Gonad dose from diagnostic procedures and its genetic effects

J. LEJEUNE

Symposium sur les unités de mesure des radiations ionisantes. Rome, 14-15 avril 1958.


Sommaire

The essential characteristic of hereditary qualities is their stability during successive generations. However, a new character may suddenly appear and be transmitted indefinitely as such. Such an unforeseeable variation is extremely rare, but in 1927 Muller (1) proved that the frequency of such an event could be considerably increased by exposure to X-rays.

Subsequently, this phenomenon has also been observed in the most varied living organisms, from bacteria to Drosophila and from fungi to mice, and may be considered as established in man himself.

This change in the genetic heritage of the irradiated cells seems to amount to a chemical alteration in the gene substance, and the molecular scale on which this occurs explains the four main laws governing mutagenesis caused by radiation:

1) The mutations are of a chance nature, i.e. the new character produced by the disturbance of a few atoms is completely unforeseeable.

2) The mutations are generally unfavourable, by reason of their chance nature. The random changing of a character selected for generations has, in fact, very little chance of being immediately favourable to the individual that receives it.

The following comparison, illustrating the harmfulness of non-adaptive changes, has often been made: imagine an amateur with a screw-driver who decides to make a random change in one of the connexions in a radio-receiver ; it is extremely improbable that this blind interference will immediately improve the functioning of the apparatus ; on the contrary, there is every likelihood that the result will be unfortunate.

3) Once they are produced, mutations are stable and are thereafter transmitted indefinitely as such ; they can henceforth only be modified by a new process of mutation.

4) Although the new character cannot be foreseen, it is possible to predict the mutation rate. This rate is directly proportional to the dose received by the cells ; for example, 200 r an the gonads will give twice as many mutations as 100 r.

The extrapolation of this ratio to very small doses (25 r in Drosophila) (1), and even limiting doses (a few photons of X-radiation on the lysogenic system, of Escherichia coli) (2) indicates that any dose, no matter how small, has a certain mutagenic power which persists, although very feeble.

Moreover, with the same total dose, the effect of small repeated doses is identical to that of one massive dose. Thus, an irradiation of 30 milliroentgens per day over 30 years is as dangerous genetically as a sudden irradiation of 330 r. This absence of a threshold of action, combined with the additive nature of the effects of repeated doses, shows that no irradiation of the gonads is negligible, since the genetic effect depends an the sum of the doses received from birth until reproduction.

As the time interval separating two human generations is about 30 years, it has been agreed to speak of the gonad dose per 30 years, these 30 years being obviously the first 30 years of life.

To evaluate the dangers arising from a given irradiation, the simplest and most representative method is to compare the affects with those of the inevitable natural mutations which occur without any human intervention.

Generally a parameter is used, known as the doubling dose, which corresponds to the gonad dose per 30 years, capable of producing as many additional mutations as those appearing spontaneously between two generations.

This doubling dose is fairly well established for insects such as Drosophila, or even for the mouse, the only mammal chose genetics is well known, and in whose case about 50 r are sufficient to double the mutation rate (3) (4).

Experiments cannot be carried out with human beings, but observed results agree fairly well with the order of magnitude of the experimental figure just quoted.

Three major classes of mutagenic effects have been studied and detected in the progeny of irradiated parents:

1) lethal effects taking the form of an increase in miscarriages and stillbirths ;

2) harmful effects leading to an increase in congenital malformations ;

3) lethal effects restricted to the male sex and taking the form of a decrease in the relative number of boys after irradiation of the mother.

These various findings are summarized in the table below:

Table I : Remarks on the progeny of irradiated individuals
Observed effectsIrradiation during the warOccupational irradiation (radiologists)Therapeutic irradiation
Intra-uterine and neonatal mortalityA not significant increase (5)A not significant increase (8) (9)No effect observed (7) No effect observed (6)
Malformation at birthNo significant effect observed (5)Significant increase of congenital heart malformations (9)No significant effect (2) No effect observed (7)
Decrease in the relative number of males bornDecrease in the number of boys after irradia-tion of the mother (5)A not significant decrease in the number of boys in the progeny of male radiologists (9)Decrease in the number of boys after irradiation of the mother (6) (7)

On the basis of deviations in the proportion of males born after irradiation of the mother, on the one hand, and in relation to the ageing of the mother an the other (10), we have attempted to calculate a doubling dose directly, and found it to be about 30r.

