Oral Radiation Death Research Articles

The Nature of Intestinal Radiation Death1

This paper, and the two which will follow it (1, 2), deal with the intestinal mode of acute radiation death. Some new observations will be presented. However, this paper is mainly concerned with the relations between observed facts. It is an attempt to give a coherent account of one mode of radiation death, studied at various levels of organization from the cell to the whole organism. We shall try to identify the critical event on the cellular level; to trace its effects through the biology of the tissue involved, the intestinal epithelium; to relate the tissue changes to responses of the whole intestine; and to see in what manner the organ changes are responsible for the death of the whole animal. The picture is rough and unfinished in spots, but it leads to an interpretation which, though tentative, is unified. Some years ago, ‘‘acute radiation death’’ was, to most investigators, simply that mode of death which occurs after whole-body irradiation with X-rays or c-rays, with doses in the neighborhood of the LD50. This has changed. Since investigations have been extended to wider dosage domains, more species, a wider range of conditions, and, in particular, since it has become possible to prevent marrow death by specific treatments, other modes of radiation death have grown in importance. This has created a need for more precise concepts. A particular mode of acute radiation death occurs if a particular component of the acute radiation syndrome is severe enough to cause death. The isolation of a particular process can be difficult. Any mode can be expressed only if not masked by another lethal process. A faster process masks a slower one; a more sensitive process, a less sensitive one. For instance, death due to late changes of the central nervous system cannot be observed after wholebody irradiation; it is masked by marrow death. Therapeutic measures, or modifications of the radiation conditions, may unmask modes of radiation death which are not expressed under standard conditions. For instance, oral radiation death can be unmasked by treatment with spleen, or by regional irradiation. Use of fast neutrons brings out a mode of death which is recessive after treatment with X-rays and c-rays (3–6). Under the conditions most commonly used, marrow death masks all other modes (7).

Modification of oral radiation death syndrome with combined WR–2721 and misonidazole

We wish to respond to the opinion stated in the letter by Drs. Hewitt and Porter (1982). It is not unreasonable to conclude that irradiation of the head region will lead to oral reaction and cause animal starvation. However, such a conclusion may not be warranted based upon the work of Quastler et al (1956).

Modification of the oral radiation death syndrome with combined WR–2721 and misonidazole

We have read with grief and indignation the paper by Grigsby and Maruyama (1981). It appears that the mice in their experiments suffered, or narrowly escaped, death from starvation and thirst while their mucosae were too sore to permit swallowing. Experimental animals should not be subjected to such misery, and it is no credit to The British Journal of Radiology to publish a paper that recommends so cruel a procedure as providing “an excellent endpoint”.

Modification of the oral radiation death syndrome with combined WR-2721 and misonidazole

In order to investigate the combined use of radioprotective and radiosensitizing chemicals we have used WR--2721 and misonidazole to study their combined chemical toxicity and radiomodifying effects in our model using the oral radiation death (ORD) syndrome as the endpoint. Our data demonstrate that WR-2721 does protect against the ORD syndrome. Misonidazole does not protect against the ORD syndrome. Misonidazole does not sensitize the normal oral cavity to local irradiation. WR-2721 and misonidazole produce additive toxicity when injected simultaneously and the combination can provide an overall protective response to the ORD syndrome. We conclude that the combination may be potentially useful for the treatment of cancers of the oral cavity.

Radioprotection of oral cavity structures by wr-2721

The finding of a high concentration of 35S WR-2721 in mouse salivary glands led to studies of possible radioprotection of these glands from ionizing radiation. Oral effects of radiation in the presence of WR-2721 were studied in mice and dogs. The dose required to induce the oral radiation death syndrome (LD50/8–10) was increased by a factor of 2.1 in BALB/c mice when WR-2721 was given 30 minutes before irradiation of the head. Salivary flow in mongrel dogs following doses of 1000–3000 rad showed similar depression with and without the use of WR-2721. Therefore, the salivary gland may be an organ for metabolism or secretion of WR-2721 accounting for its high drug concentration. The skin and oral mucosa were protected by a factor of 1.7 (2500 rad with WR-2721 = 1500 rad without WR-2721) at moderate radiation reactions. This protection decreased to 1.2 at the level of radionecrosis (3000 rad with WR-2721 = 2500 rad without WR-2721). At clinically acceptable radiation reactions, WR-2721 offers the possibility of significant protection of normal epithelial structures of the head and neck.

Local protection against x-irradiation by dimethylsulphoxide.

