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The relative biological effectiveness of cyclotron fast neutrons for early and late damage to the small intestine of the mouse
Europ. J. Cancer Vol. 10, pp. 99-I02. Pergamon Press 1974. Printed in Great Britain
The Relative Biological Effectiveness of Cyclotron Fast Neutrons for Early and Late Damage to the Small Intestine of the Mouse J. P. GERACI, K. L. JACKSON, G. M. CHRISTENSEN, R. G. PARKER, M. S. FOX and P. D. T H R O W E R Department of Radiology, University of Washington, Seattle, Washington 981.95, U.S.A.
Abstract--The R B E for damage to the small intestine should be determined prior to treatment of cancer in the abdomen and pelvis with fast neutrons. It is particularly important to make certain that the R B E for late damage is no greater than the R B E for acute injury to this organ. In the present study the LD s o/ 5 aayfollowing whole-body irradiation was used to measure the sentivity of the intestinal tract to acute injury. The LD 50/9 o day,following irradiation of a 4 cm segment of small intestine, was used to assess late damage to this structure. Relative to X-radiation, thefast neutron R B E for late damage (1 "9) did not differ significantly from the fast neutron R B E for acute injury (1.8). The mechanism of death following partial intestine irradiation with neutrons or X-radiation was associated with bowel obstruction. A neutron dose of 1 "2 krad delivered to only a small segment of the small intestine produced 50 ~ mortality within 90 days.
INTRODUCTION
ulceration, fibrosis, and stricture leading to luminal obstruction and death if not surgically corrected. The purpose of the present study was to determine the RBE for fast neutron-produced late death of mice as a result of segmental small intestine exposure. LD 5 o/5 day measurements following whole-body irradiation also were made in order to compare in the same laboratory the RBE of fast neutrons for acute intestinal iniury.
ThE RELATIVE biological effectiveness (RBE) for damage to the small intestine, a normal tissue at risk, should be determined prior to treatment of cancer in the abdomen and pelvis with fast neutrons. It is particularly important to make certain that the RBE for late damage is no greater than the RBE for acute injury to this organ. Several investigators have estimated the acute RBE for fast neutron damage to the intestine by measuring the LD s o/s day or the survival of stem cells in the intestinal mucosa following whole body exposure [i-3]. The values obtained varied between 1.4 and 3-0, depending on the energy of the neutron beam used. However, in radiation therapy usually only a portion of the intestine is included in the treatment field. The potential late complications resulting from irradiation of only a segment of intestine include local mucosal
MATERIAL AND METHODS Animals
Female Swiss I C R mice (18-22g) were obtained from Charles River Laboratory (Wilmington, Mass.) and were housed in the University of Washington vivarium for at least one week prior to experimentation. The animals were given Purina chow and water ad libitum.
Accepted 12 December 1973. 99
100
J. P. Geraci, K. L. Jackson, G. M. Christensen, R. G. Parker, M. S. Fox and P. D. Thrower
Whole-body irradiation Mice were retained in plexiglass boxes of sufficient size to allow them to turn around during irradiation and groups of 8 mice were exposed to graded doses of neutrons or X-rays. X-rays were generated by a General Electric Maxitron therapy unit (dose rate about 100 rad/min; 50 cm tube target to animal distance; 250 kVp; 0.5 m m Cu, 1 m m A1 added filtration). The absorbed dose was measured with thermoluminescent dosimeters (TLD) surgically inserted in the abdomen of the animals. Neutrons of 8 MeV mean energy were produced by bombarding a beryllium target with 21 MeV deuterons at the University of Washington cyclotron. The animalswereirradiated at 125 cm from the Be target at a neutron dose rate of about 35rad/min. Neutron dosimetry was carried out with a tissue equivalent ionization chamber in conjunction with aluminum pellet activation analysis. Aluminum pellet activation was used to determine the dose rate in various areas of the beam. Partial intestine irradiation Under nembutal anesthesia, 4 cm segments of surgically exteriorized small intestines immediately proximal to the ceca were exposed to graded doses of X-rays or neutrons according to a modification of the procedure described by Osborne [4]. For X-irradiation, 4 animals were positioned around the sides of an 8 x 8 cm square aperture in a ,Xin. thick sheet of lead with the 4 cm segment of intestine located in the primary beam. For neutron irradiation a similar technique was employed. A square field was produced by means of a square aperture in an aluminum-bronze alloy, borated plastic collimator (Fig. 1). The radiation field produced by this collimator has been described previously [5]. To keep the intestine moist and to supply radiation dose "build-up" material, the exteriorized segment of intestine was sandwiched between several thicknesses of saline soaked gauze. The X-ray dose rate at 30 cm from the X-ray tube target was about 200 rad] min as determined with TLD. The neutron dose rate was about 175 rad/min at the intestine position as determined with a tissue equivalent ionization chamber. The segment of intestine was located 70 cm from the beryllium target. Statistics LDso and RBE and their 95% confidence intervals were calculated by graphical probit analysis according to the procedure described by Litchfield and Wilcoxon [6].
