to our current appreciation of the epigenetic and other molecular adaptations that occur with exposure to heat.

Introduction

Heat acclimation is a physiological adaptation by which an organism can survive and even be comfortable in an environment previously intolerable. It can be acquired in most individuals after only a few heat exposures and with minimal provocation. Only recently are we beginning to understand the cellular adaptations which create not only resistance to heat, but at the same time, protection against other environmental and disease stressors.

In this paper I present an occupational scenario in which researchers have used several approaches to acclimate thousands of workers, allowing them to perform moderately heavy work under extreme heat and humidity conditions. The scenario is the deep gold mines of South Africa and the time period I highlight is from the 1890s until around 1940, a period before mechanized tools and artificial cooling were introduced to the mines. I use this historical example to contrast how our knowledge today has evolved from this basic example.

The Witwatersrand Gold Mines: A broad overview of underground gold mining history

In 1884 Jan Gerritze Bantes discovered gold in the Witwatersrand Basin near present day Johannesburg, beginning the great South African gold rush. This area is approximately 217 miles long and 124 miles wide. The geological conditions allow the mines to be the deepest in the world, currently at a depth of up to 2 miles. Peak gold production occurred in the 1970s and has declined since then, but is expected to continue until at least 2024. The high occupational workloads and rock temperatures approaching 140°F make this environment uniquely challenging in terms of thermal stress. The critical temperature at which heat stroke becomes a risk factor under these conditions, and requires that workers first become acclimated, is about 82°F.¹ The method of allaying dust by water sprays in the early years of mining, ensured that the ambient humidity in the mines remained near 100%. The mining companies in this region have faced a constant dilemma – how to prevent heat casualties while still maximizing gold production.

The heat mitigation protocols used in the mines evolved as the ambient conditions varied over time (Table 1). From the opening of the mines until the late 1940s, acclimation was performed using 7–14 d underground protocols as described by Dr. Aldo Dreosti.^2,3 Beginning around 1940, mechanized mining techniques and cooling plants were installed which temporarily lowered mine temperature and humidity enough so that the heat mitigation protocols were eased. However, the depth of the mines continued to increase and heat stroke again became an issue. By the late 1950s, Cyril Wyndham and coworkers conducted heat-stress studies which resulted in a new, 12-d underground heat acclimation protocol.⁴ Unlike the previous underground acclimation protocols developed by Dreosti, the miners were able to complete a full level of work while acclimating, thus maintaining gold production. But by 1965, heat-related deaths again increased. Wyndham and coworkers then recommended a rigorously controlled, 4-hr, 8-d above-ground acclimation protocol and standardized heat tolerance testing (block stepping in an environmentally-controlled tent).^4,5 This artificial acclimation approach, while shortening the process, was difficult and costly to administer and reduced gold production.

Table 1.

Heat acclimation procedures used in Witwatersrand Gold Mines.

1886	Witwatersrand gold rush starts
1924	Deep City Mine reaches 0.6 miles and first recorded death from heat stroke occurs
1925	Underground acclimation being used in mines, but 4 deaths occur this year
1927	First recorded investigation into on-going heat-related deaths: acclimation modified:
	Natives without previous mining experience: 10 d light work in cooler areas
	Natives with previous experience: 5 d light work in cooler areas
1928	4 more heat-related deaths. Acclimation modified (“locally recruited assumes they were only recently discharged from service in some other mine”):
	New natives from native territories: 14 d
	New natives from local region: 7 d
	Natives discharged from hospital: 7–14 d
Jan 1930	An “alarming increase” in heat deaths even after 14 d acclimation.
	Add a 7-d red armlet period after acclimation
Late 1930	4 more heat-related deaths: modify acclimation:
	All new natives: 14 d acclimatization plus 16 d red armlet period
1930	Huge loss in working efficiency and still more deaths. Dreosti is employed to screen workers who need a longer acclimation by using a HTT (1 h shoveling rock in 95°F dry bulb, sat.)
Mar 1932	HTT used to identify 3 groups: Heat tolerant, Heat intolerant, Normal natives. Red armlet period is still 16 d.
	Acclimation protocols: HT (2–4 d)
	HIT (1–14 d)
	Norm (3–7 d)
Mar 1934:	Reduce red armlet period to 8 d.
1939:	Mechanical ventilation added to mines. HTT discontinued due to improved mine conditions. Minimal acclimation for all new natives.
1953:	Mining conditions worsen. Chamber of mines funds studies by Wyndham et al. to study ways to reduce acclimation protocols. New acclimation protocol is developed and found more effective while allowing more productive work to be done during acclimation.
	New acclimation protocol: 6 d normal mining load in a cooler slope (86.5°F, sat), then 6 d normal load in a hot slope (92°F).
1960s	Portable climatic tent used by Wyndham, Strydom, Mitchell et al to conduct a wide variety of scientific studies comparing Bantu, Bushmen, Caucasians, women, fitness, diet, and development of heat stress prediction equations.
1965	Climatic room acclimation procedures introduced:
	Miners block step for 4 h/d in a climatic room at 89°F, with workload increasing from 35 to 70 W over 12 d.
1976	Begin administration of Vitamin C which reduced the acclimation period from 12 to 8 d and reduced the % of heat intolerant miners from 5 to 1%.
1977	HTT reintroduced to assess acclimation. Block step at 54 W for 4 h at 92°F db/89°F wb
1982	Microcimate cooling is used to allow underground acclimation again at normal work rates and sites.
1991	A new HTT introduced for screening and a health monitoring program adopted:
	30 min block stepping at 80 W at a temperature of 85°F db/82 wb°F. Development of risk profile to determine fitness for work in a hot environment (age, obesity, medications, fitness, HTT results, med history). Heat stress monitoring procedures standardized (measure ambient conditions, fluid-replacement beverages, work-rest cycles, remedial actions for heat stress, communication facilities and action plans).

