•
•
Time/Dose Relationships in Experimental Radiation Cataractogenesis 1
Radiation Biology
Larry L. Schenken, Ph.D. and Ronald F. Hagemann, Ph.D. The response of the mammalian lens to fractionated radiation exposures was evaluated as a model system for predicting delayed radiation effects on normal tissue. Only the heads of male HallCR mice were irradiated with 14 different time-dose schedules and followed for cataractous changes. A log-log plot of dose vs time yielded a line with a slope of 0.303 and ordinate intercept of 1050 R; a similar plot tor dose vs fraction number yielded a slope of 0.382 and ordinate intercept of 835 R. Results suggest that the lenticular response to radiation may be a useful model for studying late effects. INDEX TERMS: Cataracts. Lens, crystalline. Radiobiology, ophthalmologic studies. Radiobiology, time-dose studies
Radiology 117:193-198, October 1975
•
• in the history of investigations involving elucidation of biologic effects of ionizing radiation, Birch-Hirschfeld (1) reported that an exposure of roentgen radiation was capable of inducing cataracts in exposed human eyes. Later studies involving experimental animals and summations of data from radiotherapeutic efforts aimed at the management of neoplastic disease (2, 3) suggested that there was a threshold of exposure (400-600 R in most systems) below which lenticular damage was not manifest, and that progressively higher incidences of cataractogenesis resulted from greater radiation exposures, until 100 % of irradiated populations showed cataracts. The orderly and predictable progression of damage through stages of slight polar condensation to complete lens opacity Was reported by many investigators (4-8). Further elucidation of the temporal sequence of lens damage (8, 9) led investigators to conclude that not only was severity of damage a function of radiation exposure, but that the latent period between exposure and lens opacity varied inversely with dose. That is, higher radiation exposures led to more severe damage (progressive cataracts) and a more rapid manifestation of the damage. The response of the lens to fractionated exposures of ionizing radiation has been investigated by several groups (8-11). These investigators generally agreed that, if exposures were given over several equal fractions, the cataractogenic effect would be less than if the total dose were given in one exposure. Merriam and Focht (8) also noted that the radiobiologic response of the lens could be related to dose-time-fractionation patterns in a manner similar to those reported for other tissues by Strandqvist (12), anti for other radiobiologic effects by Ellis (13-15). For an in-depth discussion of ARLY
E
the response of the eye to ionizing radiation, the reader is referred to an article by J. L. Bateman in Pathology of Irradiation (16). The radiosensitivity of the lens epithelium as manifest by cataract formation is of considerable interest to investigators for several reasons. First, the lens represents a structure in man whose function can be impaired by relatively low doses of conventional radiation. Second, because of a renewed interest in high linear energy transfer (LET) radiotherapy for the management of cancer (17, 18), which is used currently in the treatment of neoplastic diseases of the head and neck, the lens becomes a "critical" normal tissue for the radiotherapist to consider (even though the restoration of vision in a patient with radiation-induced cataracts Can be accomplished surgically). Consistent with interest in high LET radiotherapy are studies of other densely ionizing radiations, indicating that the severity and onset of lenticular changes are extremely dependent on LET. Finally, radiation cataractogenesis may be utilized as a test system for comparing therapeutic modes of differing timedose-fractionation character and modes of differing LET. Cataractogenesis represents a late effect that is readily measurable in the same animal at different time intervals, is easily quantitated, and is. for single exposures, predictable in stage and severity. Specifically, the purpose of these studies was to: 1) provide an accurate base of information about the response of the mouse lens to selected dose-time combinations that will allow future determinations of fractionated exposure relative biological effectiveness (RBE) for high LET therapeutic beams now being developed for clinical trial, and 2) to evaluate the use of cataractogenesis as a predictive model for delayed radiation effects on normal tissue.
