g) The appearance of conjugated fatty acids as an effect of radiation has posed the problem of the role of these abnormal fatty acids as intermediary agents in the biological changes induced by radiation. In trying to solve it, we compared the effects obtained by administration of conjugated fatty acids with those of radiation at different levels of organization. This study was facilitated by considering the changes which take place in the cellular cytoplasm and nuclei as induced by various substances designated as radiomimetic agents.

Table XVI. Oxalic Index Of Fatty Acids Of Radiation Burns

Elapsed Time

Average

Normal Skin Non treated wound

Wound with 25 mg. radium in monel metal for 2 hours

24 hours 48 hours 72 hours 6 days 2 hours 24 hours 48 hours 4 days

1 week

2 weeks

3 weeks

0.1 2.2 3.9 2.3 1.8 1.2 6.1 13.9 19.1 31.0 46.0 49.4

It could be seen that apparently all agents which induce radiomimetic effects are lipoids with negative polar groups. The effects of higher polyunsaturated fatty acids, and especially the conjugated isomers, appear to be the same as those of known radiomimetic agents. The similarity between the effects of these fatty acids and those of radiation makes it logical to consider that at least some of the radiation induced changes result from the intervention of these abnormal fatty acids.

We have seen that the changes induced by fatty acids upon cell metabolism are in large part due to an increase in cell membrane permeability. A similar change of cell membrane permeability could be recognized among the effects of radiation. Following radiation, it could be seen that sodium of the interstitial fluids penetrates into the cells more readily. This was observed when radioactive sodium was used. (42) The cellular vacuolization seen to follow radiation, especially higher doses, represents a corollary of the abnormal penetration of sodium into the cells which partly results from the increase in membrane permeability.

h) At the tissular level, the influence exercised by radiation upon pain was seen to greatly resemble that induced by administration of fatty acids. Radiation efficiently relieves pain that has an acid pattern but it may increase pain of an alkaline pattern. Furthermore, pain which appears following radiation has an alkaline pattern and consequenUy is increased by further radiation, or administration of unsaturated fatty acids. (Note 4) i) At the tissular level, it could be seen that the area of ulceration of the standard lesions obtained through irradiation of skin wounds was increased by the administration of polyunsaturated fatty acids in general. In some cases the ulceration doubled in size as compared to controls. The administration of fatty acids also markedly delayed wound healing. When the quantity of fatty acids administered was great enough, the wounds did not heal at all. Six daily subcutaneous injections, each of 1 cc. of a 10% oily solution of cod liver oil fatty acids, prevented healing. (Fig. 92) The area of ulceration was even greater when only 1/4 cc. of a 10% solution of the conjugated fatty acid isomers, obtained through an in vitro conjugation of the preparation of cod liver oil fatty acids, was administered under the same conditions. This showed that conjugated fatty acid isomers had a more manifest effect upon radiation wounds than the unconjugated acids obtained from the same source.

j) We followed effects of intensive radio and radium therapy in humans at organic levels. In cases with radiation induced proctitis, mucositis, or epidermitis, the changes observed were seen to correspond to the pattern encountered with fatty acid predominance, and especially to the pattern induced by abnormal fatty acids. The appearance of oxidizing substances in the urine is frequently observed in patients with radiation burns after extensive X ray therapy. They were almost consistently seen in those cases in which radiation lesions were produced. The administration of fatty acids, and particularly of conjugated fatty acids, to these patients increased the intensity of the lesions.

k) Systemic changes induced by intensive radiotherapy were also analyzed. Here again, the changes followed the pattern observed when there is a predominance of fatty acids, particularly of abnormal fatty acids. The appearance of oxidizing substances in the urine was frequently noted after intensive X ray therapy and, as mentioned previously, was consistently observed in those cases in which a radiation lesion was produced. Other systemic effects of intensive radiotherapy were seen to include an increase in urinary excretion of surface active substances, an increase of potassium in serum, a retention of chlorides and water, and particularly, an increase in the sulfhydryl index indicating an exaggerated excretion of this group. These changes following intensive radiation are, as previously noted, similar to those seen when a predominant intervention of fatty acids occurs.

Certain of these changes appear to have prognostic importance for radiation therapy. For example, in several cases with very low urinary surface tension, high retention of chlorides and absence of urinary peroxides. The continuation of irradiation led to death. (Note 4) This is consistent with the findings in animals that lethal effects of irradiation are directly related to the appearance of large amounts of surface active substances in the urine.

Lipids and radiation wounds

Fig. 92. Lipids and radiation wounds. Radiation wounds 5 weeks after exposure to 10 mgr. radium in platinum—for 96 hours, (a) Untreated controls; (b) treated daily with 1 cc of a cod liver oil fatty acids 10% solution; (c) treated daily with 0.5 cc of a 10% solution of unsaponifiable lipid fraction extracted from human placenta. The treatment with fatty acids results in larger lesions than in controls, with no tendency to heal. The treatment with the unsaponifiable fraction leads to a healing of the lesion in around three weeks.