Comprehensive Physiology Wiley Online Library

Thermal Stress and Toxicity

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Abstract

Elevating ambient temperature above thermoneutrality exacerbates toxicity of most air pollutants, insecticides, and other toxic chemicals. On the other hand, safety and toxicity testing of toxicants and drugs is usually performed in mice and rats maintained at sub‐thermoneutral temperatures of ∼22°C. When exposed to chemical toxicants under these relatively cool conditions, rodents typically undergo a regulated hypothermic response, characterized by preference for cooler ambient temperatures and controlled reduction in core temperature. Reducing core temperature delays the clearance of most toxicants from the body; however, a mild hypothermia also improves recovery and survival from the toxicant. Raising ambient temperature to thermoneutrality and above increases the rate of clearance of the toxicant but also exacerbates toxicity. Furthermore, heat stress combined with work or exercise is likely to worsen toxicity. Body temperature of large mammals, including humans, does not decrease as much in response to exposure to a toxicant. However, heat stress can nonetheless worsen toxic outcome in humans through a variety of mechanisms. For example, heat‐induced sweating and elevation in skin blood flow accelerates uptake of some insecticides. Epidemiological studies suggest that thermal stress may exacerbate the toxicity of airborne pollutants such as ozone and particulate matter. Overall, translating results of studies in rodents to that of humans is a formidable task attributed in part to the interspecies differences in thermoregulatory response to the toxicants and to thermal stress. Published 2014. Compr Physiol 4:995‐1016, 2014.