Local radiation protection by the topical application of cysteamine was demonstrated by Fogh (1960) who found that the application of 1 per cent cysteamine in Vaseline before X-irradiation lessened the degree of epilation and ulceration in irradiated patches of rabbit skin. Goepp and Fitch (1968) protected mice against oral radiation death by painting saturated aqueous solutions of AET or cysteamine on the surface of the tongue. Several investigations have demonstrated the radioprotective properties of dimethylsulphoxide (DMSO); in different systems.

Topical Chemical Protection against Oral Radiation Death in Mice

The effect of topical application of protective chemicals on the mortality and histopathologic changes of oral radiation death in mice was studied. The chemicals mercaptoethylamine (MEA), aminoethylisothiuronium (AET), and p-aminopropriophenone (PAPP) were applied to the dorsal surface of the tongue in C57B1 male mice. Preirradiation treatment with MEA produced a calculated dose-reduction factor of 1.35, and AET produced a calculated dose-reduction factor of 1.29. Repeated trials with PAPP failed to produce any detectable protection. The postirradiation histologic changes in the tongues of protected mice were the same as those seen in irradiated control mice except that the changes were far less severe and the protected tongues had recovery at 1 week after irradiation, while the irradiated controls exhibited ulceration on the ninth postirradiation day. The histologic evidence suggested that there was appreciable protection by two of the chemicals, MEA and AET, and further that the DRF values, which are based on mortality, do not fully indicate the degree of chemical protection because it was apparently impossible to consistently apply the chemicals to the posterior area of the tongue, the area most critically sensitive to irradiation.

The Use of Parenteral Chemicals for Protection against Oral Radiation Death in Mice

The effect of parenteral administration of protective chemicals on mortality in oral radiation death was studied. The chemicals p-aminopropriophenone (PAPP), mercaptoethylamine (MEA), and aminoethylisothiuronium (AET) were administered intraperitoneally in C57Bl male mice at the following dosage levels: PAPP, 30 and 60 mg/kg in propylene glycol and water; MEA, 400 mg/kg aqueous; and AET, 225 mg/kg aqueous. Anesthetized mice were irradiated to the head in a manner to produce oral radiation death. Preirradiation MEA treatment produced an LD50 of 2159 R as compared to irradiated control groups LD50 of 1624 R, giving a DRF of 1.33. Similarly AET treatment produced an LD50 of 1902 R compared to a control LD50 of 1626 R, giving a DRF of 1.16. PAPP at 30 mg/kg produced an LD50 value of 1880 R and at 60 mg/kg 2049 R, with controls at 1626 R, thus giving a DRF of 1.16 and 1.26, respectively. Further studies with PAPP as related to methemoglobinemia and under conditions of hyperbaric oxygen produced results which i...

Effects of Radioprotective Chemicals on the Histopathologic Changes of Oral Radiation Death in Mice

Effects of Radioprotective Chemicals on the Histopathologic Changes of Oral Radiation Death in Mice

Prevention of Death in Mice after Lethal Irradiation of the Head

Several species of laboratory animals die 9 to 14 days after irradiation of the head with 2000 to 4000 r. Such is preceded by a progressive weight loss starting about 5 days after irradiation and has been termed by Quastler et al. oral radiation death (1). Previous studies on mice in this laboratory have indicated that starvation and dehydration play a major role in the of the animals (2). Changes in the mucosa of the posterior dorsum of the tongue and of the soft palate became evident about 5 days after irradiation, the mice began to lose weight, and the water intake and urine output decreased markedly. The weight loss was progressive, amounting to about 39% at the time of 9 to 11 days after irradiation. The changes in the mucosa progressed to frank ulceration about 8 to 9 days after irradiation. These ulcerations, occurring always in the same place, apparently interfered with the normal ingestion of food and water. It appeared that, if nutrition and hydration could be maintained in some manner other than the normal way of feeding, might be prevented. The present study was undertaken to investigate the effects of liquid diets, parenteral feedings, and gastrostomy tube feedings.