In the early 1980s, micro-climate cooling was introduced for the miners and the acclimation process again was moved underground.^1,6 Approximately 1/3 of a miner's body surface area is covered by a dry- ice containing vest, which allows the miners to work at full work levels while preventing an excessive rise in body temperature. These new cooling procedures together with the political and cultural changes that have occurred in South Africa, now allow a more varied makeup of the mining workforce that now includes a broad racial makeup and even a few female miners.⁵ South African researchers still today continue to use some of the testing protocols and acclimation procedures developed by Dreosti and Wyndham and they are in the forefront of determining the molecular markers of heat acclimation.⁷

The early mine conditions (pre-1940)

The first recognized case of heat stroke in the City Deep Mine, one of the first and deepest mines, occurred in 1926. The heat acclimation procedure for new natives employed at this time consisted of 5–10 d of shoveling at a reduced workload as they progressively moved to hotter regions of the mine. The modified workload consisted of an 8-hr shift of “lashing,” where 2 natives worked together using only one shovel, alternately shoveling for short periods. Despite these precautions, by 1930 the mine depth exceeded half a mile, and 8 heat-related deaths occurred during this single year. These conditions led the Manager of the Rand Mines Ltd and their chief medical officer, Dr. A.J. Orenstein to hire Dr. Aldo Dreosti and instruct him to institute a series of experiments to prepare recruits for the working environment. Dr. Dreosti joined the medical services of the Rand Mines Ltd in 1927 and remained there until he retired in 1963. He received the prestigious Gold Medal of the South African Institute of Mining and Metallurgy for his work on heat acclimation.⁸ This author feels his work has been largely overlooked by the scientific community, despite its significant historical and scientific value.

In the early 1900s all mining recruits underwent the same underground heat acclimation protocol as described above. But by 1930, the number of acclimation days was modified to consider the regional origin of the native worker. New recruits from tropical homelands would acclimate for 7 d while natives from temperate regions would receive up to 14 d of acclimation. Consideration also was given for workers newly discharged from a hospital, where they would acclimate for 7–14 d as recommended by their medical officer. As the mining conditions worsened, a “red armlet period” of up to 16 d was added after the acclimation period. In this way, new workers could be identified and more carefully monitored by the “boss boys” for signs of heat distress.

Acclimating with reduced work rates however resulted in a great loss of work efficiency, considering the large number of new recruits each year (90% turnover) and the short duration (90 – 130 days) of their contracts. Since relatively few miners suffered deleterious effects, it was assumed that those having difficulty must be unusually susceptible to heat. Therefore, a new philosophy was adopted: to first identify those recruits who need a longer acclimation period, allowing a shorter acclimation for the majority of miners who already were heat tolerant. The length of the acclimation period was thus customized for each recruit, based on his results from a standardized heat tolerance test (HTT). Thus began the experimental studies described by Dr. Aldo Dreosti.^2,3

Two unused hospital wards were converted into environmental chambers with ambient conditions similar to the hottest underground mine locations; 95°F wet bulb, 95°F dry bulb, with stagnant airflow. Each experimental chamber had 2 trays running longitudinally along the floor. The trays contained broken rock which the recruits shoveled to simulate the work performed in the mines, although the amount of rock shoveled was less than during a regular shift. Up to 50 miners at a time could be tested.

