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Leukemia
170
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
the offspring of male workers exposed to from the first study, particularly the asso-
100 Millie Sieverts (mSv) or higher of io- ciations with paternal exposures, and thus
nizing radiation prior to conception demon- in the vast majority of cases (92%) and
strated a six-fold elevation in risk of leu- controls (94%), both parents were inter-
kemia [3]. Considerable debate has been viewed in person about their own exposures
focused on whether such an association is [10]. Exposure information was obtained
just a chance finding. The absence of an in- from 642 pairs of childhood cancer cases
creased risk of leukemia in offspring of Ja- and individually matched controls, inclu-
panese atomic bomb survivors [4], and ding 166 acute leukemia cases who were
offspring of nuclear workers in other set- under the age of 15 years with a newly dia-
tings [5,6], the lack of statistical compati- gnosed leukemia during June 1, 1986 and
bility of the distribution of paternal pre- December 31, 1991 and their matched con-
conceptional radiation exposure dose, and trols. The three U.S. studies (designated
the clustering of childhood leukemia oc- protocols CCG-E09, CCG-EI4 and CCG-
curring in Seascale [7] have added to this E15) were conducted by the Children's
debate. The association between paternal Cancer Group (CCG), a cooperative clini-
diagnostic X-ray exposure and the risk of cal trials group with approximately 100
childhood cancer has received little atten- members and affiliated institutions in the
tion. [8,9] Over the last 10 years, we have United States, Canada and Australia
conducted five case-control studies of [11,12]. Cases were identified from the
childhood leukemia in China and the U.S., CCG registration files. Controls were ran-
in which diagnostic X-ray was one of the domly selected using a random digit dialing
major study hypotheses. This report sum- procedure and individually matched to ca-
maries the findings of these studies regar- ses on the year of birth (within a year of
ding parental preconception X-ray exposu- age of the case for the CCG-E09 study,
re and the risk of childhood leukemia, with within 25% at the age of diagnosis of the
a focus on the association of leukemia risk case for the CCG-EI4 and CCG-EI5
among children during the first two years study), on geography (telephone area code
of life. and exchange), and ethnicity (black, non-
black, for E14 and EI5). The CCG-E09
Subjects and Methods study, including 302 leukemia cases and
The designs of the five studies are briefly 558 controls, was designed to examine the
summarized in Table 1. The cases of the association of parental exposures with leu-
two Chinese studies were identified from a kemia in children diagnosed under the age
population-based Shanghai tumor registry, of 18 months. The CCG-E14 study, inclu-
and controls were randomly selected from ding 558 cases and 619 matched controls,
the general population in Shanghai and in- was conducted to examine parental and
dividually matched to cases on sex and ca- childhood exposures associated with acute
lendar year of birth. The first Shanghai myeloid leukemia (AML) in children under
study included 309 cases diagnosed with the age of 18 years. The CCG-EI5 study
leukemia before the age of 15 years during included 1842 acute lymphocytic leukemia
January 1, 1974 and May 31,1986 and 618 (ALL) cases and 1986 matched controls
individually matchedcontrols [9]. The ex- and was designed to examine the role of
posure information was obtained from in- parental and childhood exposures in child-
person interviews with mothers of study ren with ALL diagnosed under the age of
participants. The second Shanghai study 15. Exposure information of all three U.S.
was designed to follow-up on the findings studies were collected through a telephone
171
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
interview with mothers and fathers (if ever, when analyses were restricted to leu-
available) of the study subjects. The father's kemia cases diagnosed under the age of 2
questionnaires were completed for 280 ca- years, a non-statistically significant asso-
ses and 511 controls for CCO-E09 study, ciation between paternal X-ray exposure
490 caSes and 566 controls for CCO-EI4 and childhood leukemia was observed
study, and 1801 cases and 1813 controls for (OR=1.94, 95%CI=0.3-12.6). But neither
CCO-EI5 study. Of these completed pater- the point estimates nor the trend test was
nal questionnaires, direct interviews with statistically significant, perhaps due to a
fathers were obtained for 89% of cases and small sample size. Moreover, there were al-
71 % of controls for CCO-E09 study, 82.4% so too few study subjects under age of 2 to
cases and 64.0% of controls for CCO-El4 allow for a stratified analysis by leukemia
study and 83.4% of cases and 67.7% of types. Nevertheless, this study suggested
controls for CCO-E15 study. The remai- that age at diagnosis of leukemia might be
ning interviews were completed by mothers an important modifying factor in the asso-
as surrogates for the fathers. ciation of paternal X-ray exposure with
Odds ratios (ORs), as approximations of childhood leukemia.