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Figure 1. Figure 1. An idealized thermoregulatory profile of metabolic rate (MR) and evaporative water loss, including passive and active components. MR‐metabolic rate or whole‐body oxygen consumption, passive EWL‐evaporative water loss by passive mechanisms (diffusion through skin, respiratory losses); active EWL‐evaporative water loss arising from active mechanisms including sweating, panting, or grooming moisture on the skin; LCT‐lower critical temperature; UCTE‐upper critical temperature as defined by the demarcation between passive and active EWL; UCTM‐upper critical temperature as defined by rise in MR above basal levels in the heat.
Figure 2. Figure 2. Examples of core temperature monitored by radiotelemetry or data loggers in a C57 BL 6 mouse, long‐Evans rat, and adult human. Data for mouse and rat collected by surgically implanted radiotransmitters. Data for human collected with ingested data loggers. Graphs modified, with permission, from Gordon ().
Figure 3. Figure 3. General scheme of how environmental heat stress and hyperthermia affect the biological dose, metabolism, and excretion of toxic chemicals, toxins, and drugs. See text for details.
Figure 4. Figure 4. General scheme of how the thermoregulatory response to a toxic agent may affect its toxicity and biological dose through the lungs, skin, or GI (gastrointestinal) tract. See text for details.
Figure 5. Figure 5. Idealized plot showing how ambient temperature affects the core temperature of a normal or toxicant‐treated rodent. One would expect these relationships if the animal is either held at different ambient temperatures or allowed to behaviorally thermoregulate in a temperature gradient. The ambient temperature limits of normothermia of the untreated animal (indicated by horizontal blue bar) are relatively wide. There is a regulated decrease in core temperature and thermoeffectors for heat production and heat loss are impaired in the toxicant‐treated animal, resulting in a limited ambient temperature range of normothermia (indicated by horizontal red bar). The vertical blue and red arrows are of similar magnitude and indicate the variability of core temperature within the limits of normothermia. Graph modified, with permission, from Gordon ().
Figure 6. Figure 6. Relationship between ozone concentration and the total number of respiratory and other symptoms (e.g., shortness of breath, cough, wheezing, etc.) in healthy human females exercising under relatively cool and marked heat stress conditions. Data adapted, with permission, from Gibbons and Adams (; see Table 4 of original study).
Figure 7. Figure 7. Relationship between respiratory responses (frequency, tidal volume, and minute ventilation) and thermoregulatory response of rats exposed for 3 h to 0.8 ppm ozone. Data adapted, with permission, from Mautz and Bufalino ().
Figure 8. Figure 8. Effect of air temperature (Ta) and perfusate temperature (Tp) on the passive absorption of parathion (dose = 40 μg/cm2) in vitro in porcine skin. Data adapted, with permission, from Chang and Riviere ().
Figure 9. Figure 9. Effect of ambient temperature on the transcutaneous absorption of parathion from the hand and arm of human volunteers as estimated by the excretion of paranitrophenol, a metabolite of parathion. Data adapted, with permission, from Funckes et al. ().
Figure 10. Figure 10. Effects of heat stress on the thermoregulatory response of beef heifers while feeding on endophyte‐infected feed containing the fungal toxin ergovaline (6.1‐8.7 μg/kg/day). Cattle were maintained in a thermoneutral (19°C) or heat stress environment (4 h at 31°C during the day then 4 h at 25°C at night). Data adapted, with permission, from Burke et al. ().
Figure 11. Figure 11. Annual changes in plasma cholinesterase activity of lawn care workers in 1987. Also plotted is the percentage of the cholinesterase activity using the value of January as 100%. Numbers next to data points are average air temperatures in Florida for a given month. Data adapted, with permission, from Yeary et al. ().
Figure 12. Figure 12. Effect of 3 h of exposure to different ambient temperatures on the hepatic response to sodium selenite (45 umol/kg) as measured by plasma levels of lactic dehydrogenase (LDH) measured 3 days after exposure. Data adapted, with permission, from Watanabe et al. ().
Figure 13. Figure 13. Effect of housing at different ambient temperatures on the hypothermic response to ethanol and ethanol clearance in mice. Data adapted, with permission, from Bejanian et al. ().
Figure 14. Figure 14. Effect of 4 weeks of acclimation to ambient temperatures of 8, 22, or 38°C on the lethal dose of solvents, heavy metals, and pesticides in mice. All solvents and metals administered intraperitoneally. Pesticides administered orally. Note difference in scales of ordinate. Data adapted, with permission, from Nomiyama et al. ().
Figure 15. Figure 15. Depiction of behavioral and autonomic thermoregulatory responses under conditions where there is a forced or regulated change in body temperature. (A) Regulated hypethermia or fever—as core temperature rises from exposure to infectious agent or pyrogen and animal vasoconstricts peripheral blood flow, shivers, and prefers warmer temperature; (B) forced hyperthermia‐environmental heat stress forces core temperature above set‐point and subject attempts to reverse rise by selecting cooler temperature, increase skin blood flow and evaporation; (C) forced hypothermia‐environmental cold stress lowers core temperature below set‐point and animal shivers, vasoconstricts, and selects warmer temperatures; (D) regulated hypothermia‐chemical or drug directly affects CNS control, lowering set‐point temperature and subject prefers cooler temperatures to lower core temperature. Data adapted, with permission, from Gordon ().
Figure 16. Figure 16. (A) Time course of core temperature of mice injected IP with saline or two doses of selenium and maintained at ambient temperatures of 20 or 33°C. (B) Time course of preferred ambient temperature of mice injected with the same treatments and placed in a temperature gradient. Data adapted, with permission, from Watanabe and Suzuki ().
Figure 17. Figure 17. Time course of core temperature monitored by telemetry, selected ambient temperature in a temperature gradient, and motor activity of rats dosed with corn oil or 25 mg/kg chlorpyrifos, an anti‐ChE insecticide. Note hypothermic phase and preference for cooler Ta's during the first light phase (L1), preference for warmer Ta's during dark phase (D1) and delated elevation in core temperature during L2. Data adapted, with permission, from Gordon ().
Figure 18. Figure 18. Depiction of a regulated hypothermic response to a toxicant and how subjecting animal to heat stress and forcing core temperature above normal set‐point leads to increased thermal load and more stress. Red arrow represents magnitude of load error with hyperthermia alone; blue arrow represents load error with animal exposed to toxicant and hyperthermia.
Figure 19. Figure 19. Effect of increasing dose of tetramethrin, a pyrethroid, on depolarization in crayfish giant axons. Lowering temperature from 21 to 10°C exacerbates depolarizing effects of the pyrethroid insecticide. Data adapted, with permission, from Salgado et al. ().
Figure 20. Figure 20. Example of an acute hypothermic response followed by a delay fever in rats dosed with the organophosphate (OP) insecticide chlorpyrifos. Arrow indicates time of oral dosing with corn oil vehicle or chlorpyrifos. Note different scales of Y‐axis of the two graphs to illustrate the delayed elevation in daytime core temperature. L = light phase; D = dark phase. Adapted, with permission, from Gordon et al. ().
Figure 21. Figure 21. Example of time course of acute and delayed fever following oral dosing with the carbamate‐based insecticide carbaryl in rats. Note different scales of Y‐axis. Adapted, with permission, from Gordon and Mack ().
Figure 22. Figure 22. Ozone‐induced fever in Brown Norway rats. Rats had been exposed to 1 ppm ozone for 6 h/day for 2 consecutive days and left undisturbed in home cages while monitored by radiotelemetry. Data adapted, with permission, from ().
Figure 23. Figure 23. Epidemiological analysis of the effects of air temperature on mortality in The Netherlands. Data replotted, with permission, from Kunst et al. ().


