INT . J . RADIAT . BIOL .,
1977,
VOL .
32,
NO .
2, 1 8 5-190
Can radiation induce interstitial-cell (Leydig-cell) tumours of the testis? E . V. HULSE
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
Medical Research Council, Radiobiology Unit, Harwell, Didcot, Oxon OXI1 ORD, England (Received 15 April 1977 ; accepted 4 May 1977)
1 . Introduction There are many reports about radiation causing tumours of the ovary, but very few about radiation causing tumours of the testis . There is no mention of radiation-induced testicular tumours in man in the early reviews of radiation carcinogenesis (Warren 1943, Furth and Lorenz 1954, Glucksmann, Lamerton and Mayneord 1957), and none in the whole of Nuclear Science Abstracts from the first to the last volume (1948-1976), or in Atomindex (INIS) to the time of writing . Twenty years ago there were no reports of testicular tumours in experimental animals (Glucksmann et al. 1957), and little has been added since . Small numbers of testicular tumours have been reported from time to time as incidental findings in long-term radiation studies of rats and mice but, with two exceptions, their incidence was not obviously correlated with the radiation (Koletsky and Gustafson 1955, Upton, Kimball, Furth, Christenberry and Benedict 1960, Reincke, Stutz and Wegner 1964, Reincke, Stutz and Hunstein 1965, Castanera, Jones, Kimeldorf and Rosen 1971) . In contrast, Berdjis (1964) found a fourfold increase in interstitial-cell (Leydig-cell) tumours in rats after whole-body exposure to 500 R or 3 x 350 R of X-rays ; a few other testicular tumours also occurred . Lindsay, Nicols, Sheline and Chaikoff (1969) also found that exposing the scrotal area of rats to 150 or 500 R of X-rays increased the incidence of interstitial-cell tumours, by as much as 50 times after the higher exposure . The original aim of the present experiment was to extend the observations after local irradiation in order to obtain a dose-response curve and to test, in part, the supposed mechanism by comparing bilateral and unilateral irradiation . Both Berdjis (1964) and Lindsay et al . (1969) had considered that hormonal imbalance following testicular radiation damage could have played a part in the genesis of the tumours . If so, a difference in tumour incidence per testis should occur when only one testis was exposed instead of two . 2 . Materials and methods Conventionally bred albino rats derived from the Alderley Park (Strain 1) S .P .F . strain (Paget and Lemon 1965) were X-irradiated when 3 months old . The strain was being inbred in this laboratory, and the animals in this experiment were of the twelfth to fifteenth generation . The rats were sedated, but not anaesthetized, with 18 mg of pentobarbitone sodium, intraperitoneally, so that they slept in a supine position while being irradiated . Unirradiated control rats were similarly sedated . Either both testes were irradiated through the ventral wall of the scrotum, or the left testis was gently pushed into the abdomen
186
Correspondence
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
and only the right irradiated . Three overlapping lead sheets, each 3 . 3 mm thick, were used to shield the rest of the rat, so that only the scrotum, its contents and the underlying root of the tail were irradiated . The radiation factors were 250 kV, 134 R/min with a h .v .1 . of 1 . 1 mm Cu . The dose-rate from scattered radiation measured by an ionization chamber placed in the abdomen of a dead rat by the side of a shielded testis was 0 . 49 R/min . 3 . Results 3 .1 . Testicular tumours The number of rats whose testes were irradiated, either bilaterally or unilaterally, the number of unirradiated rats, and the number of tumours occurring in both irradiated and unirradiated testes are given in table 1 . All the tumours were interstitial-cell tumours . Incidence is given as tumours per testis rather than tumours per rat . There was no statistically significant evidence that irradiation played any part in the production of the testicular tumours . The incidence was not significantly different whether the exposure was bilateral or unilateral, and did
Exposure
Bilateral exposures
Unilateral exposures Number of tumours
(R)
Number of rats
Number of tumours
Number of rats
100
17
200
16 15 15 15 14 14 14 120
3 3
15 15 16 15 15 15 14 14 119
300 400 500 900 1200 1500
Total Frequency (tumours per 100 testes) Unirradiated Frequency (tumours per 100 testes)
30
0 0 1 3 2 1 13 5 .4
1 1 .7
-
Irradiated
Unirradiated
0 2 0 1 0 0 1 0 4 3.4
0 0 1 0 3 1 2 0
-
7 5 .9
-
Table 1 . Interstitial-cell tumours of the testis in rats subjected to localized X-radiation and in control rats . The numbers of tumours in the different groups were compared in pairs, and Fisher's exact test gave P=0 . 61 for bilaterally and unilaterally irradiated testes, P=0 . 55 for irradiated and unirradiated testes of unilaterally exposed rats, and P=0 . 28 for testes of unirradiated rats and unirradiated testes of unilaterally exposed rats . An exact test on the combined data for bilaterally and unilaterally irradiated testes, based on the mutinomial distribution, gave P=0 . 28 for homogenity amongst the eight groups, 100-1500 R .