relative risk, were used to measure the as-
sociation between X-ray exposures and the CCG-E09 Infant Leukemia Study [11]
risk of childhood leukemia. Conditional The CCO-E09 study was designed to study
logistic regression was employed in data the pre-conception and pre-natal exposure
analyses to obtain ORs and 95% confidence as risk factors of childhood leukemia. Of
intervals (CIs), adjusting for potential con- the 302 cases included in this study, 203
founders. [13] were diagnosed with ALL and 88 with
AML. The remaining 11 patients had other
Results types of leukemia. The large series of
young leukemia cases included in this study
Shanghai Childhood Leukemia Studies provided us an unique opportunity to eva-
[9,10] luate in depth the effect of parental X-ray
In the first Shanghai leukemia study, the exposure in the development of childhood
number of paternal pre-conception dia- leukemia.
gnostic X-ray was significantly higher It was shown in this study that the risk of
among leukemia cases than controls. The infant leukemia was significantly increased
risk of both ALL and AML was positively among those children whose fathers repor-
correlated with the number of paternal pre- ted ever having pre-conception X-ray expo-
conception X-ray exposure but was unrela- sure of the chest (OR=1.44), limb
ted to maternal pre-conception diagnostic (OR=I.46), upper 01 tract (OR=1.87) or
X-ray exposure (Table 2). This study, how- lower GI tract (OR=2.24). The elevated
ever, was limited because father's exposure risk tended to be higher for exposures that
information was provided by the mother occurred in the month or the year before
and thus might result in misclassification. conception than for those occurring earlier,
A new study was initiated to follow"up on although most point estimates were not sta-
the findings from the first study. In the tistically significant due to the small num-
second study, both mother and father of the ber of exposed subjects (Table 4). X-ray
study subjects were independently inter- exposures of the head and neck (mainly
viewed. Overall, paternal or maternal X-ray dental X-rays) were not related to risk.
exposure was not related to an increased The relation of paternal pre-conception X-
risk of childhood leukemia (Table 3). How- ray exposure to leukemia risk was further
172
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
evaluated according to the number of X-ray 0.98-4.48) for the highest exposure catego-
exposures at specific sites and by major ries of lower GI/abdomen, upper GI, and
histopathologic types of leukemia (Table chest X-ray, respectively.
5). The risk of ALL increased with the Maternal diagnostic X-ray examination a
number of X-rays the father received to the month or more before conception of the in-
upper GI (trend test P=0.04), lower GI and dex child was not related to the risk of in-
lower abdomen (P<O.Ol), and chest fant leukemia, irrespective of timing or ex-
(P=0.08). Risk of ALL was also substan- posure site (Table 6). Maternal X-ray expo-
tially elevated (OR=2.48, 95%CI=0.85- sure in the month prior to conception of the
7.29), although not statistically signifi- index child, however, was related to an in-
cantly, among children whose fathers had creased risk (OR=4.5, 95%CI=1.05-19.28).
five or more X-rays of the back and spine. Although based on the small numbers of
In contrast, risk of ALL was not associated exposed subjects, elevated risks with X-ray
with paternal X-ray exposure of the head exposure within a month prior to pregnancy
and neck or limbs. The risk of AML was were observed for most exposure sites
less consistently associated with paternal (Table 6).
X-ray exposure, with an indication of a po- Leukemia risk was unrelated to the number
sitive association for X-rays of the upper of maternal pre-conception X-rays, even
GI (trend test P=0.07) but not for other ana- when examined within histopathologic
tomic locations (Table 5). types and exposure sites (Table 7). There
Analyses restricted to subjects with direct was no appreciable confounding effect of
father interview data revealed that the ORs paternal exposure on maternal exposure or
of ALL related to lower GI and abdomen vice versa, and no indication of interaction
X-ray were increasingly higher (OR=3.9, between paternal and maternal X-ray expo-
95%CI=1.77-8.58 and OR=5.64, 95%CI= sure.