TARGEIL_BRONZE/
STEELf
BORATED WEP-REStN
DIAGRAM OF RADIOBIOLOGY COLLIMATOR
Fig. 1. Biology collimator used for partial intestine irradiation with fast neutrons. Four anesthetized mice were positioned at the face of the collimator such that a 4 cm segment of the small intestine of each mouse protruded into the neutron beam while the rest of the animal was shielded.
RESULTS
The mortality curves used to estimate the LDso/5 day for single whole-body neutron and X-ray exposures are shown in Fig. 2. The LDs0/s day for X-radiation was 1-06 krad and for neutrons it was 0.59 krad, giving an RBE of 1.8. Figure 3 illustrates the cumulative mortality after partial intestine irradiation with single exposures of neutrons or X-rays. The data show a high incidence of mortality during the second week after exposure followed by a slower rate of death. Most of the deaths observed occurred by 60 days but there were a few deaths as late as 9 months after irradiation. The data in Fig. 3 also indicate that when the ratio of mean X-ray dose to mean neutron dose was approximately 2 :l, there was no difference in the cumulative mortality produced by the two types of radiation. Figure 4 illustrates the gross pathology of the gastrointestinal tract observed at, or shortly before, death as a result of partial intestine irradiation with neutrons or X-rays. The animals exhibited distension of' the small intestine proximal to bowel obstruction at the irradiated site. This response was seen in all animals examined that died between 6 days and 9 months post-irradiation. Post-mortem histological examination of the irradiated segment of bowel showed the lumen to be obliterated by inflammatory tissue in animals which
The Relative Biological Effectiveness of Cyclotron Fast Neutrons NEUTRONS A-A
LDso= 5 8 5
X-RAY
LD=o= 1 0 6 2
(3"0
RBE = 1.8
the villi in a shielded area of the intestine (Fig. 5a). Adjacent to the irradiated segment the intestine was altered by vascular engorgement with focal hemorrhage, edema, and sparse and short villi (Fig. 5d). No unique differences were noted between X-irradiated and neutron-irradiated intestines. The dose-mortality curves used to estimate the LDso/90 day for partial intestine exposure are shown in Fig. 6. With X-rays the LDso/9o d.y was 2"26 krad and with neutrons it was 1.18 krad, yielding an RBE of 1.9.
(537-637) (969-1162| (2.0-1.7)
100
f
75
101
IZ t4J
~Oso O_
Z~
NEUTRONS ~
LDso=IISO(II09-1255)
X-RAY
LDso=2260(2132-2395) R BE=1,9(1.8-2.2)
~
25 10C
0
S
I 5
0
-
I0
15
DOSE RADS x I0 =
75
Fig. 2. Dose-mortality response 5 days following single whole-body neutron or X-ray exposures. Each point represents the per cent mortality of 7-8 animals. Best fit curves were determined by chi square analysis of probit curves. LD so and RBE values are followed by the 95% confidence limits.
o
Z~ a.