Correspondence
187
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
not differ significantly between irradiated and unirradiated testes . The combined tumour data for bilaterally and unilaterally irradiated testes showed no variation with the amount of radiation exposure . There was no statistical evidence that irradiating only one testis altered tumour incidence in the other unirradiated testis (table 1) .
3.2 . Other tumours The scrotum and the root of the tail were also irradiated, and the tumours that occurred in these tissues are listed in table 2, together with the numbers of comparable tumours in unirradiated tissue . Because the amount of unirradiated tissue was so much greater, tumours would be expected to be much more numerous in the unirradiated than in the irradiated areas . This was so for benign epidermal tumours and subcutaneous fibrosarcomas, which were 10-12 times more common in the unirradiated parts . However, malignant epidermal tumours were four times more common in the irradiated zone, which, compared with the other relatively common tumours, corresponds to a forty fold increase. The excess followed the two highest exposures only, and the incidence after 1500 R was particularly high . The dose-response curve appeared curvilinear but an exact test did not rule out linearity (P=0 . 18) . Only two osteosarcomas occurred outside the irradiated zone, one each in an irradiated and an unirradiated rat . As the one which occurred within an irradiated zone followed the highest exposure, it may possibly have been radiation-induced . 4. Discussion Exposure to X-rays has been listed as one of a wide variety of procedures, including the administration of chemical carcinogens and hormones, which will produce interstitial-cell tumours of the testes in the rat (Lacassagne 1971). In our investigation, there were eight different exposure levels instead of two, and they covered a wider dose-range than previous authors used (Berdjis 1964, Lindsay et al. 1969) . Thus, although this experiment did not involve many more rats, the possibility of demonstrating any positive relationship between radiation and the incidence of interstitial-cell tumours should have been improved . In spite of this, there was no evidence that X-irradiation produced testicular tumours . The original suggestion that hormonal imbalance after radiation damage to the testes produced interstitial-cell tumours (Berdjis 1964, Lindsay et al. 1969) was not supported when the pituitaries of the part-body-irradiated rats of Lindsay, Nichols and Sheline (1970) were examined for gonadotropic hyperplasia and adenomas . If such an imbalance does follow radiation damage of the testis, then, in the present experiment, it should have been pronounced after the testes had been irradiated bilaterally, particularly after 500-1500 R, and less marked or absent after unilateral irradiation . However, neither group showed any significant difference in interstitial-cell tumour incidence. Thus, even when these tumours do occur after irradiation, the postulated mechanism cannot be very important . Berdjis (1964) used Sprague-Dawley rats, Linsday et al. (1969) used LongEvans rats and, in the present investigation, the rats were partly-inbred albinos which may have been derived from Wistar rats imported into this country many
1 88
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Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
Correspondence
1 89
years ago, perhaps at the beginning of the century (D . G . Davey, personal communication) . The difference between this investigation and the other two could be due to strain differences . Certainly, the number of interstitial-cell tumours varies from strain to strain (Berdjis 1964) and can be very low in some (MacKenzie and Garner 1973) . However, the unirradiated control incidence in our rats (table 1) was intermediate between those of the two other experiments . Thus, the possible strain differences in susceptibility to radiation-induction of the tumour do not appear to be related to differences in its spontaneous incidence . The incidence of squamous-cell carcinomas in the relatively small area of skin irradiated was almost 30 per cent after 1500 R (table 2) . Radiationinduced skin tumours have been extensively studied in rats, usually using a greater area of skin and radiation which was less penetrating, though sufficiently so to irradiate the whole epidermis . When data from various sources were normalized to tumours per unit area of irradiated skin, exposures comparable in size to those used in this experiment produced 0 . 3-0 . 7 carcinomas per 100 cm 2 (Hulse 1962) . In the present experiment the incidence per unit area was very similar. As about 26 cm 2 of skin was exposed, it was 0 . 55 per 100 cm 2 after 1200 R and 1 . 10 per 100 cm2 after 1500 R . Thus, the lack of radiation-induced testicular tumours cannot be explained by suggesting that our rats are resistant to radiation carcinogenesis in general . 5.
