Thresholds for thermal damage to normal tissues: An update

Figures & data

Table I.  Keywords used in database searches.

Hyperthermia damage	Laser burn	Skin
Heat damage	Heat	Tendon
High temperature damage	Soft tissue	Muscle
Heat exposure damage	Adipose	Epicardium
Hyperthermia injury	Tissue	Bone
Heat injury	Liver	Spine
High temperature injury	Oesophagus	Fat
Heat exposure injury	Intestine	Foot
High temperature tissue destruction	Testis/testes	Tail
High temperature tissue damage	Prostate	Spleen
Heat tissue destruction	Bladder	Bone marrow
Heat temperature tissue damage	Urethra	Brain
Heat inflammation	Kidney	Spinal cord
Heat exposure damage	Eye	Blood vessels
Heat exposure injury	Cornea	Gonads
CNS/Central Nervous	Retina	Ovaries/ovary
Blood–brain barrier	Lens	Gonads
Peripheral nerve system	Iris	Burn injury
	Eyelids

Table II.  Summary of thermal damage threshold data compiled in the earlier review updated with newer literature.

		Type and degree change
		Acute		Chronic
CEM43 (min)	Tissue type	Minor	Significant	Minor	Significant	Animal	Reference
0–20	BBB		H*/F, H/F			Rat/Rabbit, Dog	[4], [5], [32], [33]
	Bone				G	Rabbit	[80]
	Bone Marrow	F/H	H*			Mouse, Rat	[11]
	Brain	H/H	H	H		Rat/Dog, Rabbit, Cat	[4], [5], [10], [11], [34]
	Cornea		F			Human	[74]
	Esophagus		H			Pig	[77]
	Kidney	H	F			Rabbit, Rabbit	[9]
	Muscle		F*/H			Human/Pig	[58], [61]
	Retina			G/H		Rabbit
	Testis	F, F/H	H, H/F/G	F, H	F, F	Mouse, Mouse	[39], [42–44]
	Testis		G, H*			Rat	[10], [41]
	Thymus		H*			Rat	[11]
	Small Intestine		F/H			Rat	[78]
	Nerve		F			Rat	[25], [29], [31]
21–40	BBB		H/F			Rabbit/Dog	[32]
	Brain	H/G	H	H/G		Dog, Rabbit	[34]
	Cornea	G/G				Rabbit/Rabbit	[73]
	Eyelid	G				Rabbit
	Mammary Gland		H			Goat	[81]
	Prostate			H		Dog
	Retina	G				Rabbit
	Skin	F				Mouse
	Small Intestine		H			Mouse
41–80	Bladder		F↓			Rat	[53]
	Bone				G	Rabbit	[80]
	Brain		H*, H/G		H/G	Rabbit, Dog	[34]
	Cornea		G			Rabbit
	Kidney		H			Pig	[63]
	Liver	F ↑*/H				Dog/Rabbit	[52]
	Muscle	H				Pig
	Prostate	H	G			Dog
	Retina		G	G		Rabbit
	Skin		G/H		G/H	Mouse
	Testis		H/F↓		F	Monkey	[45]
	BBB		H			Rabbit	[32]
80–240	Bladder		F ↓		G	Rat, Dog	[53]
	Bone				G	Rabbit	[80]
	Eyelid	G				Rabbit
	Muscle		H	G/H	G/H	Rat, Pig	[56]
	Skin		G/H		G	Pig
	Small Intestine		H		G/H	Pig/Dog
	Testis		G/F		G/F	Rat	[37], [38]
	Testis		F↓	F		Monkey	[46]
	Testis	H/F	H/F↓	F		Human	[40]
	Brain		H		H	Monkey	[35]
	BBB		H			Rabbit	[32]
>240	Cornea		G			Rabbit	[73]
	Esophagus		G			Pig	[77]
	Kidney		H			Pig/Dog	[63–66]
	Liver		H			Rabbit/Pig	[47–49], [51]
	Muscle		H/G			Rabbit/Pig	[51], [59], [60]
	Prostate		H			Dog	[67–70], [72]
	Retina		G/G			Rabbit/ Rabbit	[75]
	Skin		H			Human	[54]
	Brain		H/G		H	Rabbit/Pig/Monkey	[34–36]

Bold, black: new data, Bold, underlined, red: new organs not covered in the previous review, Italicized, blue: data from Table 3 in [1] (reference numbers are not stated in the table). Acute (Tissue evaluated 0–30 days after heat exposure); Chronic (Tissue evaluated >30 days after heat exposure). Damage quantification: Histolopathology (H); Gross appearance (G); Function (F).

