Effect of low doses of ionising radiation in infancy on cognitive function in adulthood: Swedish population based cohort study
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《英国医生杂志》
1 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, PO Box 281, SE-171 77 Stockholm, Sweden, 2 Department of Epidemiology, Harvard Center for Cancer Prevention, Harvard School of Public Health, 677 Huntington Avenue, Boston MA 02115, USA, 3 Department of Hygiene and Epidemiology, School of Medicine, University of Athens, Greece, 4 Department of Clinical Neuroscience, Karolinska University Hospital, SE-171 76 Stockholm, Sweden, 5 Department of Hospital Physics, Karolinska University Hospital
Correspondence to: P Hall Per.Hall@mep.ki.se
Abstract
Ionising radiation may impair the developing human brain and adversely affect cognitive processes, as documented among children exposed in utero after the bombing of Hiroshima and Nagasaki or treated with radiation for ringworm of the scalp.1-5 Evidence also comes from young children treated for leukaemia or brain tumours6-9; but in these studies it is difficult to distinguish the effect of radiation from that of underlying diseases, concomitant surgery or chemotherapy, or hormonal abnormalities.7 Existing data are based mostly on high doses of ionising radiation ( 1 Gy), therefore little is known about the effects of low doses of radiation or a possible threshold value. Also inadequately documented is the effects of age at exposure. Lack of such evidence is of concern because modern imaging techniques such as computed tomography, which deliver high doses of ionising radiation, are increasingly being used in even young children after minor head trauma. The dose delivered to the brain of an infant during computed tomography of the skull is around 120 mGy.10
We analysed cognitive function in a large population based cohort of men at the time of military enlistment who had received low dose ionising radiation for cutaneous haemangioma before age 18 months. Based on previous experience, we hypothesised that damage to the frontal part of the brain would have a more severe effect on mental capacity than damage to the posterior part.11
Participants and methods
During 1930-59, 4577 boys aged under 18 months received radiotherapy for cutaneous haemangioma at the Karolinska University Hospital, Stockholm. Information was missing on the names and dates of birth for four children and dose of radiation for one child, and two children were lost to follow up. Hence 4570 men in the original cohort were available for follow up (figure). We excluded 1439 men tested after 1968 because the retrieval of data was administratively complicated then, and we excluded 37 men tested before 1954 because the tests of cognitive function changed after that time. The military records of 220 men could not be found, and the test results of five men were missing. Information was missing on education for 53 boys and number of siblings for another 265, leaving 2551 boys for analysis of high school attendance. We excluded 160 men from analyses of cognitive function as they were tested during 1954-8 before the battery of cognitive tests was expanded from three to four, making it difficult to compare their results with those of the 2869 men who took the test during 1959-68. In addition, we excluded 180 boys without information on fathers' occupation. This left 2211 for analysis of cognitive function.
Flow of patients through trial
The mean number of haemangiomas per child was 1.5 (range 1-16). Overall, 49% (n = 1380) of the men were irradiated when aged under 6 months, 39% (n = 1098) at 6-11 months, and 12% (n = 338) at 12-17 months. The mean age of the men at first treatment was 7 months (median 6 months). The average estimated absorbed dose to the brain was 52 mGy (median 20 mGy, range 0-2800 mGy) and the largest contribution came from irradiation of haemangiomas in the head region (table 1). The average and median dose to the frontal part of the brain was slightly higher than to the posterior part. An estimated dose of 100 mGy or more was delivered to the frontal part of the brain in 661/2816 (23.5%) men and to the posterior part in 384/2816 (13.6%; table 2).
Table 1 Average and median absorbed doses of ionising radiation to frontal and posterior parts of brain in relation to location of cutaneous haemangioma
Table 2 High school attendance in relation to part of brain receiving dose of radiation and father's socioeconomic status in cohort of 2816 Swedish men irradiated for cutaneous haemangioma when aged under 18 months. Values are numbers (percentages) unless stated otherwise
High school attendance
A decrease in high school attendance was seen in all socioeconomic groups at radiation doses greater than 100 mGy when compared with the lowest dose of 1-20 mGy (table 2). No consistent difference was seen between the two lowest dose categories (1-20 mGy and > 20-100 mGy); however, the increment of exposure was limited, with median values of only 0 and 30-40 mGy.
We found an overall statistically significant decreasing probability of attending high school in relation to radiation dose (table 3). Adjustment for potential confounders changed risk estimates only marginally. The probability of attending high school was reduced by around 50% in greater than 100 mGy category compared with the 1-20 mGy, and it decreased by 11-14% per 50 mGy increment in dose in the multivariate analyses. We found no appreciable difference in the dose-response relation between frontal and posterior dose of radiation to the brain. The relative decrease in high school attendance was greater for sons of low level white collar workers. The dose-response relations in the three socioeconomic classes, however, were not significantly different from each other when dose was used as a continuous variable (table 4).