Conclusion Two reports, involving two different strains of rats, state that testicular tumours (interstitial-cell tumours) were induced by exposures of 150-1500 R . However, the present extended investigation using a third strain and covering the wider range of 100-1500 R failed to confirm these findings . As the rat is the only species in which radiation-induced testicular tumours have been reported, this suggests that such tumours need not be regarded as an important hazard to mammals in general and man in particular . This conclusion may be of practical importance, particularly as it concerns interstitial-cell tumours, since plutonium is deposited in or near the interstitial cells (Green, Howells, Humphreys and Vennart 1975, Taylor 1977) and this variety of tumour can occur spontaneously in man . ACKNOWLEDGMENTS
I am very grateful to Mr . D . G . Papworth for doing the statistical tests quoted in this paper . I also wish to thank Mr . M . J . Corp for the irradiations and the related measurements . REFERENCES BERDJIS, C . C ., 1964, Oncologia, 17, 197 . CASTANERA, T . J ., JONES, S . C ., KIMELDORF, D . J ., and ROSEN, V. J ., 1971, Cancer Res ., 31, 1543 . FURTH, J ., and LORENZ, E ., 1954, Radiation Biology, Vol . 1, edited by A . Hollander (New York : McGraw-Hill), p . 1145 . GLUCKSMANN, A ., LAMERTON, L . F ., and MAYNEORD, W . V ., 1957, Cancer, Vol . 1, edited by R . W . Raven (London : Butterworth), p . 497 . GREEN, D ., HOWELLS, G . R., HUMPHREYS, E . R ., and VENNART, J ., 1975, Nature, Lond ., 255, 77 . HULSE, E . V ., 1962, Br . .7 . Cancer, 16, 72 . R .B .
0
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
190
Correspondence
KOLETSKY, S ., and GUSTAFSON, G . E ., 1955, Cancer Res., 15, 100 . LACASSAGNE, A ., 1971, Bull . Ass . fr . Etude Cancer, 58, 235 . LINDSAY, S ., NICHOLS, C . W., and SHELINE, G . E ., 1970, Proc . Soc . exp . Biol . Med., 134, 523 . LINDSAY, S ., NICHOLS, C . W., SHELINE, G . E ., and CHAIKOFF, 1 . L ., 1969, Radiat . Res., 40, 366 . MACKENZIE, W . F ., and GARNER, F . M ., 1973, J. natn . Cancer Inst ., 50, 1243 . PAGET, G . E ., and LEMON, P . G ., 1965, The Pathology of Laboratory Animals, edited by W . E . Ribelin and J . R . McCoy (Springfield : Thomas), p . 382 . REINCKE, U ., STUTZ, E ., and HUNSTEIN, W ., 1965, Strahlentherapie, 128, 426 . REINCKE, U ., STUTZ, E ., and WEGNER, G ., 1964, Z . Krebsforsch ., 66, 165 . TAYLOR, D . M., 1977, Hlth Phys ., 32, 29 . UPTON, A . C ., KIMBALL, A . W ., FURTH, J ., CHRISTENBERRY, K . W ., and BENEDICT, W. H ., 1960, Cancer Res ., 20 (8) part 2 . WARREN, S ., 1943, Archs Path ., 35, 121 .
1977,
VOL .
