ABSTRACT
The toxicity of oxygen to higher animals presents a major problem in the clinical use of high concentrations for treatment of conditions such as gas gangrene9 and carbon monoxide poisoning. The tissues most sensitive to oxygen damage are the lung, which is exposed to the highest 0, concentration of any tissue in the body, and the eye. Exposure of humans to pure 0, at 1 atm pressure for as little as 6 hr can cause respiratory symptoms such as substernal soreness, cough, and sore throat, although some people remain unaffected.lO," Exposure for longer than 24 to 48 hr inevitably causes damage to the alveoli of the lung, manifested at first as an increased thickness of the air-blood barrier caused by edema. Further oxygen exposure causes necrosis of the alveolar epithelium and replacement of the normally thin type-I alveolar cells by larger cells. At a later stage, increased collagen production and lung fibrosis ~ c c u r . ~ . ' ' As for the eye, in 1942 the disease retrolental fibroplasia was identified as the most common cause of infant blindness. Later work confirmed that the occurrence of this disease was correlated with excessive use of 0, therapy in the treatment of premature babies, and more careful control of 0, concentrations within incubators has greatly decreased its incidence. Retrolental fibroplasia has been observed to develop in premature babies exposed to as little as 35 to 40% 0, for 10 days.' Initially there is constriction of ocular blood vessels and necrosis of immature retinal vessels. This is followed by a proliferation of new capillaries in the inner layer of the retina, which extend into the vitreous humor behind the lens and eventually cause retinal detachment. Similar phenomena have been described in other newborn animals, such as kittens.I2
Tissues other than the lung and eye do not escape damage when animals are exposed to high O,, however. Sudden exposure to high-pressure oxygen causes acute central-nervoussystem toxicity, producing convulsions, which are followed by chronic damage.' Lesions of heart, skeletal muscle, and of almost every other tissue have been reported in a wide range of animals. Table 1 lists some typical experimental results. High 0, concentrations also cause a "general stress reaction" in animals, which stimulates the action of some endocrine glands. Administration of thyroxine, cortisone, or adrenaline often potentiates 0,- toxicity symptoms, whereas hypophysectomy, adrenalectomy, or thyroidectomy decreases the sensitivity of animals to oxygen. Exposure of pregnant animals to elevated 0, concentrations has been reported to increase the incidence of fetal abnormalities. Finally, 0, enhances the damaging effects of ionizing radiation; e.g., exposure of Escherichia coli or other bacterial cells to such irradiation in the presence of 0, is much more damaging than is exposure under anoxic condition^.'^'^ Indeed, use is made of this effect in the radiation treatment of cancer of the head and neck with supplemental hyperbaric O2.I4
The damaging effects of 0, on aerobic organisms vary considerably with the type of organism used, its age, physiological state, and diet. To take some examples, cold-blooded animals such as turtles are relatively resistant to 0, toxicity, but they become more sensitive
Adult, male rats
Cats
Rats
Monkeys
Male hamsters
Humans Guinea pigs
Pure 0, at 8 atm for 50 min
Pure 0, at 0.33 atm for 3 days
70% 0, for 3 - 4 weeks
"Hyperbaric 0, therapy" 70% 0, at 1 atm for 6 3 6 days
Heart Mitochondrial swelling, followed by damage to myofibrils
Kidney Swelling of tubules, glomemlar abnormalites
Liver Mitochondrial damage
Liver Proliferation and abnormality of smooth endoplasmic reticulum, decrease in glycogen content
Testes Degeneration of seminiferous epithelium, cessation of sperm production
Ear Hemonhages of inner ear, deafness Bone-marrow Inhibition of erythroid cell development
Oxygen toxicity is also influenced by the diet of an animal, in particular its content of vitamins A and E, heavy metals, antioxidants, and polyunsaturated fatty acids.16 Iron salts generally potentiate oxygen t o x i ~ i t y ~ , " , ' ~ - ~ ~ and there have been several reports of protection against 0, toxicity by metal-ion chelators.I7 Rats fed on a fat-free test diet supplemented with cod-liver oil can tolerate pure oxygen much better than rats supplemented with coconut oil." Vitamin E deficient animals are more sensitive to oxygen than normal animals.,'
Even so-called "obligate anaerobes" display a wide spectrum of oxygen tolerance.23 Some are killed by even a brief exposure to O,, whereas others can survive exposure to O,, albeit with growth inhibition, i.e., 0, is bacteriostatic rather than bactericidal. Some bacteria, the "microaerophiles", require a little 0, for growth but cannot tolerate atmospheric concentrations.