During this period, approximately 8,500 natives were employed in the mines, with about 600 new natives recruited each month from various regions of Africa. About 60% of the new recruits were brought from a hot, tropical climate while the remainder were recruited from more temperate regions. Job positions were racially segregated; with Black natives assigned to manual labor in the mines while Whites served in supervisory positions.⁹ Dreosti followed the common belief at this time, that Black natives were more tolerant of work in hot conditions than other ethnic groups. Dreosti wrote in his 1935 report that the Bantu possessed lower basal body temperature and more sweat glands per unit area of skin than Europeans and that “their pigmented skin, although preventing the absorption of ultra-violet rays, allows the absorption of infra-red rays thus raising the skin temperature to facilitate sweat secretion more rapidly than occurs in Europeans.”²

Fact or fiction: Genetic selection for heat tolerance?

So let's take a moment to consider this belief that indigenous natives are genetically endowed to better tolerate working in the mines. Such assumptions can have deleterious consequences if they are false.⁹ For example, it was also assumed that Black miners were more resistant to silicosis from the coal dust than Caucasians. And at this time it was not understood that silica exposure lowers the immune response to tuberculosis, which is then contagious to all members of the miner's community when he returns home. This false assumption led to a lower level of medical surveillance for Black miners and contributed to the tuberculosis crisis that still exists in South Africa today.

Prior to the 20th century, most non-scientists and even scientists supported the concept that indigenous populations of hot climates had greater heat tolerance than non-natives. According to Sir Arthur Keith¹⁰, residing in a hot climate caused evolutionary changes in the endocrine organs such as the thyroid and adrenals, which may help explain racial differences in heat tolerance. Another popular theory as mentioned by Dreosti, was that darker skin provides a heating effect which leads to an earlier onset of sweating and a greater transfer of heat to the environment. Native populations were thought to possess a greater total number of sweat glands than Europeans.¹⁰

Further, it was hypothesized that Caucasians would suffer adverse health effects if they remained in a hot environment. The harmful rays of the sun (“actinic rays”) were thought to be particularly damaging to the reproductive organs, especially in white women.¹⁰ Reports from explorers and missionaries traveling in the tropics appeared to support this hypothesis. Even veteran adventurers such as Samuel Livingstone eventually succumbed to the tropical environment, dying at the age of 60 from malaria and dysentery.¹¹ An acknowledged expert at the time, Dr. Andrew Balfour was quoted “So far as the race is concerned, I am persuaded that the hot and humid tropics are not suited to white colonization and never will be with our present knowledge, even if they were rendered as free from disease as England.”¹⁰

Contrary to these theories supporting the superiority of the Black race for work in hot climates, there were specific instances where Whites successfully immigrated to hot regions, especially if they followed careful sanitary measures and were cautious with food and drink. Huxley and Haddon concluded that “cultural factors are of more importance than biological factors in human groups moving to the tropics.¹⁰ Some optimists even believed that the tropics are the natural home of all races and disease is the only real barrier to white settlement.¹⁰

An American Geographical publication in 1939 compiled the experiences of various groups of White settlers in the tropics.¹⁰ In it were documented the successes of White settlements such as in Florida, Queensland, Cuba and Porto Rico. It was observed that in settlements which failed, the immigrants relied on “persons of color” to do their labor, for example the British settlements of the West Indies. A revolutionary proposal was presented by Sir Raphael Cilento that “it is essential for the Whites to engage in manual work if they are to acclimate to the heat.”¹⁰

Nigel Taylor extensively reviewed this topic of racial differences in heat tolerance and concluded that he “is not entirely convinced by the premise of a genetic predisposition toward thermal tolerance.¹² Instead, given the considerable plasticity of human thermoregulation, ethnic differences in heat tolerance may simply represent unique phenotypic adaptation in response to a diversity of lifestyles and environments.”¹³ Phenotypic variations, which are adaptations that occur during a lifetime, may involve changes in body morphology such as a smaller body size, an increased output and sensitivity of sweat glands, increased cutaneous perfusion, and a redistribution and greater mobility of body fluids. Many of these adaptations are changes that occur during heat acclimation. Yas Kuno made the interesting observation in his book on “Human Perspiration,”¹⁴ that the number of active sweat glands in an adult is determined by ambient conditions during the first 2 y of life. After this, the number of active glands cannot be altered. Heat acclimation alters the output per gland, not the number of active glands.