Table 3 Odds ratios and 95% confidence intervals of high school attendance in relation to dose of radiation to the brain in 2551 Swedish men irradiated for cutaneous haemangioma aged when aged under 18 months
Table 4 Multivariate analysis of high school attendance in relation to radiation dose to brain in 2371 Swedish men irradiated for cutaneous haemangioma when aged under 18 months, stratified by father's socioeconomic status. Values are odds ratios (95% confidence intervals) unless stated otherwise
The statistical power to separate the effect of dose to the frontal and posterior part of the brain was low due to a high degree of colinearity between dose estimates (r = 0.84, P < 0.0001). The dose to the frontal part of the brain provided a slightly better fit to the data than did the dose to the posterior part. Furthermore, adding frontal and posterior doses did not significantly improve the fit of the model (P = 0.29).
To explore a possible modifying effect by age at treatment, we stratified the men into those treated at age 6 months and those treated at age 6-18 months. We found no evidence of a difference between these strata in the strength of association between frontal dose and probability of attending high school. When radiation dose was analysed as a continuous variable, the change in risk per 50 mGy was 9% for age 6 months and 14% for age 6-18 months. Similar results were obtained when we analysed posterior dose (data not shown).
Cognitive tests
In univariate analyses, a significant dose-response relation was seen for all cognitive tests except spatial recognition (results not shown). Frontal dose had a stronger association with the outcome variables than did posterior dose and was therefore considered in further analyses. In the multivariate setting we took into consideration age at treatment, number of siblings, and year of test. Significant trends of decreasing test results with increasing dose were seen for concept discrimination and general instruction (P = 0.03) and technical comprehension (P = 0.003). No trend was seen for spatial recognition (P = 0.50; table 5).
Table 5 Mean test results adjusted for number of siblings, age at treatment, and year of test in relation to radiation dose in 2211 Swedish men irradiated for cutaenous haemangioma when aged under 18 months. Values are mean (standard error) unless stated otherwise
To investigate whether the difference in dose-response between cognitive tests reflecting learning ability and logical reasoning was consistent within the men, we used as a response variable the individual difference between the results of the spatial recognition test and the average of the three tests. The unadjusted individual discrepancy between the different tests increased significantly with dose (table 6, P = 0.0002). Furthermore, both the significance and the estimated changes per unit dose remained essentially unchanged after adjustment not only for the potential confounders (P = 0.0003) but also for high school attendance (P = 0.0008).
Table 6 Average difference between scores on spatial recognition test and on combined tests in 2211 Swedish men irradiated for cutaneous haemangioma when aged under 18 months. Values are changes in mean (SE) scores, unless stated otherwise; reference value for regression is dose of 0 mGy
Discussion
Otake M, Schull WJ. In utero exposure to A-bomb radiation and mental retardation; a reassessment. Br J Radiol 1984;57: 409-14.
Yoshimaru H, Otake M, Schull WJ, Funamoto S. Further observations on abnormal brain development caused by prenatal A-bomb exposure to ionizing radiation. Int J Radiat Biol 1995;67: 359-71.
Schull WJ. Brain damage among individuals exposed prenatally to ionizing radiation: a 1993 review. Stem Cells 1997;15(Suppl 2): 129-33.
Schull WJ, Otake M. Cognitive function and prenatal exposure to ionizing radiation. Teratology 1999;59: 222-6.
Ron E, Modan B, Floro S, Harkedar I, Gurewitz R. Mental function following scalp irradiation during childhood. Am J Epidemiol 1982;116: 149-60.
Fogarty K, Volonino V, Caul J, Rongey J, Whitman B, O'Connor D, et al. Acute leukemia. Learning disabilities following CNS irradiation. Clin Pediatr (Phila) 1988;27: 524-8.
Skowronska-Gardas A. Radiotherapy of central nervous system tumors in young children: benefits and pitfalls. Med Pediatr Oncol 1999;33: 572-6.
Riva D, Giorgi C. The neurodevelopmental price of survival in children with malignant brain tumours. Childs Nerv Syst 2000;16: 751-4.
Anderson VA, Godber T, Smibert E, Weiskop S, Ekert H. Cognitive and academic outcome following cranial irradiation and chemotherapy in children: a longitudinal study. Br J Cancer 2000;82: 255-62.
