With a view of bringing out possible sex linked lethal mutation
induced by ionizing energy, we have studied the off springs of parents treated
by pelvic radio-therapy.
The present report will be restricted on the study of the sex ratio of
the offspring of irradiated parents.
I. The data
A. Selection of Patients
Thanks to material help from the " Securité Sociale " and the "
Institut National d'Hygiéne " radio-therapy files of all hospitals in and
around paris have been examined.
All in all, out of 238,800 complete files checked in twenty
differents hospitals, 4428 cases of pelvic irradiation were found. The
irradiations were carried out on account of various complaints, of a
non-cancerous character, among adults younger than 35 for the women and 40 for
These treatments were carried out before the month of December 1952,
the years checked on dating from 1940 in the case of most hospitals but going
back to 1930 and even 1925 in certain instances.
In all cases considered, the skin /dose was greater than 300 r and
the characteristics of the radiation were known.
Of these 4428 cases :
3579 related to men
849 related to women
This is doubtless due to the different frequency of pelvic
radio-therapy indications according to sex, but may also result from the
reluctance of radiologists to use a therapy liable quickly to give rise to
A questionnaire, enabling the offspring of individual cases to be
established, was therefore sent to each of these 4428 subjects, followed by as
many reminders as proved necessary.
It may be pointed out that r doses, mentioned hereafter, always
represent the amount of ionizing radiation reaching the skip as the
radio-therapist, giving the treatment, had calculated. The average doses given
here are therefore skin /doses and not gonad /doses.
B. The offspring of irradiated males
Of 3579 questionnaires send out, 1334 or 37,4% suitable for our
purpose were returned.
These 1334 answers obviously concerned with the cases treated for
different reasons and under varying conditions, a fact which induced us to
divide them into the following three categories :
a) 368 irradiated, either high up on the lumbar
région, or on the thigh
For the most part (320), these cases suffering from sciatic
neuralgia were irradiated an the upper lumbar region ; the remainder (48) on
the thigh for various reasons. This group is therefore excluded from the
b) 180 cases irradiated on the pelvic area, whose
gonads being probably shielded
In actual fact, during radiations through the forelimbs, it is
customary to shield the testicules by means of a strip of lead placed an the
thighs. Unfortunately, there is no way of ascertaining how faithfully this rule
These 180 subjects comprise :
109, rheumatism or coxo-femoral arthrosis cases ;
64, inguinal adenopathic complaints (chiefly Nicolas Favre);
7, cases of pubic or super pubic dermatosis.
The above subjects, who doubtless received a weak dose of r since
they had been probably protected, had offspring before and after treatment.
Sex ratio :
Before treatment 0.554 ± 0. 050 (115 children)
After treatment 0.437 ± 0.051 (101 children)
This rather special post-X ray s.r. makes it hard to differentiate
this sample from the test of the present statistics.
However, as these fluctuations do not exceed what might be
expected by chance, the exclusion of this data on grounds of irradiation
conditions would not seem unwarranted.
c) 786 subjects irradiated on the pelvic area under
conditions making protection of the gonads impossible
These 786 cases comprise :
517 all treated by test-limb radio-therapy, focused on the
sacro-lumbar region and the two initial sacrum vertebrae, for sciatic
neuralgia, on the one hand :
269 treated for various reasons :
either by sacra-lumbar rear-limb treatment
or by ano-genital fore-limb treatment
for different causes :
pruritic dermatoses : 120
sacra-iliac neuralgia : 59
sacra-lumbar rheumatisn : 79
spina bifida : 11
These two samples, 517 and 269, cannot be considered as strictly
comparable and we shall therefore consider them separately.
C. The offspring of irradiated women
Of 849 women questioned, 284 or 33,5 % sent answers suitable to our
purpose (a percentage similar to that of the male), but obtained after two and
sometimes three reminders.
All the data available for the present study can be summarized in
the following table :
|Before treatment ||Men (137) Various
|Men (284) Sciatica
|Women (154) All
|After treatment ||Men (95) Various cases
|Men (194) Sciatica cases (1295
|Women (97) All cases ; (1360
II. Study of the sex ratio
From the chromosomic determination of the sex it follows that in case
of female subjects dominant lethal mutations induced on X can not be detected,
because both sexes of the offspring should be equally affected, but recessive
one will affect selectively the orale offspring, i.e. cause decrease of s.r.
While, in case of male subjects, dominant lethal mutations only should be
detected and affect selectively female offspring, i.e. cause increase of s.r.
A. Sex ratio of the progeny of irradiated
For reasons already stated, this study was carried out on sample of
786 subjects treated for sciatic neuralgia or other complaints without
receiving gonad protection.
a) Now 92 cases treated for sciatic neuralgia had children before
and after treatment and thus make an ideal subject-matter for the study of s.r.
variations following treatment and previously
Before : s.r. 0.526 ± 0.042 (150 children)
After : s. r. 0.555 ± 0.045 (119 children)
b) Similarly 42 cases treated for various reasons had children
before and after treatment.
Before : s.r. 0.448 ± 0.060 (67 children)
After : s.r. 0.530 ±0.071 (51 children)
Pooling these two samples, we find 134 fathers who has prior to
treatment : 217 children : s.r. 0.502 ± 0.035
Following treatment : 170 children : s. r. 0.547 ± 0.083
The s.r. difference is not statistically significant, but, as might
be expected, the trend of variation is towards an increase.
c) on combining the progeny of all cases who had children previous
to treatment, with a view to comparising them with that of subjects who had
children after treatment, we find on combining both samples
s. r. before treatment : 0.514 ± 0.019 (696 children)
s.r. after treatment : 0.555 ± 0.026 (405 children)
an increasing s.r. as before, but still not significant.