Figure 1. An idealized thermoregulatory profile of metabolic rate (MR) and evaporative water loss, including passive and active components. MR‐metabolic rate or whole‐body oxygen consumption, passive EWL‐evaporative water loss by passive mechanisms (diffusion through skin, respiratory losses); active EWL‐evaporative water loss arising from active mechanisms including sweating, panting, or grooming moisture on the skin; LCT‐lower critical temperature; UCTE‐upper critical temperature as defined by the demarcation between passive and active EWL; UCTM‐upper critical temperature as defined by rise in MR above basal levels in the heat.


Figure 2. Examples of core temperature monitored by radiotelemetry or data loggers in a C57 BL 6 mouse, long‐Evans rat, and adult human. Data for mouse and rat collected by surgically implanted radiotransmitters. Data for human collected with ingested data loggers. Graphs modified, with permission, from Gordon ().


Figure 3. General scheme of how environmental heat stress and hyperthermia affect the biological dose, metabolism, and excretion of toxic chemicals, toxins, and drugs. See text for details.


Figure 4. General scheme of how the thermoregulatory response to a toxic agent may affect its toxicity and biological dose through the lungs, skin, or GI (gastrointestinal) tract. See text for details.


Figure 5. Idealized plot showing how ambient temperature affects the core temperature of a normal or toxicant‐treated rodent. One would expect these relationships if the animal is either held at different ambient temperatures or allowed to behaviorally thermoregulate in a temperature gradient. The ambient temperature limits of normothermia of the untreated animal (indicated by horizontal blue bar) are relatively wide. There is a regulated decrease in core temperature and thermoeffectors for heat production and heat loss are impaired in the toxicant‐treated animal, resulting in a limited ambient temperature range of normothermia (indicated by horizontal red bar). The vertical blue and red arrows are of similar magnitude and indicate the variability of core temperature within the limits of normothermia. Graph modified, with permission, from Gordon ().


Figure 6. Relationship between ozone concentration and the total number of respiratory and other symptoms (e.g., shortness of breath, cough, wheezing, etc.) in healthy human females exercising under relatively cool and marked heat stress conditions. Data adapted, with permission, from Gibbons and Adams (; see Table 4 of original study).


Figure 7. Relationship between respiratory responses (frequency, tidal volume, and minute ventilation) and thermoregulatory response of rats exposed for 3 h to 0.8 ppm ozone. Data adapted, with permission, from Mautz and Bufalino ().


Figure 8. Effect of air temperature (Ta) and perfusate temperature (Tp) on the passive absorption of parathion (dose = 40 μg/cm2) in vitro in porcine skin. Data adapted, with permission, from Chang and Riviere ().


Figure 9. Effect of ambient temperature on the transcutaneous absorption of parathion from the hand and arm of human volunteers as estimated by the excretion of paranitrophenol, a metabolite of parathion. Data adapted, with permission, from Funckes et al. ().


Figure 10. Effects of heat stress on the thermoregulatory response of beef heifers while feeding on endophyte‐infected feed containing the fungal toxin ergovaline (6.1‐8.7 μg/kg/day). Cattle were maintained in a thermoneutral (19°C) or heat stress environment (4 h at 31°C during the day then 4 h at 25°C at night). Data adapted, with permission, from Burke et al. ().


Figure 11. Annual changes in plasma cholinesterase activity of lawn care workers in 1987. Also plotted is the percentage of the cholinesterase activity using the value of January as 100%. Numbers next to data points are average air temperatures in Florida for a given month. Data adapted, with permission, from Yeary et al. ().