1.52-20.95 for one and two or more expo- Mothers of cases were more likely, al-
sures, respectively). The ORs of ALL rela- though not statistically significantly, than
ted to upper GI X-ray (OR=1.33, control mothers to report ever having been
95%CI=0.65-2.7, and OR=2.15, 95%CI= exposed occupationally to radioactive ma-
0.67-6.96 for one and two or more exposu- terials (OR=1.82, 95%CI=0.93-3.56). No
res) and chest X-ray (OR=1.38, difference, however, was observed for ca-
95%CI=0.54-3.57 for 10 or more exposu- ses and controls with respect to mothers'
re), however, were attenuated. No signifi- reported use of radiation badges on the job
cant association between paternal pre-con- (OR=1.05,95%CI=0.34-3.18).
ception X-ray exposure and risk of AML
was observed (data not shown). CCG-E14 Childhood AML Study and
More fathers of cases than controls reported CCG-E15 Childhood ALL Study
exposure to radioactive materials in an oc- In these two recent completed case-control
cupational setting (OR=1.7, 95%CI=1.07- studies, we again found that paternal pre-
2.71) or had worn a radiation badge at work conception X-ray exposure was related to a
(OR=2.25, 95%CI=1.l6-4.37). The asso- moderately elevated risk of ALL, with risk
ciation between paternal diagnostic X-ray being slightly higher among young child-
and the risk of infant leukemia remained af- ren, although the later was not statistically
ter adjustment for occupational radiation significant. No significant association 'was
exposure. The adjusted ORs for ALL were observed between paternal X-ray and risk
4.02 (95% CI=1.55-1O.44), 2.72 of AML. Similarly, maternal pre-concep-
(95%CI=0.98-7.55) and 2.18 (95%CI= tion X-ray exposure was not associated
173
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
with the risk of childhood leukemia, re- were under age 6 at diagnosis (Table 9).
gardless the leukemia type and age at dia- [14] Another UK-based study found that
gnosis (Table 8). paternal pre-conception occupational expo-
sure to radiation, even at doses lower than
Discussion the 5 mSv level, was associated with an in-
Although the studies evaluating the as- creased risk of leukemia among children
sociation of paternal pre-conception occu- under the age of five. [15] These observa-
pational exposure to radiation and risk of tions provided further support of our fin-
childhood leukemia in offspring were equi- ding that age at diagnosis of leukemia may
vocal, a positive association of paternal be the crucial factor in determining the ef-
pre-conception diagnostic X-ray exposure fect of paternal radiation exposure and risk
and the risk of childhood leukemia, particu- of leukemia in offspring.
larly among young children, has been re- The association between paternal pre-con-
peatedly demonstrated in several studies [8- ception radiation exposure and risk of in-
11]. Early in the 1960's, Graham et al. re- fant leukemia is intriguing. Alternative ex-
ported that parents of childhood cancer ca- planations, however, need to be considered
ses are more like to be exposed to diagno- before any etiologic connection can be
stic X-ray prior to conception [8]. The five made. Of major concern is the accuracy of
studies under review suggested that pater- exposure assessment, since only interview
nal exposure to radiation prior to concep- information was obtained for five studies.
tion is associated with an increased risk of Although the short time period between
leukemia among young children. The CCG conception and diagnosis of disease among
studies, particularly the CCG-E09 also re- young children substantially reduced the
vealed that the elevated risks were mainly likelihood of recall bias, we can not ex-
attributable to the excess risk of ALL and clude the possibility that parents of cases
the positive association was more evident might recall exposures more readily than
for exposures of high frequency, occurring parents of controls and might telescope the
at sites closer to the gonads or time periods time of exposures. However, the elevated
closer to conception. risk associated with paternal pre-conception
It is conceivable that if pre-conception ra- X-ray exposure being confined to specific
diation exposure is indeed related to the leukemia type (ALL) and anatomic sites
risk of leukemia in offspring, a stronger as- (e.g., GI, lower abdomen and chest), and no
sociation would be observed among the excess risk being linked to maternal expo-
youngest children (i.e., those diagnosed in sure suggested that recall bias is unlikely
the first two years of life) due to the pre- the sole explanation.