Brenner D, et al. Estimated risks of radiation-induced fatal cancer from pediatric CT. Am J Roentgenol 2001;176: 289-96.
Duncan J, Seitz RJ, Kolodny J, Bor D, Herzog H, Ahmed A, et al. A neural basis for general intelligence. Science 2000;289: 457-60.
Lundell M, Holm LE. Risk of solid tumors after irradiation in infancy. Acta Oncol 1995;34: 727-34.
Lundell M, Mattsson A, Karlsson P, Holmberg E, Gustafsson A, Holm LE. Breast cancer risk after radiotherapy in infancy: a pooled analysis of two Swedish cohorts of 17,202 infants. Radiat Res 1999;151: 626-32.
Hall P, Granath F, Lundell M, Olsson K, Holm LE. Lenticular opacities in individuals exposed to ionizing radiation in infancy. Radiat Res 1999;152: 190-5.
Karlsson P, Holmberg E, Lundell M, Mattsson A, Holm LE, Wallgren A. Intracranial tumors after exposure to ionizing radiation during infancy: a pooled analysis of two Swedish cohorts of 28,008 infants with skin hemangioma. Radiat Res 1998;150: 357-64.
Kallen B, Karlsson P, Lundell M, Wallgren A, Holm LE. Outcome of reproduction in women irradiated for skin hemangioma in infancy. Radiat Res 1998;149: 202-8.
Lundell M. Estimates of absorbed dose in different organs in children treated with radium for skin hemangiomas. Radiat Res 1994;140: 327-33.
Carlstedt B. Cognitive abilities—aspects of structure, process and measurement. University of Gothenburg (Thesis), 2000.
National Board of Health and Welfare. Reports on statistical co-ordination. Stockholm: National Board of Health and Welfare, 1982.
Lundell M, Furst CJ, Hedlund B, Holm LE. Radium treatment for hemangioma in early childhood. Reconstruction and dosimetry of treatments, 1920-1959. Acta Oncol 1990;29: 551-6.
Kolb B, Wishaw IQ. Fundamentals of human neuropsychology, 3rd ed. New York: WH Freeman, 1990: 412-97.
Husen T. The induction test 1944. Requirements and organization. Tidskrift Psykologi Pedagogik 1944;43: 114-8. (In Swedish.)
Leitz W, Jonsson H. Patient doses from X-rays in Sweden—a summary of results from healthcare reports in 1999. Stockholm: Swedish Radiation Protection Institute, 2001. (In Swedish.)
UNSCEAR, United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and effects of ionising radiation. New York: United Nations, 2000.(Per Hall, associate profe)
Correspondence to: P Hall Per.Hall@mep.ki.se
Abstract
Ionising radiation may impair the developing human brain and adversely affect cognitive processes, as documented among children exposed in utero after the bombing of Hiroshima and Nagasaki or treated with radiation for ringworm of the scalp.1-5 Evidence also comes from young children treated for leukaemia or brain tumours6-9; but in these studies it is difficult to distinguish the effect of radiation from that of underlying diseases, concomitant surgery or chemotherapy, or hormonal abnormalities.7 Existing data are based mostly on high doses of ionising radiation ( 1 Gy), therefore little is known about the effects of low doses of radiation or a possible threshold value. Also inadequately documented is the effects of age at exposure. Lack of such evidence is of concern because modern imaging techniques such as computed tomography, which deliver high doses of ionising radiation, are increasingly being used in even young children after minor head trauma. The dose delivered to the brain of an infant during computed tomography of the skull is around 120 mGy.10
We analysed cognitive function in a large population based cohort of men at the time of military enlistment who had received low dose ionising radiation for cutaneous haemangioma before age 18 months. Based on previous experience, we hypothesised that damage to the frontal part of the brain would have a more severe effect on mental capacity than damage to the posterior part.11
Participants and methods
During 1930-59, 4577 boys aged under 18 months received radiotherapy for cutaneous haemangioma at the Karolinska University Hospital, Stockholm. Information was missing on the names and dates of birth for four children and dose of radiation for one child, and two children were lost to follow up. Hence 4570 men in the original cohort were available for follow up (figure). We excluded 1439 men tested after 1968 because the retrieval of data was administratively complicated then, and we excluded 37 men tested before 1954 because the tests of cognitive function changed after that time. The military records of 220 men could not be found, and the test results of five men were missing. Information was missing on education for 53 boys and number of siblings for another 265, leaving 2551 boys for analysis of high school attendance. We excluded 160 men from analyses of cognitive function as they were tested during 1954-8 before the battery of cognitive tests was expanded from three to four, making it difficult to compare their results with those of the 2869 men who took the test during 1959-68. In addition, we excluded 180 boys without information on fathers' occupation. This left 2211 for analysis of cognitive function.