Taylor reviewed the evidence that there are no racial differences in thermal tolerance in individuals in equal state of heat acclimation.¹² With proper controls, no racial differences can be documented in the number of sweat glands, the sensitivity of glands to cholinergic stimulation, or in the core temperature threshold for the onset of sweating. Instead, a consistent finding is that persons indigenous to tropical climates have an attenuated sweating response compared to people from cooler regions. Similarly, in studies by Katsuura et al.¹⁵ and Fox et al.,¹⁶ indigenous groups had lower skin blood flows and higher skin temperatures. By having higher skin temperatures, heat transfer from the body is attained with less water loss by evaporation. These latter 2 observations, where native people have less vigorous sweating and cutaneous vasodilation, are believed to be due to a long-term adaptation to a hot environment. Again, Taylor concludes this is a phenotypic response rather than a true racial difference.¹²

Heat tolerance screening

Dreosti's approach of first screening individuals using a HTT proved an efficient way to reduce heat casualties yet minimize the time for acclimation. Dr. Dreosti performed his standardized HTT on more than 42,000 mining recruits from 1932 to 1939.³ Less than 1% of the new recruits were unable complete the 60 min HTT due to collapse or excessive fatigue. When these fatigued recruits were removed from the heat chamber their core temperatures were less than 100°F, suggesting their failure was not related to their inability to thermoregulate, but was attributed to “cardiovascular collapse.”³ The remaining new recruits completed the HTT with varying levels of difficulty. Dr. Dreosti investigated which physiological responses and what physical characteristics of a new recruit could predict his core temperature response. He took careful measurements of oral temperature (where the subjects did not drink during the HTT), heart rate, blood pressure, and total body sweat rate. Of the physical characteristics, he considered body morphology (height, weight, skin surface area), climate of origin, mining experience, and time since last heat exposure. In this relatively non-homogeneous population, he found no correlation between the heart rate and blood pressure responses during a HTT and the rise in core temperature. Similarly, there was no consistent relationship between total body sweat loss and rise in body temperature. Nor, could he predict the final core temperature from any morphological measurement, including body weight or surface area. Dreosti concluded that the only measurement he could use to assign an effective hot acclimation protocol was the final core temperature after a HTT. If the final core temperature was less than 100.6°F, he classified the recruit as heat tolerant and such a recruit was assigned only 4 acclimation sessions before advancing to normal mining operations. If the final core temperature was greater than 102°F, the recruit was considered heat intolerant and he would be assigned a full 14 d of acclimation. The majority of new recruits had a final core temperature between 100.6 and 102°F, and 7 acclimation sessions were assigned. This reduction in number of heat acclimation sessions for the majority of recruits increased mine production while still protecting the workers.

Dreosti also performed HTT studies on veteran miners.² These were natives who had worked in the mines for 9 to 12 months without signs of heat intolerance and were considered thoroughly heat acclimated. Not one of over 50 veteran miners had a final core temperature above 100.6°F during a HTT. He also observed that the pre-HTT core temperatures of the acclimated miners were lower than new recruits. A lower basal body temperature is an inconsistent finding in modern artificial heat acclimation studies in humans. It occurs only after a very prolonged heat acclimation program as described by Taylor.¹³ Another observation from the studies with veteran miners, was that miners performing the same level of work but in cooler areas of the mine, did not have the same degree of acclimation; their final HTT core temperatures were greater than 100.6°F. Indeed, there was an inverse correlation between their final core temperature and the ambient temperature at their worksite. This early observation precedes later debates about whether the rise in temperature with physical exertion alone can induce heat acclimation.¹⁷

The HTT used by Dreosti was unique and specific to the conditions of the gold mines, and therefore his results differ in many ways from heat assessment tests used today. One difference was that all his subjects performed the exact same task, regardless of their age, fitness or size. Thus, their cardiovascular responses were influenced by factors other than their level of heat strain. This inhomogeneity of subjects and work may explain the failure of heart rate or blood pressure to predict the level of thermal strain for these individuals. Another possibly unexpected finding, was that sweat rate did not differ between acclimated and unacclimated miners, even when they were matched for body weight or surface area. Indeed, sweat rates were lowest in the most acclimated miners. This finding also may relate to the inhomogeneity of his population; some had moved from a hot tropical region. Dreosti, ahead of his time, recognized that copious sweating is “wasteful from a cooling point of view in an atmosphere already saturated with moisture.” Thus heavy sweating, especially under conditions of restricted drinking may be detrimental to heat tolerance. As a result of the specific conditions and the population being tested, core temperature alone proved to be the simplest yet most accurate measurement to screen mining recruits.

By 1953 Cyril Wyndham and coworkers developed a new HTT to screen this same population of gold miners.¹⁸ Wyndham and colleagues constructed portable, temperature controlled tents to perform HTTs and to evaluate new artificial acclimation protocols. They used block stepping instead of rock shoveling to allow more precise control of work rate and to be able to adjust the work rate for subjects of differing size, fitness, ethnicity and even gender. The level of work was more closely matched to the actual working level in the mines, at an oxygen consumption of approximately 1.0 L/min, and the HTT was extended to 4 hours. With these more controlled conditions and the use of more sensitive measurement devices which allowed continuous sampling, Wyndham and coworkers developed a statistical model, which uses the standard deviations of rectal temperature, heart rate, and sweat rate to predict heat tolerance.¹⁹ They performed this new HTT on a wide range of individuals of varying ethnic groups, ages, fitness, and gender.^20-22 With these new standardized procedures heat casualties were contained, until conditions worsened again and microclimate cooling was introduced.