zygotic nature and minimum of confoun- Selective participation of subjects casts
ding from post-natal exposures. It is notice- some concerns for the U.S. studies since
able that among the sub-group of cases who 13-26% of eligible cases and 28-31 % of
were resident in Seascale near Sellafield at eligible controls did not have paternal ex-
diagnosis, all four acute lymphocytic leu- posure information. For those with comple-
kemia cases with a higher paternal occupa- ted paternal questionnaire data, mother was
tional radiation exposure (> 50 mSv) were the surrogate respondents for 11-18 % of
diagnosed before age 6 (2 cases were age 2, case fathers and 29-36% of control fathers.
one age 4, and one age 5 at diagnosis of It is noted that non-participating parents
leukemia), while only one of the four ALL were less educated compared to participa-
cases with very low (0.1 to 49 mSv, 1 case) ting parents. To control for this potential
or no (3 cases) paternal radiation exposure selection bias, we adjusted for parental
174
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
education throughout our analyses. Resi- mutation or genomic instability in the deve-
dual bias, if any, resulting from selective lopment of cancers among experimental
participation according to educational level, settings. For example, exposure of bone
would tend to lead to an under-estimation marrow stem cells to X-rays or a-particles
of the disease-radiation association, since has been shown to be related to about 2%
high education was found to be related to and 40%, respectively, of chromosome ab-
more X~ray exposure. [16] Additional normalities in the daughter celIs.[17] A
analyses restricted to subjects with\par di- delayed chromosomal instability was found
rect father interview did not show an indi- in cultured cells several generations after
cation of major misclassification of expo- X-ray exposure. [18,19] Experiments on
sure by including the surrogate interview 15,000 mice demonstrated that X-ray expo-
data. sure of parental gonads substantially in-
Another alternative explanation is that the creased the incidence rate of both lung can-
underlying diseases that required X-ray cer and leukemia in offspring. [20] The
examination or their related medications dose of radiation used in those experiments,
might cause mutation of the parental germ however, was much higher than that used
cells and, in turn, increase the risk of leu- for human X-ray examinations.
kemia in their offspring. To address this
It is well accepted that cancers are conse-
concern, we reviewed the questionnaires of
quences of the combined effect of en-
CCG-E09 study participants to evaluate if
vironmental exposures and ~ost response.
the excess lower GI and abdomen X-ray
Therefore, to understand the etiologic role
exposure among cases was attributed to an
of paternal diagnostic X-ray exposure on
excess of certain diseases or medications.
childhood cancer, we need to consider both
We did not observe any patterns of disease
environmental exposures and host suscep-
or medications that could account for the
tibility factors. Working towards this, we
excess of X-rays among cases. Therefore, if
have developed the following hypothesis
an underlying disease or medication was
(Figure). Radiation exposure to gonads may
the cause of infant leukemia, we would
cause DNA damages in spermatogonia. If
have to assume that many paternal diseases
the radiation dose is high and DNA damage
or medications were involved. Unfortuna-
is severe, the germ cells will die. Low dose
tely, a detailed medical history of parents
radiation, however, may result in minor
prior to conception of the index child was
damage in germ cells (detectable or yet not
not obtained for the five studies, which
detectable), which are not fatal to germ
precluded a thorough evaluation of the con-
cells. This damage may be repaired among
founding effect of medical conditions on X-
subjects with normal DNA repair capacity
ray exposure. Nevertheless, the association
but persist and accumulate among subjects
between paternal occupational radiation
with impaired DNA repair function. If one
exposure prior to conception and risk of in-
of these germ cells results in a pregnancy, it
fant leukemia observed in the CCG-E09
might result in miscarriage, stillbirth, or a
study would argue against paternal disease
susceptible offspring who would develop
history and medication use as a sole expla-
leukemia once he/she is exposed in utero or
nation of the radiation/leukemia association
post-natally to a leukemogenic factor.
that we observed.