1 From the Clinical Radiation Therapy Research Center, Divlsion of Oncology/Radiotherapy, Allegheny General Hospitai, Pittsburgh, Pa. Accepted for publication in May 1975. Supported by American Cancer Society Grant ET43 and NIH Grant CA 10438-07. dk
193
&
200 200 200
200 200 200
200 200 200
200 200 200
300 300 300
400 400 400
200 200 200
200 200 200
7a 7b 7c
8a 8b 8c
9a 9b 9c
lOa lOb 10c
11a lIb 11c
12a 12b 12c
13a 13b 13c 14a 14b 14c
==
G G
150 150 150 175 175 175
5a 5b 5c 6a 6b 6c
schedules: A
F F F
100 100 100 125 125 125 150 150 150
2a 2b 2c 3a 3b 3c 4a 4b 4c
2 2 2
4 4 4
1 1 1
1 1 1
==
0 0 0 60 80 100 0 25 80 80 100 100 20 60 80
450 450 450 750 750 750 875 875 875 400 400 400 600 600 600
1750 2100 2450 2400 2800 3200 1800 2200 2600
18 22 23 11
5 5 5 5 5 5
7 7 7
5 5 5
5 5 5 7 7 7
3 3 3
2 2 2
3.0 4.0 5.0
2.0 2.25 2.5
1400 1800 2200
1800 2000 2200
1200 1600 2000
1200 1500 2100
4 5 8 3 4 5
1400 1400 1400
1400 1800 2200
7 9 11
2800 2800 2800
1500 1500 1500
1000 1000 1000
1400 1800 2200
8 10 15
19 23 28
39 46 53
15 17
12 20 50
50 70 100
10 50 100
40 80 100
10 20 40
==
2200 R
1800 R
1600 R
1280 R
2400 R
2000 R
2100 R
2150 R
2250 R
1960 R
.. .
2660 R
3100 R
825 R
Exposure to 50% Stage III
5 days/week; C == 3 days/week; D == 2 days/week; E == 7 days/week; F
9 11
7
9
10 11
3 4 5
4 5 7
7 9 11
7 9 11
9 11 13
10 17 19 10 12 14
1 1 1
1 1 1
0 33 87
625 625 625
0 0 100
0 0 40
500 500 500
2000 2500 3000 2000 2500 3000 2700 3000 3300 2100 2550 2850
26 33 40 22 26 31 39 44 49
5 5 5 5 5 5 3 3 3
20 25 30 16 20 24 18 20 22
12 14 16
1 1 1
0 80 100
1 1 1
700 900 1100
Per cent Stage
700 900 1100
Sing exp
Wk.
tions/
Total Exposure (R)
Overall Time (Days) III
Frac-
Exposure Per Week (R)
1 1 1
Total Fractions
1 1 1
1 1 1 1 1 1
1 1 1 1 1 1 1 1 1
1 1 1
single exposure; B
G
E E E
B B B
E E E
B B B
C C C
D D D
B B B
B B B
C C C
B B B
B B B
A A A
700 900 1100
1a 1b 1c
FracSched- tions/ Day ule
Experimental Group
B.:
Exposure Per Fraction (R)
==
5
2
4
4
12
13
22
38
17
16
. ..
28
41
1
2650 R
2075 R
1850 R
1500 R
2950 R
2125 R
2600 R
2550 R
2450 R
2500 R
. ..
2925 R
3400 R
900 R
Exposure to 80% Stage III
every 12 hours.
Days to 50%
every 6 hours; G
11
9
4
4.2
12.0
10
10.5
10.8
12.9
13.3
.. .
21.3
31.0
1
Fractions to 50%
Table I: Treatment Schedules And Resultant 6-Month Cataract Incidence
13.2
10.4
4.6
5
14.8
10.6
13
12.8
14
16.7
...
23.4
34
1
Fractions to 80%
7
2.5
5
5
14
14
28
42
18
22
. ..