Figure 12. Effect of 3 h of exposure to different ambient temperatures on the hepatic response to sodium selenite (45 umol/kg) as measured by plasma levels of lactic dehydrogenase (LDH) measured 3 days after exposure. Data adapted, with permission, from Watanabe et al. ().


Figure 13. Effect of housing at different ambient temperatures on the hypothermic response to ethanol and ethanol clearance in mice. Data adapted, with permission, from Bejanian et al. ().


Figure 14. Effect of 4 weeks of acclimation to ambient temperatures of 8, 22, or 38°C on the lethal dose of solvents, heavy metals, and pesticides in mice. All solvents and metals administered intraperitoneally. Pesticides administered orally. Note difference in scales of ordinate. Data adapted, with permission, from Nomiyama et al. ().


Figure 15. Depiction of behavioral and autonomic thermoregulatory responses under conditions where there is a forced or regulated change in body temperature. (A) Regulated hypethermia or fever—as core temperature rises from exposure to infectious agent or pyrogen and animal vasoconstricts peripheral blood flow, shivers, and prefers warmer temperature; (B) forced hyperthermia‐environmental heat stress forces core temperature above set‐point and subject attempts to reverse rise by selecting cooler temperature, increase skin blood flow and evaporation; (C) forced hypothermia‐environmental cold stress lowers core temperature below set‐point and animal shivers, vasoconstricts, and selects warmer temperatures; (D) regulated hypothermia‐chemical or drug directly affects CNS control, lowering set‐point temperature and subject prefers cooler temperatures to lower core temperature. Data adapted, with permission, from Gordon ().


Figure 16. (A) Time course of core temperature of mice injected IP with saline or two doses of selenium and maintained at ambient temperatures of 20 or 33°C. (B) Time course of preferred ambient temperature of mice injected with the same treatments and placed in a temperature gradient. Data adapted, with permission, from Watanabe and Suzuki ().


Figure 17. Time course of core temperature monitored by telemetry, selected ambient temperature in a temperature gradient, and motor activity of rats dosed with corn oil or 25 mg/kg chlorpyrifos, an anti‐ChE insecticide. Note hypothermic phase and preference for cooler Ta's during the first light phase (L1), preference for warmer Ta's during dark phase (D1) and delated elevation in core temperature during L2. Data adapted, with permission, from Gordon ().


Figure 18. Depiction of a regulated hypothermic response to a toxicant and how subjecting animal to heat stress and forcing core temperature above normal set‐point leads to increased thermal load and more stress. Red arrow represents magnitude of load error with hyperthermia alone; blue arrow represents load error with animal exposed to toxicant and hyperthermia.


Figure 19. Effect of increasing dose of tetramethrin, a pyrethroid, on depolarization in crayfish giant axons. Lowering temperature from 21 to 10°C exacerbates depolarizing effects of the pyrethroid insecticide. Data adapted, with permission, from Salgado et al. ().


Figure 20. Example of an acute hypothermic response followed by a delay fever in rats dosed with the organophosphate (OP) insecticide chlorpyrifos. Arrow indicates time of oral dosing with corn oil vehicle or chlorpyrifos. Note different scales of Y‐axis of the two graphs to illustrate the delayed elevation in daytime core temperature. L = light phase; D = dark phase. Adapted, with permission, from Gordon et al. ().


Figure 21. Example of time course of acute and delayed fever following oral dosing with the carbamate‐based insecticide carbaryl in rats. Note different scales of Y‐axis. Adapted, with permission, from Gordon and Mack ().


Figure 22. Ozone‐induced fever in Brown Norway rats. Rats had been exposed to 1 ppm ozone for 6 h/day for 2 consecutive days and left undisturbed in home cages while monitored by radiotelemetry. Data adapted, with permission, from ().


Figure 23. Epidemiological analysis of the effects of air temperature on mortality in The Netherlands. Data replotted, with permission, from Kunst et al. ().
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Christopher J. Gordon, Andrew F.M. Johnstone, Cenk Aydin. Thermal Stress and Toxicity. Compr Physiol 2014, 4: 995-1016. doi: 10.1002/cphy.c130046