Flow of patients through trial
The mean number of haemangiomas per child was 1.5 (range 1-16). Overall, 49% (n = 1380) of the men were irradiated when aged under 6 months, 39% (n = 1098) at 6-11 months, and 12% (n = 338) at 12-17 months. The mean age of the men at first treatment was 7 months (median 6 months). The average estimated absorbed dose to the brain was 52 mGy (median 20 mGy, range 0-2800 mGy) and the largest contribution came from irradiation of haemangiomas in the head region (table 1). The average and median dose to the frontal part of the brain was slightly higher than to the posterior part. An estimated dose of 100 mGy or more was delivered to the frontal part of the brain in 661/2816 (23.5%) men and to the posterior part in 384/2816 (13.6%; table 2).
Table 1 Average and median absorbed doses of ionising radiation to frontal and posterior parts of brain in relation to location of cutaneous haemangioma
Table 2 High school attendance in relation to part of brain receiving dose of radiation and father's socioeconomic status in cohort of 2816 Swedish men irradiated for cutaneous haemangioma when aged under 18 months. Values are numbers (percentages) unless stated otherwise
High school attendance
A decrease in high school attendance was seen in all socioeconomic groups at radiation doses greater than 100 mGy when compared with the lowest dose of 1-20 mGy (table 2). No consistent difference was seen between the two lowest dose categories (1-20 mGy and > 20-100 mGy); however, the increment of exposure was limited, with median values of only 0 and 30-40 mGy.
We found an overall statistically significant decreasing probability of attending high school in relation to radiation dose (table 3). Adjustment for potential confounders changed risk estimates only marginally. The probability of attending high school was reduced by around 50% in greater than 100 mGy category compared with the 1-20 mGy, and it decreased by 11-14% per 50 mGy increment in dose in the multivariate analyses. We found no appreciable difference in the dose-response relation between frontal and posterior dose of radiation to the brain. The relative decrease in high school attendance was greater for sons of low level white collar workers. The dose-response relations in the three socioeconomic classes, however, were not significantly different from each other when dose was used as a continuous variable (table 4).
Table 3 Odds ratios and 95% confidence intervals of high school attendance in relation to dose of radiation to the brain in 2551 Swedish men irradiated for cutaneous haemangioma aged when aged under 18 months
Table 4 Multivariate analysis of high school attendance in relation to radiation dose to brain in 2371 Swedish men irradiated for cutaneous haemangioma when aged under 18 months, stratified by father's socioeconomic status. Values are odds ratios (95% confidence intervals) unless stated otherwise
The statistical power to separate the effect of dose to the frontal and posterior part of the brain was low due to a high degree of colinearity between dose estimates (r = 0.84, P < 0.0001). The dose to the frontal part of the brain provided a slightly better fit to the data than did the dose to the posterior part. Furthermore, adding frontal and posterior doses did not significantly improve the fit of the model (P = 0.29).
To explore a possible modifying effect by age at treatment, we stratified the men into those treated at age 6 months and those treated at age 6-18 months. We found no evidence of a difference between these strata in the strength of association between frontal dose and probability of attending high school. When radiation dose was analysed as a continuous variable, the change in risk per 50 mGy was 9% for age 6 months and 14% for age 6-18 months. Similar results were obtained when we analysed posterior dose (data not shown).
Cognitive tests
In univariate analyses, a significant dose-response relation was seen for all cognitive tests except spatial recognition (results not shown). Frontal dose had a stronger association with the outcome variables than did posterior dose and was therefore considered in further analyses. In the multivariate setting we took into consideration age at treatment, number of siblings, and year of test. Significant trends of decreasing test results with increasing dose were seen for concept discrimination and general instruction (P = 0.03) and technical comprehension (P = 0.003). No trend was seen for spatial recognition (P = 0.50; table 5).
Table 5 Mean test results adjusted for number of siblings, age at treatment, and year of test in relation to radiation dose in 2211 Swedish men irradiated for cutaenous haemangioma when aged under 18 months. Values are mean (standard error) unless stated otherwise
To investigate whether the difference in dose-response between cognitive tests reflecting learning ability and logical reasoning was consistent within the men, we used as a response variable the individual difference between the results of the spatial recognition test and the average of the three tests. The unadjusted individual discrepancy between the different tests increased significantly with dose (table 6, P = 0.0002). Furthermore, both the significance and the estimated changes per unit dose remained essentially unchanged after adjustment not only for the potential confounders (P = 0.0003) but also for high school attendance (P = 0.0008).