32,
NO .
2, 1 8 5-190
Can radiation induce interstitial-cell (Leydig-cell) tumours of the testis? E . V. HULSE
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
Medical Research Council, Radiobiology Unit, Harwell, Didcot, Oxon OXI1 ORD, England (Received 15 April 1977 ; accepted 4 May 1977)
1 . Introduction There are many reports about radiation causing tumours of the ovary, but very few about radiation causing tumours of the testis . There is no mention of radiation-induced testicular tumours in man in the early reviews of radiation carcinogenesis (Warren 1943, Furth and Lorenz 1954, Glucksmann, Lamerton and Mayneord 1957), and none in the whole of Nuclear Science Abstracts from the first to the last volume (1948-1976), or in Atomindex (INIS) to the time of writing . Twenty years ago there were no reports of testicular tumours in experimental animals (Glucksmann et al. 1957), and little has been added since . Small numbers of testicular tumours have been reported from time to time as incidental findings in long-term radiation studies of rats and mice but, with two exceptions, their incidence was not obviously correlated with the radiation (Koletsky and Gustafson 1955, Upton, Kimball, Furth, Christenberry and Benedict 1960, Reincke, Stutz and Wegner 1964, Reincke, Stutz and Hunstein 1965, Castanera, Jones, Kimeldorf and Rosen 1971) . In contrast, Berdjis (1964) found a fourfold increase in interstitial-cell (Leydig-cell) tumours in rats after whole-body exposure to 500 R or 3 x 350 R of X-rays ; a few other testicular tumours also occurred . Lindsay, Nicols, Sheline and Chaikoff (1969) also found that exposing the scrotal area of rats to 150 or 500 R of X-rays increased the incidence of interstitial-cell tumours, by as much as 50 times after the higher exposure . The original aim of the present experiment was to extend the observations after local irradiation in order to obtain a dose-response curve and to test, in part, the supposed mechanism by comparing bilateral and unilateral irradiation . Both Berdjis (1964) and Lindsay et al . (1969) had considered that hormonal imbalance following testicular radiation damage could have played a part in the genesis of the tumours . If so, a difference in tumour incidence per testis should occur when only one testis was exposed instead of two . 2 . Materials and methods Conventionally bred albino rats derived from the Alderley Park (Strain 1) S .P .F . strain (Paget and Lemon 1965) were X-irradiated when 3 months old . The strain was being inbred in this laboratory, and the animals in this experiment were of the twelfth to fifteenth generation . The rats were sedated, but not anaesthetized, with 18 mg of pentobarbitone sodium, intraperitoneally, so that they slept in a supine position while being irradiated . Unirradiated control rats were similarly sedated . Either both testes were irradiated through the ventral wall of the scrotum, or the left testis was gently pushed into the abdomen
186
Correspondence
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
and only the right irradiated . Three overlapping lead sheets, each 3 . 3 mm thick, were used to shield the rest of the rat, so that only the scrotum, its contents and the underlying root of the tail were irradiated . The radiation factors were 250 kV, 134 R/min with a h .v .1 . of 1 . 1 mm Cu . The dose-rate from scattered radiation measured by an ionization chamber placed in the abdomen of a dead rat by the side of a shielded testis was 0 . 49 R/min . 3 . Results 3 .1 . Testicular tumours The number of rats whose testes were irradiated, either bilaterally or unilaterally, the number of unirradiated rats, and the number of tumours occurring in both irradiated and unirradiated testes are given in table 1 . All the tumours were interstitial-cell tumours . Incidence is given as tumours per testis rather than tumours per rat . There was no statistically significant evidence that irradiation played any part in the production of the testicular tumours . The incidence was not significantly different whether the exposure was bilateral or unilateral, and did
Exposure
Bilateral exposures
Unilateral exposures Number of tumours
(R)
Number of rats
Number of tumours
Number of rats
100
17
200
16 15 15 15 14 14 14 120
3 3
15 15 16 15 15 15 14 14 119
300 400 500 900 1200 1500
Total Frequency (tumours per 100 testes) Unirradiated Frequency (tumours per 100 testes)
30
0 0 1 3 2 1 13 5 .4
1 1 .7
-
Irradiated
Unirradiated
0 2 0 1 0 0 1 0 4 3.4
0 0 1 0 3 1 2 0
-
7 5 .9
-
Table 1 . Interstitial-cell tumours of the testis in rats subjected to localized X-radiation and in control rats . The numbers of tumours in the different groups were compared in pairs, and Fisher's exact test gave P=0 . 61 for bilaterally and unilaterally irradiated testes, P=0 . 55 for irradiated and unirradiated testes of unilaterally exposed rats, and P=0 . 28 for testes of unirradiated rats and unirradiated testes of unilaterally exposed rats . An exact test on the combined data for bilaterally and unilaterally irradiated testes, based on the mutinomial distribution, gave P=0 . 28 for homogenity amongst the eight groups, 100-1500 R .