BBB - blood brain barrier.

Eyelid study showed no damage up to CEM₄₃ = 9.08 min.

Bladder function (volume) showed the opposite trend at different CEM₄₃.

Ultrasound heating caused tissue damage in cornea at CEM₄₃ as low as 2.7 min, whereas diode laser heating did not show any damage at CEM₄₃ up to 1.26*10³ min.

*signifies whole body heat treatment.

Fig 1. Changes in regional blood brain barrier permeability vs. CEM₄₃ after hyperthermia treatment in rats. (A) Fold increase in BBB permeability immediately after whole body heating with a warming pad by Kiyatkin et al. [4]. (B) Increase in BBB permeability immediately following heating in an incubator to CEM₄₃ = 1.3 min by Sharma [5] and 24 h following heating on a warming pad to CEM₄₃ = 0.1–0.7 min by Noor et al. [6]. In (B), some of the data was offset along the x-axis to show all the data points clearly. All data bound by the dashed lines refer to CEM₄₃ = 1.3 min.

Fig 2. Change in cerebral blood flow vs. CEM₄₃. Measurements were made either during or immediately after whole body hyperthermia treatment in rats, humans, and rabbits [5], [7–9].

Fig 3. Heat-induced cell death in the rat brain. (A) Cell death in several brain regions at multiple assessment times after whole body hyperthermia treatment in rats at CEM₄₃ = 5.9 min [10]. (B) Fold increase in cell death in several brain regions in rats compared to unheated animals, 10 hours after whole body hyperthermia treatment to CEM₄₃ = 15 min [11].

Fig 4. Changes in neuronal excitability in two regions of hippocampus following whole body hyperthermia in rats (immediately and 30 min after heating). Data are shown as percent change with respect to baseline measurements (data connected by lines where assessed at both time points). Two different CEM₄₃ are plotted for the mature rats. (A) P1 Amplitude, (B) P1 Onset Latency [15].

Fig 5. Heat-induced neurotransmitter concentration changes in the rat brain. (A) glutamate, (B) glycine, and (C) GABA levels are shown in relation to CEM₄₃ in various rat brain regions immediately following whole body hyperthermia [5].

Fig 6. Changes in rat brain metabolism immediately after whole body hyperthermia. (A) Metabolic changes were assessed by lactate dehydrogenase (LDH) and succinate dehydrogenase (SDH) activity and RNA content at CEM₄₃ = 1.07 min in three rat brain regions [20], and (B) metabolic changes vs. CEM₄₃, as assessed by extracellular brain lactate, pyruvate, glutamate, and glycerol concentrations vs. CEM₄₃ [8].

Fig 7. Probability of brain lesion induction and blood brain barrier disruption vs. CEM₄₃ in (A) rabbits and rhesus monkeys and (B) pigs [32–36]. In (A), some of the data were offset along the y-axis to show all the data points above CEM₄₃ = 100 min.

Fig 8. Decrease in testes weight compared to control. (A) % Decrease in weight of tested vs. assessment time at several thermal doses. (B) Changes in testicular weight assessed at various times, grouped by CEM₄₃. Human data are included for comparative purposes, but human data was reported as a measure of % decrease in volumetric measures. This chart highlights the differences in thermal sensitivity between mouse, rat, and human testes (blue symbols) [37–41].

Table III.  Changes in testicular tubule dimensions in human subjects heated with CEM₄₃ = 180 min.

Evaluation time point post-treatment	% Change in tubule diameter	% Change in tubule	% Change in lumen volume
2 weeks	−10%	−3%	−3%
9 weeks	+2%	+6%	−11%

Fig 9. Fold increase in cell damage parameters after various heat treatments in mice. (A) Long-term effects, which illustrate that cell damage increases with thermal dose and that the effects occur in two phases: an early and a late phase. (B) Acute cell damage during the first two days.

Fig 10. Indications of sperm function after heating in mice and humans. (A) Early effects of heating on sperm characteristics. (B) Late effects of heating on sperm characteristics. Dashed lines: mouse data with a thermal dose of CEM₄₃ = 7.5 min [44]. Solid lines: human data with a thermal dose of CEM₄₃ = 180 min [40].

Fig 11. Thresholds of thermal damage in eye in rabbits and humans assessed immediately after heating. In rabbits, CEM₄₃ > 21.3 min [73] started causing thermal damage in cornea while thermal lesion in retina was induced at CEM₄₃ = 926 min [75]. In humans, heat treatment at CEM₄₃ = 0.015–34.5 min was not sufficient to cause damage to eyelids [76].

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