50-
90 80 25 7C )k-
2.0 krad x-roy
-; 60
(n:llT, ronge l.O-3.0krad) ~ d L
k-
..,,s
o 50 =E
0
A
0 z~
40
'"
AA~ 5
I
~
I0 v
v
L~
m
25
]
30
Dose Rods x 102
bJ 0 n
-
Fig. 6. Dose-mortality response 90 daysfollowing segmental intestine irradiation with neutrons or X-rays. Each point represents the per cent mortality of 8-12 animals. Best fit curves were determined by chi square analysis of probit curves. LDso and RBE values are foUowed by the 95% confidence limits.
3(]
20 I.I kraal neufron (n=142, ronge O.2-2.5krad)
I0
0
20
30
I I 40 50 DAYS
I 60
! 70
I 80
I 90
Fig. 3. Cumulative mortality following graded doses neutrons or X-rays delivered to a 4 cm segment of small intestine.
succumbed during the second week (Fig. 5b). Animals dying after the second week had a reduced bowel lumen, hypertrophy of the muscularis, and sometimes a regenerated mucosa with blunted villi (Fig. 5c) as compared to
DISCUSSION
Animals receiving whole-body radiation exposures which result in gastro-intestinal death succumb within 5 days because of fluid and electrolyte loss, toxemia, and nutritional impairment [7]. In contrast, most of the animals receiving segmental intestine irradiation with fast neutrons or X-rays die from bowel obstruction between 6 and about 60 days after exposure. The high mortality rate which occurs
~
~
:: 17 ~?:-~ i!¸
:
~;?:
::
L:::
Fig. 5. Histological cross sections oJ" hematoxylin-eosin stained, shielded and irradiated small intestine. (A) Shielded area of intestine from an animal which died 25 days ajter segmental intestinal exposure. (B) Segment of irradiated intestine of an animal which died 12 days after ex/,osare. (C) Segmellt of irradiated intestine qf animal which died 34 dcL~,sq/?er ex/~osure. (1)) Segment of i~te.~lip~eadjacent /o a bo~,el obstr~wtion (!/"animal which died 25 days after exposure.
Fig. 4.
Gross pathology resulting from neutron or X-ray exposure oJ a 4 cm segment of small intestine.
[to lace p. t02
102
J. P. Geraci, K. L. Jackson, G. M. Christensen, R. G. Parker, M. S. Fox and P. D. Thrower
during the second week (Fig. 3) post-exposure appears to result from complete obliteration of the lumen by inflammatory tissue (Fig. 5b) whereas later deaths are associated with stricture (Fig. 5c). However, the potency of neutrons relative to X-radiation for production of these forms of late damage to the intestine is not significantly different from that for production of acute intestinal damage. The confidence limits of the RBE for the LDso/5 day overlapped those of the RBE for the LDso/9o day (Fig. 2 and 6). Thus, the intestine is similar to skin [8] in that there is little difference in the neutron RBE values for early v late responses in these tissues. The neutron LD 5 o/9 o day of 1"18 krad for late death from irradiation of only a small segment of the intestine may be of clinical
importance. In the treatment of intrapelvic and intra-abdominal cancers by protracted, fractionated neutron exposures the accumulated dose to portions of the small intestine may exceed 1.2 krad. This becomes important when one considers that the rather large capacity of the small intestine to repair iniury following photon irradiation is markedly reduced with fast neutrons [3, 9-11]. Therefore, the possibility of intestinal damage should be seriously considered in fast neutron therapy of abdominal and pelvic tumors where the same segment of intestine is repeatedly exposed. Acknowledgments--Appreciation is expressed to the Medical Radiation Physics Division for the X-radiation and neutron dosimetry. This work was supported by U.S. Public Health Service Grant CA 12441 and Research Career Development Award CA 41735.
REFERENCES
1.
J . j . BROERSE, Dose-mortality studies for mice irradiated with X-rays, gamma-
2.
J . J . BROERSE, G. W. BARENDSEN, G. FRERIKS and L. M. VAN PUTTEN, RBE
rays and 15 MeV neutrons. Int. J. Radiat. Biol. 15, 115 (1969). values of 15 MeV neutrons for effects on normal tissue. Europ. J. Cancer7, 171 (1971). 3.