Although germline mutation is believed to Direct evidence linking genetic markers of
be a rare origin for childhood cancers, there pre-conception exposure to diagnostic X-
are some biologic data available indicating ray and parental DNA repair function to
a potential role for germline transmission of leukemia risk among young children are
175
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
crucial for testing this hypothesis and tion doses to fathers employed at the Sellafied
nuclear installation, West Cumbria. Br. Med. J.,
should be a priority for future studies.
307:966-71,1993.
We would like to acknowledge Drs. F. Jin,
8. Graham, S., Levin, M.L., Lilienfeld, A.M.,
W. Zheng, Y.T. Gao, D.M. Yin, B.T. Ji, B. et a1. Preconception, intrauterine, and postnatal
Lampkin, M. Linet, T.G. Pendergrass, G.H. irradiation as related to leukemia. NCI Mono-
Reaman, R.N. Sather, and M. Steinbuch for graphs, 19: 347-71, 1966.
their contributions to the studies in this re- 9. Shu, X.O., Gao, Y.T., Brinton, L.A., et a1. A
ports. Two Shanghai studies were suppor- population-based case-control study of child-
ted by Shanghai Cancer Institute Research hood leukemia in Shanghai. Cancer, 62: 635-44,
Fund and a research grant from the Young 1988.
Scientist Foundation, Shanghai Municipal to. Shu X-O, Jin F, Linet MS, Zheng W, Cle-
mens J, Mills J, Gao Y-T. Diagnostic X-ray
Bureau of Health, China. The CCG studies
and ultrasound exposure and risk of childhood
were supported by NIH grants CA4279,
cancer. Br J Cancer 1994;70:531-6.
CA49450, and CA4805l. 11. Shu XO, Reaman GH, Lampkin B, Sather
H, Pendergrass TW, Robison LL. Association
of parental diagnostic X-ray exposure and risk
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18. Holmberg, K., FaIt, S., Johansson A., and 20. Nomura, T. Role of radiation-induced
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Mother**
None 98 43 1.0 25 1.0 ]3 1.0
1-5 381 170 1.] 0.7-1.7 94 1.0 0.6-1.6 55 1.6 0.7"3.3
6-10 ]09 7] 1.0 0.6-1.7 39 0.9 0.5-1.7 2] ].4 0.5-3.5
~]] 30 24 1.1 0.5-2.3 14 1.1 0.3-2.8 5 0.9 0.2-3.3
Trend Test P=0.91 P=0.82 P=0.94
Adjusted for age, sex, birth weight, birth order, born in rural area, prenatal x-ray exposure,
chloramphenicol and syntomycin usage, mother's age at menarche, and maternal occupational
exposures during pregnancy. Unknowns excluded from analysis.
* Reference group includes individuals with::::;5 reported exposures.
** Further adjusted for paternal x-ray exposure.
177
Parental PrecConception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
Maternal Exposure
ALL Cases/controls = ] 842/] 986 Cases/controls = ] 87/197
None 1.0 1.0
1 0.92 0.72-1.19 0.60 0.25-1.46
~2 1.10 0.90-1.35 1.03 0.53-] .99
AML Cases/controls = 525/6]9 Cases/controls = ] 29/147
None 1.0 1.0
1 1.06 0.74-1.51 1.32 0.55-3.15
~2 1.02 0.54-1.91 2.03 0.60-6.89
17R
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
179
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
Table 5: Risk of infant leukemia associated with the number of paternal pre-
conception X-ray exposures CCG-E09 study
Total Leukemia
Number of X-rays (N=280) ALL (N=191) AML (N=79)
by anatomic site OR! (95% CI) OR' (95% CI) ORl (95% CI)
180
Parental Pre-Conception Diagnostic X-Ray Exposure and Risk of Childhood
Leukemia
18]
Parental Pre-Conception DiagnosticX-Ray Exposure and Risk of Childhood
Leukemia
Table 7: Risk of infant leukemia associated with the number of maternal pre-
conception X-ray exposures CCG-E09 study
Total Leukemia
Number of X-rays (N=302) ALL (N=203) AML (N=88)
by anatomic site ORI (95% CI) ORI (95% CI) OR! (95% CI)
182
Parental Pre-Conception Diagnostic X-Hay Exposure and Risk of Childhood
Leukemia
Figure
1st m utali on or
infti alion
A bortio n,
still birth
183