In addition, observation of the somatic mutation rate, which in the mouse is at least as high for the same dose of X-radiations as the germinal mutation rate (11), has been attempted by Court Brown and Doll (12) by studying the increase in tee frequency of leukaemia after therapeutic irradiation.

Here again, 30 r are thought to be sufficient to double the natural mutation rate.

It can, indeed, by no means be excluded that this doubling dose is less than 30 r, but it may be taken to be at least 3 r per 30 years, since this dose corresponds to the one we receive as a result of the natural radioactivity of the earth's crust and of cosmic radiation.

The effect which a doubling of the mutation rate would have on the physical and mental characteristics of our descendants is not easy to determine.

Broadly speaking, the present frequency of genetic defects is tube result of an equilibrium between the appearance of new mutations in each generation and their removal by natural selection.

It can therefore be predicted that if the number of mutations is doubled, the frequency of genetic defects will finally be doubled also, but only after a more or less extended period, depending on the hereditary nature of the defect. Recessive defects, such as albinism or phenyl-pyruvic idiocy, for example, would in, crease in frequency only very slightly, and centuries, if not millennia, would pass before a new equilibrium is reached and the number of sufferers doubled. On the other hand, serious dominant defects, such as achondroplasia, aniridia or retinoblastoma, would become twice as frequent in less than a century. In addition to these serious abnormalities, an increase in minor hereditary defects and predispositions to diseases would also have to be feared anal would perhaps represent a much heavier burden for society than the few catastrophic defects of which we have just spoken.

It should be remembered also that these speculations ignore the influence of medicine, which, by enabling severely handicapped individuals to survive and reproduce, works, so to speak, against selection ? consequently, there are strong reasons for thinking that a doubling of the mutation rate would be much mare dangerous for modern man than for a wild species.

However, even a dose of 30 r per 30 years would probable not endanger the survival of our species (13).

The general conclusions to be drawn from this brief review of data at present available, are that any dose of ionizing radiation reaching the human gonads is genetically harmful and that all artificial irradiation should be restricted to the lowest level technically possible.

Irradiation, of the gonads during radiological examinations may result either from direct exposure to the incident flux (examinations of the pelvis for example) or from scattered radiation (all other types of examination).

Such irradiation of the gonads depends not only on the region examined and the number of examinations, but also on the type of apparatus used and the manner in which the image is received, i.e. radiography, radiophotography or fluoroscopy.

It is consequently very difficult to establish a mean value for a population as a whole. However, surveys carried out in three different countries have resulted in very comparable estimates of the gonad dose per 30 years received on the average by men and women today as a result of radiological diagnosis clone. The figures obtained are 1-3 r for England (14), 4-5 for the United States (15) and rather more than 4 for France (16) ; there is every reason to believe that these values also apply in greater or lesser degree to Italy.

These figures show that the normal practice of medicine results in an artificial irradiation of the gonads equal to or perhaps greater than natural irradiation in the technically advanced countries.

The genetic consequences of this irradiation are in proportion to the doubling dose, which we have discussed above, and it may be said that present day medical radiology probably adds a number of additional mutations amounting to one-tenth of the spontaneous mutations.

Such a genetic effect is by no means negligible in man, bearing in mind that a mutation exercises its harmful effect by inflicting on the person carrying it a morphological or biochemical defect, which finally causes suffering or disability in the individual.

Although there can be no question of indicting medical radio loge and the immense benefits which we owe to it, it may well be asked whether the present gonad dose is the inevitable concomitant of technical progress.

Happily, this is by no means so and it can be affirmed that, without limiting the effectiveness of radiological examinations, it would be possible to reduce the exposure to one-hundredth of what it is at present.

Without discussing here the special techniques which make it possible to considerably reduce the irradiation associated with a radiological picture (use of high kilovoltage and filtration of radiation, special screens and image amplifiers, use of radiography instead of fluoroscopy), it may usefully be pointed out that a few simple precautions lave already given very good results.

Recently (17) we have systematically studied the gonad dose received in radiophotographic examinations for case-finding of pulmonary tuberculosis.