Table 6 Average difference between scores on spatial recognition test and on combined tests in 2211 Swedish men irradiated for cutaneous haemangioma when aged under 18 months. Values are changes in mean (SE) scores, unless stated otherwise; reference value for regression is dose of 0 mGy
Discussion
Otake M, Schull WJ. In utero exposure to A-bomb radiation and mental retardation; a reassessment. Br J Radiol 1984;57: 409-14.
Yoshimaru H, Otake M, Schull WJ, Funamoto S. Further observations on abnormal brain development caused by prenatal A-bomb exposure to ionizing radiation. Int J Radiat Biol 1995;67: 359-71.
Schull WJ. Brain damage among individuals exposed prenatally to ionizing radiation: a 1993 review. Stem Cells 1997;15(Suppl 2): 129-33.
Schull WJ, Otake M. Cognitive function and prenatal exposure to ionizing radiation. Teratology 1999;59: 222-6.
Ron E, Modan B, Floro S, Harkedar I, Gurewitz R. Mental function following scalp irradiation during childhood. Am J Epidemiol 1982;116: 149-60.
Fogarty K, Volonino V, Caul J, Rongey J, Whitman B, O'Connor D, et al. Acute leukemia. Learning disabilities following CNS irradiation. Clin Pediatr (Phila) 1988;27: 524-8.
Skowronska-Gardas A. Radiotherapy of central nervous system tumors in young children: benefits and pitfalls. Med Pediatr Oncol 1999;33: 572-6.
Riva D, Giorgi C. The neurodevelopmental price of survival in children with malignant brain tumours. Childs Nerv Syst 2000;16: 751-4.
Anderson VA, Godber T, Smibert E, Weiskop S, Ekert H. Cognitive and academic outcome following cranial irradiation and chemotherapy in children: a longitudinal study. Br J Cancer 2000;82: 255-62.
Brenner D, et al. Estimated risks of radiation-induced fatal cancer from pediatric CT. Am J Roentgenol 2001;176: 289-96.
Duncan J, Seitz RJ, Kolodny J, Bor D, Herzog H, Ahmed A, et al. A neural basis for general intelligence. Science 2000;289: 457-60.
Lundell M, Holm LE. Risk of solid tumors after irradiation in infancy. Acta Oncol 1995;34: 727-34.
Lundell M, Mattsson A, Karlsson P, Holmberg E, Gustafsson A, Holm LE. Breast cancer risk after radiotherapy in infancy: a pooled analysis of two Swedish cohorts of 17,202 infants. Radiat Res 1999;151: 626-32.
Hall P, Granath F, Lundell M, Olsson K, Holm LE. Lenticular opacities in individuals exposed to ionizing radiation in infancy. Radiat Res 1999;152: 190-5.
Karlsson P, Holmberg E, Lundell M, Mattsson A, Holm LE, Wallgren A. Intracranial tumors after exposure to ionizing radiation during infancy: a pooled analysis of two Swedish cohorts of 28,008 infants with skin hemangioma. Radiat Res 1998;150: 357-64.
Kallen B, Karlsson P, Lundell M, Wallgren A, Holm LE. Outcome of reproduction in women irradiated for skin hemangioma in infancy. Radiat Res 1998;149: 202-8.
Lundell M. Estimates of absorbed dose in different organs in children treated with radium for skin hemangiomas. Radiat Res 1994;140: 327-33.
Carlstedt B. Cognitive abilities—aspects of structure, process and measurement. University of Gothenburg (Thesis), 2000.
National Board of Health and Welfare. Reports on statistical co-ordination. Stockholm: National Board of Health and Welfare, 1982.
Lundell M, Furst CJ, Hedlund B, Holm LE. Radium treatment for hemangioma in early childhood. Reconstruction and dosimetry of treatments, 1920-1959. Acta Oncol 1990;29: 551-6.
Kolb B, Wishaw IQ. Fundamentals of human neuropsychology, 3rd ed. New York: WH Freeman, 1990: 412-97.
Husen T. The induction test 1944. Requirements and organization. Tidskrift Psykologi Pedagogik 1944;43: 114-8. (In Swedish.)
Leitz W, Jonsson H. Patient doses from X-rays in Sweden—a summary of results from healthcare reports in 1999. Stockholm: Swedish Radiation Protection Institute, 2001. (In Swedish.)
UNSCEAR, United Nations Scientific Committee on the Effects of Atomic Radiation. Sources and effects of ionising radiation. New York: United Nations, 2000.(Per Hall, associate profe)