Predicting heat tolerance is relevant today, especially in sports, occupational and military scenarios. Today we use 2 approaches; to calculate either a heat strain index or a heat stress index. A heat strain index is similar to the approach used by Dreosti, where physiological measurements are used to predict heat tolerance. Most of the heat strain indices we use today however, use not only core temperature, but also include some assessment of cardiovascular strain. An example is the Cumulative Heat Strain Index used by the Israeli military and described by Frank et al.²³

Heat stress indices predict the level of heat strain in an individual based on measurements of the environment and using formulas derived from the heat balance equation. Most indices assume that the primary method to maintain body temperature in a hot environment is by sweating. The more sweating required to maintain body heat balance in a particular condition, the greater the strain on the body. An index of heat strain is therefore an estimate of the capacity of the sweating person to lose heat in a particular environment. Some examples include the Heat Stress Index (HSI), which is based on a comparison of the evaporation required to maintain body temperature and the maximum evaporation that could be achieved in the specific environment. The Required Sweat Rate (SWreq) and the Predicted Four-Hour Sweat Rate (P4SR) are 2 other examples of heat stress indices that evaluate the level of stress of an environment based on the capacity for evaporation.²⁴ However, these indices are intended for conditions in which heat balance can be obtained and their usefulness is limited in conditions where evaporation is limited by a saturated environment, such as in the gold mines.

Heat acclimation protocols today

Even in a homogenous group of individuals, there is a wide range of heat response and rate of acclimation. Dreosti screened over 42,000 new recruits using his HTT between 1932 and 1939, where approximately 15% were classified as heat intolerant.² To evaluate how long it would take to heat acclimate such individuals, he had a subgroup of 60 heat intolerant recruits perform HTTs on consecutive days. All but 5 were considered acclimated within 4 HTTs. The remaining 5 recruits took 7 to 14 HTTs before they met his tolerance criteria, of having a final core temperature less than 100.6°F. The individuals who required extra heat acclimation sessions usually were from a temperate region or had been away from the mines for many months.

Vernon in 1923 was one of the first to report the physiological responses to artificial heat acclimation.²⁵ He observed on himself that heart rate decreased and sweat rate increased with repeated heat exposures. Dill and colleagues in 1933 also noted a progressive increase in sweat rate and reduction in sweat chloride concentration which they attributed as signs of heat acclimation.²⁶ In the 1940s Sid Robinson and coworkers²⁷ developed what we now consider the “traditional protocol” for artificial heat acclimation. His subjects were exposed to a pre-determined hot climate and moderate exercise, at approximately 50% of maximum oxygen consumption. They would pedal or walk for a total of 100 minutes or until their core temperature or heart rate exceeded a pre-determined cut-off level. With each repeated heat exposure, their core temperature and heart rate responses would be reduced until they could easily complete a 100 min acclimation session with minimal discomfort. The 4 classic signs of heat acclimation were considered: a reduced core temperature, reduced skin temperatures, reduced heart rate, and increased sweating for a given level of exercise and heat exposure.²⁷ Eichna et al. reported similar physiological changes during acclimation to a hot and humid environment.²⁸ Additional early markers of heat acclimation include reduced electrolyte losses in sweat and an expanded plasma volume which was believed to contribute to the reduced heart rate.²⁹

This “traditional heat acclimation protocol” has many practical uses. Individuals can be acclimated to a specific stress condition; for example, before deployment to Northern Africa or to the Pacific Islands during World War II. However, as described by Nigel Taylor in his Physiological Compendium review,¹³ this traditional approach is not suitable for studying the physiological adaptations to heat acclimation. During traditional heat acclimation, with each succeeding heat exposure the rise in core temperature is reduced, providing less stimulus to the thermoregulatory system. Using this approach, some markers of heat acclimation appear to reverse after about 2 weeks, such as the increase in sweat rate or the expansion of plasma volume. Rather than representing a later stage of the acclimation process as originally proposed, Taylor ascribes this partial “normalization” of heat responses to a “habituation” response, as the routine heat exposure now represents less strain for the acclimating individual.

A second approach to heat acclimation is termed “controlled hyperthermia,” and was first described by Fox in 1963.³⁰ Using this approach, the heat/exercise stimulus first is set to quickly elevate the core temperature to approximately 102°F. The stimulus is then adjusted downward to allow the temperature to plateau at this elevated level for approximately 100 min during the remainder of the heat/exercise exposure. With each succeeding acclimation day, the intensity of the heat/exercise stimulus should be increased to maintain the same elevated core temperature. Using this protocol, the traditional signs of heat acclimation are acquired more quickly, there is a more perfect matching of the sweating and core temperature improvements, and one does not see a stage of accommodation where sweating and plasma volume recover toward pre-acclimation levels.