S. HORNSEY, S. VATISTAS, D. K. BEWLEY and C. J. PARNELL, The effects of
fractionation on four-day survival of mice after whole-body neutron irradiation. Brit. J. Radiol. 38, 878 (1965). 4.
5.
6. 7.
8. 9. 10. 11.
J.W.
OSBORNE, K. N. PRASAD and G. R. ZIMMERMAN, Changes in the rat
intestine after X-irradiation of exteriorized short segments of ileum. Radiat. Res. 43, 131 (1970). P. WOOTTON, H. BIGHSEL,J. EENMAA,R. G. PARKER, K. WEAVER, D. L. WILLIAMSand W. G. WYCKOFF,The University of Washington Fast Neutron Beam Therapy Facility. Boston Workshop on Practical Clinical Criteriafor a Fast Neutron Generator, May 28-29, (1973). J . T . LITCtlFIELD and F. W. WILCOXON,A Simplified method of evaluating dose-effects experiments. J. Pharmacol. expt. Therapy 96, 99 (1949). V . P . BOND, T. M. FLIEDNER and J. O. ARCHAMBEAU, Mammalian Radiation Lethality. Academic Press, New York (1965). S.B. FIELD, Early and late reactions in skin of rats following irradiation with X-rays or fast neutrons. Radiol. 92, 381-384 (1969). K. NAKAGAWA, Intestinal damage following a single and fractionated irradiation with fast neutrons. Nippon Igaku Hoshasen Gakki Zasshi 29, 241-450 (1969). (In Nud. Sci. Abstr. 24, 290, 1970). J . j . BROERSEand H. ROELSE, Survival of intestinal crypt cells after fractionated exposure to X-rays and 15 MeV neutrons. Int. J. Radiat. Biol. 20, 391-395 (1971). H . R . WITHERS,J. T. BRENNANand M. M. ELKIND,The response of stem cells of intestinal mucosa to irradiation with 14 MeV neutrons. Brit. J. Radiol. 43, 796-801 (1970).
The Relative Biological Effectiveness of Cyclotron Fast Neutrons for Early and Late Damage to the Small Intestine of the Mouse J. P. GERACI, K. L. JACKSON, G. M. CHRISTENSEN, R. G. PARKER, M. S. FOX and P. D. T H R O W E R Department of Radiology, University of Washington, Seattle, Washington 981.95, U.S.A.
Abstract--The R B E for damage to the small intestine should be determined prior to treatment of cancer in the abdomen and pelvis with fast neutrons. It is particularly important to make certain that the R B E for late damage is no greater than the R B E for acute injury to this organ. In the present study the LD s o/ 5 aayfollowing whole-body irradiation was used to measure the sentivity of the intestinal tract to acute injury. The LD 50/9 o day,following irradiation of a 4 cm segment of small intestine, was used to assess late damage to this structure. Relative to X-radiation, thefast neutron R B E for late damage (1 "9) did not differ significantly from the fast neutron R B E for acute injury (1.8). The mechanism of death following partial intestine irradiation with neutrons or X-radiation was associated with bowel obstruction. A neutron dose of 1 "2 krad delivered to only a small segment of the small intestine produced 50 ~ mortality within 90 days.
INTRODUCTION
ulceration, fibrosis, and stricture leading to luminal obstruction and death if not surgically corrected. The purpose of the present study was to determine the RBE for fast neutron-produced late death of mice as a result of segmental small intestine exposure. LD 5 o/5 day measurements following whole-body irradiation also were made in order to compare in the same laboratory the RBE of fast neutrons for acute intestinal iniury.