31
48
Days to 80%
m
0
01
-..j
•
Time/Dose Relationships in Experimental Radiation Cataractogenesis 1
Radiation Biology
Larry L. Schenken, Ph.D. and Ronald F. Hagemann, Ph.D. The response of the mammalian lens to fractionated radiation exposures was evaluated as a model system for predicting delayed radiation effects on normal tissue. Only the heads of male HallCR mice were irradiated with 14 different time-dose schedules and followed for cataractous changes. A log-log plot of dose vs time yielded a line with a slope of 0.303 and ordinate intercept of 1050 R; a similar plot tor dose vs fraction number yielded a slope of 0.382 and ordinate intercept of 835 R. Results suggest that the lenticular response to radiation may be a useful model for studying late effects. INDEX TERMS: Cataracts. Lens, crystalline. Radiobiology, ophthalmologic studies. Radiobiology, time-dose studies
Radiology 117:193-198, October 1975
•
• in the history of investigations involving elucidation of biologic effects of ionizing radiation, Birch-Hirschfeld (1) reported that an exposure of roentgen radiation was capable of inducing cataracts in exposed human eyes. Later studies involving experimental animals and summations of data from radiotherapeutic efforts aimed at the management of neoplastic disease (2, 3) suggested that there was a threshold of exposure (400-600 R in most systems) below which lenticular damage was not manifest, and that progressively higher incidences of cataractogenesis resulted from greater radiation exposures, until 100 % of irradiated populations showed cataracts. The orderly and predictable progression of damage through stages of slight polar condensation to complete lens opacity Was reported by many investigators (4-8). Further elucidation of the temporal sequence of lens damage (8, 9) led investigators to conclude that not only was severity of damage a function of radiation exposure, but that the latent period between exposure and lens opacity varied inversely with dose. That is, higher radiation exposures led to more severe damage (progressive cataracts) and a more rapid manifestation of the damage. The response of the lens to fractionated exposures of ionizing radiation has been investigated by several groups (8-11). These investigators generally agreed that, if exposures were given over several equal fractions, the cataractogenic effect would be less than if the total dose were given in one exposure. Merriam and Focht (8) also noted that the radiobiologic response of the lens could be related to dose-time-fractionation patterns in a manner similar to those reported for other tissues by Strandqvist (12), anti for other radiobiologic effects by Ellis (13-15). For an in-depth discussion of ARLY
E
the response of the eye to ionizing radiation, the reader is referred to an article by J. L. Bateman in Pathology of Irradiation (16). The radiosensitivity of the lens epithelium as manifest by cataract formation is of considerable interest to investigators for several reasons. First, the lens represents a structure in man whose function can be impaired by relatively low doses of conventional radiation. Second, because of a renewed interest in high linear energy transfer (LET) radiotherapy for the management of cancer (17, 18), which is used currently in the treatment of neoplastic diseases of the head and neck, the lens becomes a "critical" normal tissue for the radiotherapist to consider (even though the restoration of vision in a patient with radiation-induced cataracts Can be accomplished surgically). Consistent with interest in high LET radiotherapy are studies of other densely ionizing radiations, indicating that the severity and onset of lenticular changes are extremely dependent on LET. Finally, radiation cataractogenesis may be utilized as a test system for comparing therapeutic modes of differing timedose-fractionation character and modes of differing LET. Cataractogenesis represents a late effect that is readily measurable in the same animal at different time intervals, is easily quantitated, and is. for single exposures, predictable in stage and severity. Specifically, the purpose of these studies was to: 1) provide an accurate base of information about the response of the mouse lens to selected dose-time combinations that will allow future determinations of fractionated exposure relative biological effectiveness (RBE) for high LET therapeutic beams now being developed for clinical trial, and 2) to evaluate the use of cataractogenesis as a predictive model for delayed radiation effects on normal tissue.