These data can be analysed according the following facts.
1) The fertility after radio-therapy as appraised by
the increase of the sibship after treatment
Accepting the hypothesis of dominant lethals induced on the
chromosome X, deviation should indeed be the more striking since the individual
is more nearly sterile. This study, being focused on the increase of the
sibship after treatment, is obviously a preliminary approach to the problem,
for it does not enable the following phenomena to be taken into account :
Physiological sterility due to the increasing age of couples birth
|Size of the sibship after treatment
|Neuralgia sciatic (194
|(Sciatic + varia) (289
In agreement with hypothesis, the s.r. variation peak is reached
with sibships having the lowest increase 1 or 2 children, in the sciatica
This variation is not so great in the general sample.
2) Moment of conception after
s.r. distribution, according to the interval between the end of
irradiation and date of child-birth, leads to the following figure :
These variations show that, if there really exists a s.r. increase
due to the production of dominant lethals the chromosome X, there is no reason
to suppose that it essentially affects children born soon after treatment.
In other words, if the female deficit is a real one its occurrence
essentially concerns with children resulting from paternel gametes irradiated
in the spermatogonial stage
3) Variation of s.r. according to dose received for the
total same of treated fathers
s. r. before treatment : 0.514 ± 0.019 (696 children)
s. r. after treatment : < 1000 r (moyenne = 721) : 0.528 ±
0.039 (161 children)
s.r. after treatmeng : > 1000 r (Moyenne = 1730) : 0.574 ±
0.032 (244 children)
To summarize :
1) The observed deviations are not significant but show a trend
toward increase in keeping with the genetic hypothesis of dominant lethals
induced on the chromosome.
2) The s.r. increase seems more marked when the sibship is smaller
and the amount of radiation higher.
3) There is no reason for supposing that this s.r. deviation, if
it is real, is due to peculiar spermatozoid sensitivity, for the vast majority
of children observed were resulted from gametes irradiated in the
B. Sex ratio of the offspring of irradiated
45 mothers had children before and after treatment.
s. r. before : 0.606 ± 0.06 (61 children)
s.r. after 0.510 ± 0.07 (51 children)
If one considers the offspring of all the women
|154 mothers||130||106 = 236||0.551 ±
|97 mothers||63||73 = 136||0.463 ±
|(Moyenne = 1.360)
This deficit is not significant although the s.r. deviation follows
the trend expected. ?2 is 2.74 corresponding to a probability 10 %
that the observed difference is purely fortuitous.
If we study s.r. variations, as done with further, in terms of :
The sise of the sibship after treatment
The deficit is found to affect mainly women who have borne two
The period of conception
There is no ground for supposing that the genetic effect is stronger
soon after treatment than afterwards.
However, subdividing the material too much creates very small groups
with limited statistical value.
First of all we must admitt that the heterogeneous nature of both
father and mother samples and the small number of observations available,
considerably impair the general significance of this inquiry.
However, if we consider the s.r. of the progeny before treatment, of
men who received pelvic radio-therapy treatment without gonad protection and of
women who were submitted to pelvic radio-therapy, we find the offspring before
any treatment :
|Of male|| 0.514 ± 0.019 (696 children)
|Of female|| 0.551 ± 0.034 (236 children)
|?2 = 962 ; 0.50>P>0.30
As both these instances of male and female prior to treatment can be
considered homogeneous, it is possible to compare their offspring after
treatment : Hence
|s.r. of male||(sciatica patients)||0.571 ±
|s.r. of male||(all cases)||0.555 ±
|s.r. of female||(various complaints)||0.463 ±
It will be noted that the difference between s. r. of children of
female treated and s.r. of children of male treated for sciatica is
?2 = 4.24 ; 0.05 > P > 0.02
Comparing now the progeny of female treated with total male treated,
we do not reach the level of 0.05.
?2 = 3.49; P # 0.06
If we compare, in the last resort, the children of male who received
more than 1000 r with these of female treated, the difference becomes relevant
again. We then find :
|For male ||140 male||against 104 female
|For female||63 male||against 73 female
|?2 = 4,15; 0,05 > P >
The following conclusion can be drawn from our data: it is likely
that, the s.r. is increased in male and decreased in female after pelvic
However, this conclusion cannot be regarded as certain since these
comparisons are not free from possible distortions, due mainly to the existence
of monosexual sibships which are known to occur more frequently than would be
predicted by chance.
Thus, on confining our figures to the first child born after
irradiation, we find :
|First child form after treatment
cases)||102||76||0.573 ± 0.037
|(various conditions)||39||42||0.482 ±
conditions)||37||44||0.457 ± 0.055
Comparison between offspring of female and offspring of male treated
for sciatica yields ?2 = 3.04 or 0.10 > P > 0.05.
Comparison between the offspring of female and total progeny of male
?2 = 1.49
This decrease in the discrepancy between samples when comparison is
limited to the first child is largely due to sibships with a higher s.r. at the
2nd, 3rd and 4th birth rank in the sample of patients treated for various
The variation of s. r. in the off spring of female and male treated by
pelvic ratio-therapy are well in agreement with the hypothesis based on the
induction of dominant lethal sex-linked mutations detectable in the progeny of
male and the induction of recessive lethal sex-linked mutations detectable in
the progeny of female submitted to the same treatment.
Considering the uncertainties attending on our sampling, and the small
size of the material, we realize that our data do not constitute a formal proof
that mutations are produced by ionizing energy. However, this hypothesis seems
the only likely explanation of the peculiarities observed.