ThE RELATIVE biological effectiveness (RBE) for damage to the small intestine, a normal tissue at risk, should be determined prior to treatment of cancer in the abdomen and pelvis with fast neutrons. It is particularly important to make certain that the RBE for late damage is no greater than the RBE for acute injury to this organ. Several investigators have estimated the acute RBE for fast neutron damage to the intestine by measuring the LD s o/s day or the survival of stem cells in the intestinal mucosa following whole body exposure [i-3]. The values obtained varied between 1.4 and 3-0, depending on the energy of the neutron beam used. However, in radiation therapy usually only a portion of the intestine is included in the treatment field. The potential late complications resulting from irradiation of only a segment of intestine include local mucosal
MATERIAL AND METHODS Animals
Female Swiss I C R mice (18-22g) were obtained from Charles River Laboratory (Wilmington, Mass.) and were housed in the University of Washington vivarium for at least one week prior to experimentation. The animals were given Purina chow and water ad libitum.
Accepted 12 December 1973. 99
100
J. P. Geraci, K. L. Jackson, G. M. Christensen, R. G. Parker, M. S. Fox and P. D. Thrower
Whole-body irradiation Mice were retained in plexiglass boxes of sufficient size to allow them to turn around during irradiation and groups of 8 mice were exposed to graded doses of neutrons or X-rays. X-rays were generated by a General Electric Maxitron therapy unit (dose rate about 100 rad/min; 50 cm tube target to animal distance; 250 kVp; 0.5 m m Cu, 1 m m A1 added filtration). The absorbed dose was measured with thermoluminescent dosimeters (TLD) surgically inserted in the abdomen of the animals. Neutrons of 8 MeV mean energy were produced by bombarding a beryllium target with 21 MeV deuterons at the University of Washington cyclotron. The animalswereirradiated at 125 cm from the Be target at a neutron dose rate of about 35rad/min. Neutron dosimetry was carried out with a tissue equivalent ionization chamber in conjunction with aluminum pellet activation analysis. Aluminum pellet activation was used to determine the dose rate in various areas of the beam. Partial intestine irradiation Under nembutal anesthesia, 4 cm segments of surgically exteriorized small intestines immediately proximal to the ceca were exposed to graded doses of X-rays or neutrons according to a modification of the procedure described by Osborne [4]. For X-irradiation, 4 animals were positioned around the sides of an 8 x 8 cm square aperture in a ,Xin. thick sheet of lead with the 4 cm segment of intestine located in the primary beam. For neutron irradiation a similar technique was employed. A square field was produced by means of a square aperture in an aluminum-bronze alloy, borated plastic collimator (Fig. 1). The radiation field produced by this collimator has been described previously [5]. To keep the intestine moist and to supply radiation dose "build-up" material, the exteriorized segment of intestine was sandwiched between several thicknesses of saline soaked gauze. The X-ray dose rate at 30 cm from the X-ray tube target was about 200 rad] min as determined with TLD. The neutron dose rate was about 175 rad/min at the intestine position as determined with a tissue equivalent ionization chamber. The segment of intestine was located 70 cm from the beryllium target. Statistics LDso and RBE and their 95% confidence intervals were calculated by graphical probit analysis according to the procedure described by Litchfield and Wilcoxon [6].
TARGEIL_BRONZE/
STEELf
BORATED WEP-REStN
DIAGRAM OF RADIOBIOLOGY COLLIMATOR
Fig. 1. Biology collimator used for partial intestine irradiation with fast neutrons. Four anesthetized mice were positioned at the face of the collimator such that a 4 cm segment of the small intestine of each mouse protruded into the neutron beam while the rest of the animal was shielded.