1 From the Clinical Radiation Therapy Research Center, Divlsion of Oncology/Radiotherapy, Allegheny General Hospitai, Pittsburgh, Pa. Accepted for publication in May 1975. Supported by American Cancer Society Grant ET43 and NIH Grant CA 10438-07. dk
193
&
200 200 200
200 200 200
200 200 200
200 200 200
300 300 300
400 400 400
200 200 200
200 200 200
7a 7b 7c
8a 8b 8c
9a 9b 9c
lOa lOb 10c
11a lIb 11c
12a 12b 12c
13a 13b 13c 14a 14b 14c
==
G G
150 150 150 175 175 175
5a 5b 5c 6a 6b 6c
schedules: A
F F F
100 100 100 125 125 125 150 150 150
2a 2b 2c 3a 3b 3c 4a 4b 4c
2 2 2
4 4 4
1 1 1
1 1 1
==
0 0 0 60 80 100 0 25 80 80 100 100 20 60 80
450 450 450 750 750 750 875 875 875 400 400 400 600 600 600
1750 2100 2450 2400 2800 3200 1800 2200 2600
18 22 23 11
5 5 5 5 5 5
7 7 7
5 5 5
5 5 5 7 7 7
3 3 3
2 2 2
3.0 4.0 5.0
2.0 2.25 2.5
1400 1800 2200
1800 2000 2200
1200 1600 2000
1200 1500 2100
4 5 8 3 4 5
1400 1400 1400
1400 1800 2200
7 9 11
2800 2800 2800
1500 1500 1500
1000 1000 1000
1400 1800 2200
8 10 15
19 23 28
39 46 53
15 17
12 20 50
50 70 100
10 50 100
40 80 100
10 20 40
==
2200 R
1800 R
1600 R
1280 R
2400 R
2000 R
2100 R
2150 R
2250 R
1960 R
.. .
2660 R
3100 R
825 R
Exposure to 50% Stage III
5 days/week; C == 3 days/week; D == 2 days/week; E == 7 days/week; F
9 11
7
9
10 11
3 4 5
4 5 7
7 9 11
7 9 11
9 11 13
10 17 19 10 12 14
1 1 1
1 1 1
0 33 87
625 625 625
0 0 100
0 0 40
500 500 500
2000 2500 3000 2000 2500 3000 2700 3000 3300 2100 2550 2850
26 33 40 22 26 31 39 44 49
5 5 5 5 5 5 3 3 3
20 25 30 16 20 24 18 20 22
12 14 16
1 1 1
0 80 100
1 1 1
700 900 1100
Per cent Stage
700 900 1100
Sing exp
Wk.
tions/
Total Exposure (R)
Overall Time (Days) III
Frac-
Exposure Per Week (R)
1 1 1
Total Fractions
1 1 1
1 1 1 1 1 1
1 1 1 1 1 1 1 1 1
1 1 1
single exposure; B
G
E E E
B B B
E E E
B B B
C C C
D D D
B B B
B B B
C C C
B B B
B B B
A A A
700 900 1100
1a 1b 1c
FracSched- tions/ Day ule
Experimental Group
B.:
Exposure Per Fraction (R)
==
5
2
4
4
12
13
22
38
17
16
. ..
28
41
1
2650 R
2075 R
1850 R
1500 R
2950 R
2125 R
2600 R
2550 R
2450 R
2500 R
. ..
2925 R
3400 R
900 R
Exposure to 80% Stage III
every 12 hours.
Days to 50%
every 6 hours; G
11
9
4
4.2
12.0
10
10.5
10.8
12.9
13.3
.. .
21.3
31.0
1
Fractions to 50%
Table I: Treatment Schedules And Resultant 6-Month Cataract Incidence
13.2
10.4
4.6
5
14.8
10.6
13
12.8
14
16.7
...
23.4
34
1
Fractions to 80%
7
2.5
5
5
14
14
28
42
18
22
. ..
31
48
Days to 80%
m
0
01
-..j