Taylor further describes a long-term phase of heat acclimation.¹³ This phase is seen in individuals who reside and are active in a hot environment for many months or years, such as in the heat tolerant miners identified by Dreosti.^2,3 Since the length of the HTT protocol (60 min) was shorter than the heat acclimation approaches we use today (100 min), we can assume that the rapid acclimation seen in most of Dreosti's recruits may be related to their previous heat exposures. Then, as they continue to work in the mines, they experience an “habituation” of their heat loss responses so that they present as low-responders during a HTT, with a low sweat rate that does not increase with continued acclimation sessions. This stage is considered a more efficient state of heat acclimation, where greater heat transfer occurs through non-evaporative means; involving a better matching of skin perfusion and sweating, improved cardiac function possibly due to a reduced sympathetic drive and increased cardiac compliance, a more rapid adjustment in body fluid compartments, and finally to more efficient metabolic responses. We are just beginning to understand the molecular changes that must occur in the human to induce this state of enhanced heat tolerance. Also at this time, there are no data to compare the molecular advantages provided by the traditional vs. the controlled hyperthermia approaches to heat acclimation.

The molecular responses of heat acclimation and heat intolerance

Dr. Dreosti's goal was to induce heat acclimation as quickly as possible to prevent heat stroke in a large and varied population. This still is the goal of many applied researchers today, but we hope that by understanding the cellular mechanisms of heat acclimation we can enhance the process and perhaps identify specific markers in blood to screen for persons who are intolerant to heat. Although it is beyond the scope of this paper to go into detail, an overview of some possible molecular mechanisms for the classic adaptations during heat acclimation are presented in Table 2. Much of the information in this table were obtained from recent review articles by Dr. Horowitz.^31-34 One will note from the third column in this table, that most of this research has yet to be confirmed in human subjects.

Table 2.

Possible molecular modifications responsible for the phenotypic adaptations of heat acclimation.

Heat Acclimation Adaptation	Molecular Modification	Evidence Source
CORE TEMPERATURE
Lower resting core temp	Altered genes related to metabolic efficiency,	rat gene studies (31:211–12)
	Altered mitochondrial biogenesis	reptiles (31:213)
	Hypothalamic neurogenesis and cell type	rat brain (31:205–8)
	Altered norepinephrine/angiotensin II receptor
	densities and sensitivity	rats (31:206)
Lowered CNS thresholds	Genes encoding ion channels, ion pumps,	rat gene studies (31:208)
	and hypothalamic receptors	rats (31:206)
Increased heat loss sensitivity	Genes encoding hormone/transmitter receptors	rat gene studies (31:205)
BLOOD FLOW RESPONSE
Lower vasodilatory threshold	Altered hypothalamic CNS thresholds	rats (31:205–208)
Increased vasodilatory sensitivity	Attenuated adrenergic response	rats (31:203)
	Altered baroreceptor function	rats (32:437)
	Altered nitric oxide receptors	rats (31:216)
	Vascular remodeling	humans (31:203)
	VEGF up-regulation	rats (31:212)
Increased splanchnic blood flow	Less vasoconstriction related to increased nitric oxide	rats (31:203)
	and reduced adrenergic response
EVAPORATIVE COOLING RESPONSE
Lower saliva production threshold	CNS effects	rats (31:205–208)
Increased sweating sensitivity	Sweat gland receptor sensitivity	human sweat glands (31:203)
Reduced evaporative electrolyte loss	Altered ion transport and fluid conservation	rats (31:214)
ALTERED BODY FLUIDS
Increased plasma volume	Altered aquaporine genes	rats (31:212)
Plasma volume conservation	Maintain intravascular protein mass	rats, humans (31:214–215)
LOWER HEART RATE
Altered sympathetic response	Reduced autonomic drive	rats (31:214)
Intrinsic changes in cardiac pacer cells	Altered Ca2+ transport	rats (31:217)
Increased myocardial distensibility	Cardiac remodeling	rats (31:216–217)
Increased plasma volume	Maintain intravascular protein mass	rats, humans (31:214–215)
GREATER MUSCULAR ENDURANCE
Attenuated drop in power	Intrinsic signaling adjustment	rats (31:219)
	Altered lipid metabolism	rats (31:219)
THERMOTOLERANCE AND CRYOPROTECTION
Increased critical body temp	HSP pathway upregulation	rats, mice, humans (31:208–209)
Increased anti-oxidative pathways	ROS scavenger genes	rat gene, mice (31:208,213)
Increased anti-apoptosis pathways	Bcl-xL and pro-apoptotic death promoter Bad	rat heart cells (31:208,213)
Increased anti-inflammatory pathways	HSP-induced resistance to TNF-α and IL-1	rodents, tumor cells (32:435)
Decreased inflammatory responses	TNF-α and IL-1	human macrophages (32:435)
Activate cellular immune responses	Formation of specific immune complexes	human monocytes (32:435)
Increased resistance to ischemic damage	HSP and HIF effects on brain and heart	nematodes, rats (31:211)
Increased epithelial integrity	HSP effect on intestinal permeability	humans, human cells (32:439)