As can be seen from Fig. 1, the spin dose, i.e., the dose measured at the centre of the dorsal field, increases in proportion, to the age of the subject, corresponding to the greater thickness to be traversed by the rays. On the other hand, the lover curve in the same figure shows that the gonad dose is distinctly higher in very young children than in adults.

Still more eloquent is the curve in Fig. 2, showing the change in ratio of gonad dose to spin dose with the age of the subject. It can be seen that there is au exponential decrease in relation to age.

This fall is due to the simple fact that the gonads of adults are farther from the edge of the beam than those of small children, for obvious reasons of site, since the screen and the diaphragm, are permanently fixed in such equipment. Although the gonads are outside the beam in all cases a diaphragm, adapted to the site of the subject would make a considerable decrease possible in the scattered radiation affecting the gonads of children.

In conclusion, it is urgently necessary for radiologists to become conscious of the dangers of even very small amounts of radiation reaching the gonads of young subjects. The employment of all the technical means available should lead to the reduction of this useless irradiation almost to zero.

In addition to the simple technical problem, the use of ionizing radiation results also in a moral problem. In applying this new energy, our generation involuntarily bears an immense responsibility, that of safeguarding the physical and mental make-up of our descendants.

Even if the dangers involved in the present use of medical apparatus are probably still very small, it is urgently necessary to warn every physician and radiologist about them, since the basic principle of medicine, primum non nocere, applies not only to the patient himself but to all his future descendants.


Fig. 1. - Skin dose and gonad dose in relation to the age of the subject.


Fig. 2. - Variation of the ratio of gonad dose to skin dose with the age of the subject


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References

(1) MULLER, H. J., " Damage from point mutation in relation to radiation dose and biological conditions ", Effets génétiques des radiations chez l'homme, OMS, Genève, (1957).

(2) MARCOVICH, H., " Etude radiobiologique du système lysogène d'Escherichia coli K 12 ", thèse de Sciences, Paris, (1056).

(3) RUSSEL, W. L., " Comparison of X-ray induced mutation rates in Drosophila and mice ", Am. Natural. XC, 850, 69 (1956).

(4) CARTER, T. C., " Recessive lethal mutation induced in mouse by chronic irradiation ", Proc. Roy. Soc. London, B, 147, 402 (1957).

(5) NEEL J. V., and SCHULL, W. J., " The effect of exposure to the atomic bomb on pregnancy termination in Hiroshima and Nagasaki ", U. S. National Academy of Science (1956).

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(8) CROW, J. F., Amer. J. Roentgenol. 73, 407 (1955).

(9) MACHT S.H., and LAWRENCE, Ph.S., Amer. J. Roentgenol. 73, 442 (1955).

(10) LEJEUNE, J., and TURPIN, R., " Mutations radio-induites chez l'homme et doses de doublement - Sur la validité d'une estimation directe, ", C. R. Acad. Sci, Séance 6 mai (1957).

(11) RUSSEL, W. L., and. MAJOR, M. H., " Radiation induced presumed somatic mutations in the house mouse ", Genetics 42, 101 (1957).

(12) COURT BROWN, W. M., and DOLL, R., " Leukaemia and aplastic anaemia in patients irradiated for ankylosing spondylitis ", Spec. Rep. Ser. Med. Res. Coun. (Lond.) No. 295, (H.M.S.O. London), (1957).

(13) TURPIN, R., and LEJEUNE, J., " Influence possible sur la stabilité du patrimoine héréditaire humain de l'utilisation de l'énergie atomique ", Bull. Acad. Nat. Méd. (Paris), p. 104 (1955).

(14) " The hazard to man of nuclear and allied radiations ", Spec. Rep. Ser. Med. Res. Coun. (Lond.) H.M.S.O. (1956).

(15) LAUGHLIN, J. S., and PULLMAN, I., " The genetically significant radiation dose received by the population of the United States ", Sect. III Gonadal dose produced by the medical use of X-rays (Preliminary ed. Washington D. C.), (1957).

(16) REBOUL, (Marseille) Communication personnelle 1958.

(17) TURPIN, R., DUPIRE, M., JAMMET, H., and LEJEUNE, J., " Etude de la dose/gonade, lors des examens radio-photographiques systématiques ", (sous presse) - Document communicated to the United Nations Scientific Committee on the Effects of Atomic Radiation, (1958).