Correspondence
187
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
not differ significantly between irradiated and unirradiated testes . The combined tumour data for bilaterally and unilaterally irradiated testes showed no variation with the amount of radiation exposure . There was no statistical evidence that irradiating only one testis altered tumour incidence in the other unirradiated testis (table 1) .
3.2 . Other tumours The scrotum and the root of the tail were also irradiated, and the tumours that occurred in these tissues are listed in table 2, together with the numbers of comparable tumours in unirradiated tissue . Because the amount of unirradiated tissue was so much greater, tumours would be expected to be much more numerous in the unirradiated than in the irradiated areas . This was so for benign epidermal tumours and subcutaneous fibrosarcomas, which were 10-12 times more common in the unirradiated parts . However, malignant epidermal tumours were four times more common in the irradiated zone, which, compared with the other relatively common tumours, corresponds to a forty fold increase. The excess followed the two highest exposures only, and the incidence after 1500 R was particularly high . The dose-response curve appeared curvilinear but an exact test did not rule out linearity (P=0 . 18) . Only two osteosarcomas occurred outside the irradiated zone, one each in an irradiated and an unirradiated rat . As the one which occurred within an irradiated zone followed the highest exposure, it may possibly have been radiation-induced . 4. Discussion Exposure to X-rays has been listed as one of a wide variety of procedures, including the administration of chemical carcinogens and hormones, which will produce interstitial-cell tumours of the testes in the rat (Lacassagne 1971). In our investigation, there were eight different exposure levels instead of two, and they covered a wider dose-range than previous authors used (Berdjis 1964, Lindsay et al. 1969) . Thus, although this experiment did not involve many more rats, the possibility of demonstrating any positive relationship between radiation and the incidence of interstitial-cell tumours should have been improved . In spite of this, there was no evidence that X-irradiation produced testicular tumours . The original suggestion that hormonal imbalance after radiation damage to the testes produced interstitial-cell tumours (Berdjis 1964, Lindsay et al. 1969) was not supported when the pituitaries of the part-body-irradiated rats of Lindsay, Nichols and Sheline (1970) were examined for gonadotropic hyperplasia and adenomas . If such an imbalance does follow radiation damage of the testis, then, in the present experiment, it should have been pronounced after the testes had been irradiated bilaterally, particularly after 500-1500 R, and less marked or absent after unilateral irradiation . However, neither group showed any significant difference in interstitial-cell tumour incidence. Thus, even when these tumours do occur after irradiation, the postulated mechanism cannot be very important . Berdjis (1964) used Sprague-Dawley rats, Linsday et al. (1969) used LongEvans rats and, in the present investigation, the rats were partly-inbred albinos which may have been derived from Wistar rats imported into this country many
1 88
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Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
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1 89
years ago, perhaps at the beginning of the century (D . G . Davey, personal communication) . The difference between this investigation and the other two could be due to strain differences . Certainly, the number of interstitial-cell tumours varies from strain to strain (Berdjis 1964) and can be very low in some (MacKenzie and Garner 1973) . However, the unirradiated control incidence in our rats (table 1) was intermediate between those of the two other experiments . Thus, the possible strain differences in susceptibility to radiation-induction of the tumour do not appear to be related to differences in its spontaneous incidence . The incidence of squamous-cell carcinomas in the relatively small area of skin irradiated was almost 30 per cent after 1500 R (table 2) . Radiationinduced skin tumours have been extensively studied in rats, usually using a greater area of skin and radiation which was less penetrating, though sufficiently so to irradiate the whole epidermis . When data from various sources were normalized to tumours per unit area of irradiated skin, exposures comparable in size to those used in this experiment produced 0 . 3-0 . 7 carcinomas per 100 cm 2 (Hulse 1962) . In the present experiment the incidence per unit area was very similar. As about 26 cm 2 of skin was exposed, it was 0 . 55 per 100 cm 2 after 1200 R and 1 . 10 per 100 cm2 after 1500 R . Thus, the lack of radiation-induced testicular tumours cannot be explained by suggesting that our rats are resistant to radiation carcinogenesis in general . 5.