References where a discussion of the evidence for the molecular adaptation listed in column 2, are shown in the last column as (reference number: page numbers).

Dr. Horowitz identifies several genes that become activated during heat acclimation.³⁴ She proposes there is a 2-tiered response which is obvious at both the cellular and systemic levels. In short-term heat acclimation (STHA), genes that encode for voltage-gated ion channels, ion pumps, transporters, and certain hormone or transmitter receptors are altered which enhance neuronal excitability and increase heat loss responses. These changes are associated with the increases in evaporative cooling, skin vasodilation and heart rate noted during the first several heat exposures. STHA lasts a few days, then is followed by a period of stabilization and the development of more efficient heat-loss responses which she terms long-term heat acclimation responses (LTHA). During LTHA, the rise in body temperature for a given level of heat stress is reduced despite no further increases in heat loss response. The genes affected during LTHA are involved in cellular efficiency, such as those that control mitochondrial energy metabolism and cellular maintenance responses. Also at this time there is an up-regulation of genes that code for proteins involved in cryoprotection and cellular repair, such as proteins of the heat shock, anti-oxidative and anti-apoptotic pathways.³¹

Thermotolerance is an ability to survive an otherwise lethal heat stress after a prior heat exposure. It is clear from animal and cell studies that an “acquired thermotolerance” may be obtained after even a single, severe heat exposure.³⁵ It is unclear whether this phenomenon occurs in humans and whether a similar mechanism is involved during heat acclimation. Cellular adaptations associated with heat acclimation allow a greater tolerance to elevated ambient conditions, caused by a slower rise in body temperature, resistance to cellular injury due to heat or ischemia, and to a delay in the onset of the heat shock response. Heat Shock Proteins (HSPs) are believed to play a prominent role in both the “acquired thermotolerance” exhibited in cells and animals and in the cryoprotective responses of heat acclimation.^32,36

The HSP pathway is up-regulated after even a single bout of exercise in the heat in humans.³⁷ During a program of heat acclimation, baseline intracellular HSP levels increase and new HSP can be produced more rapidly.^32,38 Pope Moseley suggests that upregulation of HSP pathways is a signal which coordinates the integrated heat acclimation response.³⁵ Intracellular HSPs are elevated in response to cellular damage, or perhaps also as a result of the activated sympathetic responses to heat and exertion.³² As shown in Table 2, HSPs signal a multitude of cellular actions that induce many of the cardiovascular and thermal adaptations associated with heat acclimation. HSP, together with HIF (hypoxia inducible factor) which also is elevated with heat acclimation³⁹, are responsible for molecular responses which maintain blood pressure and local perfusion despite an enhanced cutaneous blood flow, thereby preventing ischemic damage to the brain⁴⁰, heart⁴¹, and splanchnic tissues.^31,32 HSPs also maintain junctional proteins that are responsible for intestinal wall integrity, thus preventing endotoxin release from the intestine which is a main contributor of the heat shock response.⁴² HSPs also enhance immune function while providing resistance against inflammatory cytokines.^32,43 Thus, as concluded by Kuennen et al., this ubiquitous, well-conserved pathway may be a common pathway for thermotolerance in humans as well as animals.³⁶

If the HSP pathway is a major trigger for heat acclimation adaptations, then a malfunction in this system should have serious consequences for heat tolerance. In a study by Moran et al.,³³ soldiers who failed to upregulate HSP during heat acclimation had more severe heart rate and body temperature responses during a HTT and were therefore classified as heat intolerant. Recent molecular studies have identified specific HSP polymorphisms that may account for individual differences in heat tolerance. Kresfelder and coworkers,⁷ for example identified a subgroup of individuals with a specific HSP70 polymorphism where HSP expression does not increase following a heat exposure. Such individuals also did not respond appropriately during a short heat acclimation protocol. Interestingly, these South African researchers used HTT protocols developed by Wyndham and coworkers during their studies of gold miners.