Pathological Study of Oral Radiation Death in Mice

Male C57BL/6 mice were given x irradiation to various areas of the head. Irradiation of the entire head with 2000 r, or of the lower jaw and tongue with 4000 r, resulted in 100% mortality. Survival time after fatal head irradiation averaged 9 days, after fatal irradiation of the tongue and lower jaw, 11 days. lrradiation of other areas of the head with these amounts of x irradiation was not fatal. Histologic damage to the posterior surface of the tongue and of the soft palate is evident beginning 5 days after irradiation. The extent of ulceration was greater when the entire head was irradiated. Atrophy of the lymphoid tissue and other organs became marked shortly before death. Fluid intake and urine output decreased after the fifth postirradiation day and was accompanied by a marked, rapid weight loss which averaged 39% at the time of death. Gross and microscopic changes and similar weight loss were found in unirradiated mice dying after deprivation of food and water. Dehydration and starvation appear to be important lethal factors in mice dying 9 to 11 days after irradiation of the head with doses of 2000 to 4000 r. This process apparently starts about the fifthmore » day after irradiation at a time when morphologic changes are present in the tongue. The mucosal damage, progressing to ulceration, appears to interfere with the ingestion and swallowing of food and water.« less

Periodontal tissue changes induced in young rats by roentgen irradiation of the molar regions or the head.

Young rats were x irradiated over the head region with single doses of 1000, 2000, and 3000 r, and other rats received single doses of 1725 and 2400 r administered to the molar regions only. The animals were observed over periods ranging from 2 to 58 days after irradiation. In the first group, the rats irradiated with 1000 r displayed a decreased cellularity of the periodontal membrane, degeneration of osteocytes, and suppressed activity of osteoblasts and osteoclasts. Rats which received 2000 and 3000 r all became moribund or died within 8 to 10 days, exhibiting a characteristic erosion of the epithelial lining of the oral cavity. In the second group, two types of periodontal lesions could be distinguished. One was characterized by severe destruction of the periodontium of either the first or the third molar, leaving the other molars relatively unaffected. These lesions were initiated by ulcerations of adjacent parts of the oral mucous membrane. The other type comprised less severe changes originating in the periodontal tissues proper. They consisted of a lack of proliferation of the interdental papilla epithelium, a deficient inflammatory response, clumping of the collagen, and suppression of the functions of the osteoblasts and osteoclasts. Erosion ofmore » the epithelial lining of the oral mucous membrane observed in the 2000 and 3000 r groups is comparable to the loss of epithelial lining of the intestine of animals given total-body irradiation, and succumbing to intestinal radiation death. The loss of oral epithelium may be an important factor in the syndrome leading to oral radiation death, a previously described syndrome. It was significant that when serious periodontal lesions did develop, they were always seen in connection with ulcerations of mucous membrane areas closely related to, but not part of the periodontal tissues. It was also characteristic that the periodontal tissues ciosest to the mucous membrane lesion were the most affected whereas the remainder were conspicuously unaffected. Severe periodontal lesions were not observed in rats which did not display lesions of the adjacent mucous membrane. Consequently, the severe periodontal destructions observed in some rats did not originate as lesions of the periodontium, but were secondary to ulcerations of the adjacent mucous membrane. The infectious processes thus established expanded relatively unopposed in the radiation-damaged tissue. This mode of development of the severe periodontal lesions is in contrast to observations made on monkeys and dogs, in which the destruction of the periodontium was initiated in the gingiva. In all species, loss or loosening of teeth, caused by inflammatory changes superimposed on decreased resistance to infection, leads to destruction of collagen fibers and resorption of alveolar bone. When rats were subjected to extraction of a molar, this resulted in the development of radioosteomyelitis in some irradiated animals. This condition was characterized by a penetrating destruction of the jaw of an infectious nature with extensive soft and hard tissue necrosis associated with resorption and sequestration of bone. It was considered to be an extension of an inflammatory necrotizing process initiated by ulcerations of mucous membrane areas adjacent to, but not part of the periodontium. (BBB)« less

Oral Radiation Death

stricted terms radiation death in covers a number of distinct modes of death. Each particular mode of death can be thought of as the fullest expression of a particular component of the radiation syndrome. The characterization and isolation of the various modes constitutes the modal analysis of radiation death. This involves the recognition of diagnostic features which differentiate one mode from the others and the development of experimental procedures which emphasize one particular component of the radiation syndrome and suppress all others as far as possible. Only three modes of acute radiation death in mammals have been identified reasonably well: marrow death, intestinal death, and brain death. There is evidence for at least half a dozen other modes, all associated with survival of less than 30 days. The present paper deals with a mode of radiation death which emerges as a distinct entity from a considerable body of experimental data. This mode of death resembles marrow death with regard to survival time, which is about 9 to 10 days and is invariant (or nearly so) over a considerable range of doses. It differs in having a higher threshold value (1 kr and up, as compared with about 0.5 kr). Also, unlike marrow death, which seems to occur only when the whole of the hemopoietic tissue is irradiated, the mode under consideration can be produced by irradiating only