RESULTS
The mortality curves used to estimate the LDso/5 day for single whole-body neutron and X-ray exposures are shown in Fig. 2. The LDs0/s day for X-radiation was 1-06 krad and for neutrons it was 0.59 krad, giving an RBE of 1.8. Figure 3 illustrates the cumulative mortality after partial intestine irradiation with single exposures of neutrons or X-rays. The data show a high incidence of mortality during the second week after exposure followed by a slower rate of death. Most of the deaths observed occurred by 60 days but there were a few deaths as late as 9 months after irradiation. The data in Fig. 3 also indicate that when the ratio of mean X-ray dose to mean neutron dose was approximately 2 :l, there was no difference in the cumulative mortality produced by the two types of radiation. Figure 4 illustrates the gross pathology of the gastrointestinal tract observed at, or shortly before, death as a result of partial intestine irradiation with neutrons or X-rays. The animals exhibited distension of' the small intestine proximal to bowel obstruction at the irradiated site. This response was seen in all animals examined that died between 6 days and 9 months post-irradiation. Post-mortem histological examination of the irradiated segment of bowel showed the lumen to be obliterated by inflammatory tissue in animals which
The Relative Biological Effectiveness of Cyclotron Fast Neutrons NEUTRONS A-A
LDso= 5 8 5
X-RAY
LD=o= 1 0 6 2
(3"0
RBE = 1.8
the villi in a shielded area of the intestine (Fig. 5a). Adjacent to the irradiated segment the intestine was altered by vascular engorgement with focal hemorrhage, edema, and sparse and short villi (Fig. 5d). No unique differences were noted between X-irradiated and neutron-irradiated intestines. The dose-mortality curves used to estimate the LDso/90 day for partial intestine exposure are shown in Fig. 6. With X-rays the LDso/9o d.y was 2"26 krad and with neutrons it was 1.18 krad, yielding an RBE of 1.9.
(537-637) (969-1162| (2.0-1.7)
100
f
75
101
IZ t4J
~Oso O_
Z~
NEUTRONS ~
LDso=IISO(II09-1255)
X-RAY
LDso=2260(2132-2395) R BE=1,9(1.8-2.2)
~
25 10C
0
S
I 5
0
-
I0
15
DOSE RADS x I0 =
75
Fig. 2. Dose-mortality response 5 days following single whole-body neutron or X-ray exposures. Each point represents the per cent mortality of 7-8 animals. Best fit curves were determined by chi square analysis of probit curves. LD so and RBE values are followed by the 95% confidence limits.
o
Z~ a.
50-
90 80 25 7C )k-
2.0 krad x-roy
-; 60
(n:llT, ronge l.O-3.0krad) ~ d L
k-
..,,s
o 50 =E
0
A
0 z~
40
'"
AA~ 5
I
~
I0 v
v
L~
m
25
]
30
Dose Rods x 102
bJ 0 n
-
Fig. 6. Dose-mortality response 90 daysfollowing segmental intestine irradiation with neutrons or X-rays. Each point represents the per cent mortality of 8-12 animals. Best fit curves were determined by chi square analysis of probit curves. LDso and RBE values are foUowed by the 95% confidence limits.
3(]
20 I.I kraal neufron (n=142, ronge O.2-2.5krad)
I0
0
20
30
I I 40 50 DAYS
I 60
! 70
I 80
I 90
Fig. 3. Cumulative mortality following graded doses neutrons or X-rays delivered to a 4 cm segment of small intestine.
succumbed during the second week (Fig. 5b). Animals dying after the second week had a reduced bowel lumen, hypertrophy of the muscularis, and sometimes a regenerated mucosa with blunted villi (Fig. 5c) as compared to
DISCUSSION
Animals receiving whole-body radiation exposures which result in gastro-intestinal death succumb within 5 days because of fluid and electrolyte loss, toxemia, and nutritional impairment [7]. In contrast, most of the animals receiving segmental intestine irradiation with fast neutrons or X-rays die from bowel obstruction between 6 and about 60 days after exposure. The high mortality rate which occurs
~
~
:: 17 ~?:-~ i!¸
:
~;?:
::
L:::
Fig. 5. Histological cross sections oJ" hematoxylin-eosin stained, shielded and irradiated small intestine. (A) Shielded area of intestine from an animal which died 25 days ajter segmental intestinal exposure. (B) Segment of irradiated intestine of an animal which died 12 days after ex/,osare. (C) Segmellt of irradiated intestine qf animal which died 34 dcL~,sq/?er ex/~osure. (1)) Segment of i~te.~lip~eadjacent /o a bo~,el obstr~wtion (!/"animal which died 25 days after exposure.
Fig. 4.
Gross pathology resulting from neutron or X-ray exposure oJ a 4 cm segment of small intestine.