An intriguing possibility may be that heat tolerance and the rate of heat acclimation might be altered by nutritional or pharmacological methods that alter the HSP pathway. In a recent human study by Kuennen et al.,³⁶ the administration of 2,000 mg/day of quercetin, an HSP pathway inhibitor, prevented the thermal responses and the improved intestinal permeability seen during a program of heat acclimation. On the other hand, ingestion of glutamine which increases HSP70 synthesis, prevented endotoxin release and the inflammatory response seen in the same unacclimated subjects without glutamine supplementation during an acute exercise bout in the heat.⁴⁴ It would be interesting to examine the effects of glutamine during a heat acclimation protocol.

In South African gold mine studies, Strydom and coworkers in mid-1970s found that administration of 250 or 500 mg of ascorbic acid to the recruits 3–4 hours before 4-hr heat acclimation sessions reduced their rectal temperature response and resulted in a faster rate of heat acclimation.^45,46 The lower core temperature response was in part related to retention of plasma volume and a more efficient sweating response. Strydom et al. could not explain the exact mechanism of action for the ascorbic acid improvement. However, they noted that most of their mining recruits had a sub-optimal level of ascorbic acid, and that without supplements the levels fell further as they continued mining operations.⁴⁵ It would be intriguing to know if ascorbic acid has any effect on the HSP pathway. The evidence in the literature of the effects of ascorbic acid on HSP is inconsistent. In fish fed ascorbic acid, there was an increased expression of hepatic HSP60 and HSP70 which was associated with increased tolerance against an induced pH environmental stress.⁴⁷ In human studies, administration of ascorbic acid increases HSP70 levels in muscle cells. However, it did not significantly alter the HSP70 content in lymphocytes.⁴⁸ Khassaf et al. speculated that the effect of ascorbic acid to increase muscle levels of HSP70 occur through direct effects on gene expression.

Conclusions

Since the early 1900s tens of thousands of African miners have undergone prescribed protocols of heat tolerance screening and heat acclimation. No other example in the literature includes such a huge and varied population working under extreme work and environmental conditions. The early research in this population was described by Dr. Aldo Dreosti. Although his work was largely descriptive, with the practical goal of reducing heat casualties without compromising gold production, his basic approach of first performing a heat tolerance test to determine a specific heat acclimation protocol is still used in military, occupational and athletic settings. His methods served as the foundation for later gold mine researchers such as Cyril Wyndham, NB Strydom, Duncan Mitchell, and Leo Senay, as well as for investigators today concerned with prevention of heat stress. Many of Dreosti's results, such as the lower sweat rate in his most acclimated subjects and the interactions between physical work and heat acclimation, raised important questions still being addressed. It is telling that current South African researchers are using similar HTT and heat acclimation protocols to test for cellular markers of heat intolerance, such as HSP polymorphisms.

Our concept of the role of genetics in heat tolerance has changed dramatically since these early gold mining studies. In the early 1900s, mining recruits were predominately Black and heat tolerance was thought to be determined by an individual's unalterable genome. For this reason, Black recruits, regardless of their region of origin were thought to possess greater heat tolerance than other ethnic groups. Wyndham's later studies of heat acclimation in Blacks and Caucasians, helped to discredit this idea of racial differences in heat response.^20,21 Currently we believe, that within each race there is considerable variation among individuals in their sensitivity to heat and in their ability to acclimate. While each individual has an innate ability to respond and a genetic ceiling for adaptation, there is such great individual variability that ethnic differences are not obvious.

Our concept of the role of the environment in heat tolerance also has changed dramatically. We now appreciate that while our genome may be unalterable, gene products are highly responsive to surrounding ambient conditions. Even a single severe heat exposure initiates a cascade of molecular events which enhance heat loss responses and produce resistance to thermal injury. It is especially intriguing that there may be “windows of opportunity” during our development where permanent changes in thermoregulation may be induced by environmental exposure; such as Kuno's observation of the varying number of active sweat glands as related to temperatures during the first 2 y of life. This ability to rapidly adapt to changes in the environment may be key to species survival in conditions of global warming, for example.

Gold mine researchers were among the first to use dietary supplementation to augment the process of heat acclimation. Now, with a greater understanding of the specific molecular changes responsible for heat acclimation, we may specifically develop new dietary and pharmacological adjuvants, that may be especially helpful for those with compromised thermoregulation or those in special occupations.

Abbreviations

BAD

Bcl-2 associated death promoter protein

Bcl xL

B cell lymphoma-extra large

Ca²⁺

calcium ions

CNS

central nervous system

HIF

hypoxia inducible factor

HSP

heat shock proteins

HTT

heat tolerance test

IL-1

interleukin-1

IL-6

interleukin-6

LTHA

long term heat acclimation responses

ROS

reactive oxygen species

STHA

short term heat acclimation responses

TNF-α

tumor necrosis factor α

VEGF

vascular endothelial growth factor

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.