Conclusion Two reports, involving two different strains of rats, state that testicular tumours (interstitial-cell tumours) were induced by exposures of 150-1500 R . However, the present extended investigation using a third strain and covering the wider range of 100-1500 R failed to confirm these findings . As the rat is the only species in which radiation-induced testicular tumours have been reported, this suggests that such tumours need not be regarded as an important hazard to mammals in general and man in particular . This conclusion may be of practical importance, particularly as it concerns interstitial-cell tumours, since plutonium is deposited in or near the interstitial cells (Green, Howells, Humphreys and Vennart 1975, Taylor 1977) and this variety of tumour can occur spontaneously in man . ACKNOWLEDGMENTS
I am very grateful to Mr . D . G . Papworth for doing the statistical tests quoted in this paper . I also wish to thank Mr . M . J . Corp for the irradiations and the related measurements . REFERENCES BERDJIS, C . C ., 1964, Oncologia, 17, 197 . CASTANERA, T . J ., JONES, S . C ., KIMELDORF, D . J ., and ROSEN, V. J ., 1971, Cancer Res ., 31, 1543 . FURTH, J ., and LORENZ, E ., 1954, Radiation Biology, Vol . 1, edited by A . Hollander (New York : McGraw-Hill), p . 1145 . GLUCKSMANN, A ., LAMERTON, L . F ., and MAYNEORD, W . V ., 1957, Cancer, Vol . 1, edited by R . W . Raven (London : Butterworth), p . 497 . GREEN, D ., HOWELLS, G . R., HUMPHREYS, E . R ., and VENNART, J ., 1975, Nature, Lond ., 255, 77 . HULSE, E . V ., 1962, Br . .7 . Cancer, 16, 72 . R .B .
0
Int J Radiat Biol Downloaded from informahealthcare.com by Thomas Jefferson University on 01/04/15 For personal use only.
190
Correspondence
KOLETSKY, S ., and GUSTAFSON, G . E ., 1955, Cancer Res., 15, 100 . LACASSAGNE, A ., 1971, Bull . Ass . fr . Etude Cancer, 58, 235 . LINDSAY, S ., NICHOLS, C . W., and SHELINE, G . E ., 1970, Proc . Soc . exp . Biol . Med., 134, 523 . LINDSAY, S ., NICHOLS, C . W., SHELINE, G . E ., and CHAIKOFF, 1 . L ., 1969, Radiat . Res., 40, 366 . MACKENZIE, W . F ., and GARNER, F . M ., 1973, J. natn . Cancer Inst ., 50, 1243 . PAGET, G . E ., and LEMON, P . G ., 1965, The Pathology of Laboratory Animals, edited by W . E . Ribelin and J . R . McCoy (Springfield : Thomas), p . 382 . REINCKE, U ., STUTZ, E ., and HUNSTEIN, W ., 1965, Strahlentherapie, 128, 426 . REINCKE, U ., STUTZ, E ., and WEGNER, G ., 1964, Z . Krebsforsch ., 66, 165 . TAYLOR, D . M., 1977, Hlth Phys ., 32, 29 . UPTON, A . C ., KIMBALL, A . W ., FURTH, J ., CHRISTENBERRY, K . W ., and BENEDICT, W. H ., 1960, Cancer Res ., 20 (8) part 2 . WARREN, S ., 1943, Archs Path ., 35, 121 .