[to lace p. t02
102
J. P. Geraci, K. L. Jackson, G. M. Christensen, R. G. Parker, M. S. Fox and P. D. Thrower
during the second week (Fig. 3) post-exposure appears to result from complete obliteration of the lumen by inflammatory tissue (Fig. 5b) whereas later deaths are associated with stricture (Fig. 5c). However, the potency of neutrons relative to X-radiation for production of these forms of late damage to the intestine is not significantly different from that for production of acute intestinal damage. The confidence limits of the RBE for the LDso/5 day overlapped those of the RBE for the LDso/9o day (Fig. 2 and 6). Thus, the intestine is similar to skin [8] in that there is little difference in the neutron RBE values for early v late responses in these tissues. The neutron LD 5 o/9 o day of 1"18 krad for late death from irradiation of only a small segment of the intestine may be of clinical
importance. In the treatment of intrapelvic and intra-abdominal cancers by protracted, fractionated neutron exposures the accumulated dose to portions of the small intestine may exceed 1.2 krad. This becomes important when one considers that the rather large capacity of the small intestine to repair iniury following photon irradiation is markedly reduced with fast neutrons [3, 9-11]. Therefore, the possibility of intestinal damage should be seriously considered in fast neutron therapy of abdominal and pelvic tumors where the same segment of intestine is repeatedly exposed. Acknowledgments--Appreciation is expressed to the Medical Radiation Physics Division for the X-radiation and neutron dosimetry. This work was supported by U.S. Public Health Service Grant CA 12441 and Research Career Development Award CA 41735.
REFERENCES
1.
J . j . BROERSE, Dose-mortality studies for mice irradiated with X-rays, gamma-
2.
J . J . BROERSE, G. W. BARENDSEN, G. FRERIKS and L. M. VAN PUTTEN, RBE
rays and 15 MeV neutrons. Int. J. Radiat. Biol. 15, 115 (1969). values of 15 MeV neutrons for effects on normal tissue. Europ. J. Cancer7, 171 (1971). 3.
S. HORNSEY, S. VATISTAS, D. K. BEWLEY and C. J. PARNELL, The effects of
fractionation on four-day survival of mice after whole-body neutron irradiation. Brit. J. Radiol. 38, 878 (1965). 4.
5.
6. 7.
8. 9. 10. 11.
J.W.
OSBORNE, K. N. PRASAD and G. R. ZIMMERMAN, Changes in the rat
intestine after X-irradiation of exteriorized short segments of ileum. Radiat. Res. 43, 131 (1970). P. WOOTTON, H. BIGHSEL,J. EENMAA,R. G. PARKER, K. WEAVER, D. L. WILLIAMSand W. G. WYCKOFF,The University of Washington Fast Neutron Beam Therapy Facility. Boston Workshop on Practical Clinical Criteriafor a Fast Neutron Generator, May 28-29, (1973). J . T . LITCtlFIELD and F. W. WILCOXON,A Simplified method of evaluating dose-effects experiments. J. Pharmacol. expt. Therapy 96, 99 (1949). V . P . BOND, T. M. FLIEDNER and J. O. ARCHAMBEAU, Mammalian Radiation Lethality. Academic Press, New York (1965). S.B. FIELD, Early and late reactions in skin of rats following irradiation with X-rays or fast neutrons. Radiol. 92, 381-384 (1969). K. NAKAGAWA, Intestinal damage following a single and fractionated irradiation with fast neutrons. Nippon Igaku Hoshasen Gakki Zasshi 29, 241-450 (1969). (In Nud. Sci. Abstr. 24, 290, 1970). J . j . BROERSEand H. ROELSE, Survival of intestinal crypt cells after fractionated exposure to X-rays and 15 MeV neutrons. Int. J. Radiat. Biol. 20, 391-395 (1971). H . R . WITHERS,J. T. BRENNANand M. M. ELKIND,The response of stem cells of intestinal mucosa to irradiation with 14 MeV neutrons. Brit. J. Radiol. 43, 796-801 (1970).