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3.9 Hereditary Effects and Irradiation In Utero Cheat Sheet (DRAFT) by

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This is a draft cheat sheet. It is a work in progress and is not finished yet.

Effect of Radiation on the Gonads

In general, the gonads are very radios­ens­itive but the biological effect of radiation varies consid­erably with the stage of develo­pment of the respective cells.
Testes
In the male, sperm production is continuous from puberty to death. The division of a sperma­tog­onium (stem cell) to the develo­pment of a mature sperm takes about 10 weeks in man, and involves several different cell popula­tions that vary in their sensit­ivity to radiation.
Since the sperma­togonia are relatively radios­ens­itive and the mature sperma­tozoa are relatively radior­esi­stant, the effect of radiation on fertility is not apparent immedi­ately. After exposure to a moderate dose of radiation, the individual remains fertile as long as mature sperm cells are available, but decreased fertility or even temporary sterility follows when these are used up.
Most of the results regarding testicular irradi­ation have been obtained from radiation therapy experi­ence. In humans, a dose above about 0.15 Gy may cause temporary sterility. A single dose of about 6.0 Gy or a fracti­onated dose of 15 Gy over 10 days will often induce permanent sterility. However, the induction of sterility in human males does not produce signif­icant changes in hormone balance, libido, or physical capabi­lity.
Ovaries
The effects of radiation on the ovaries are quite different from those on the testes.
All oocyte production (about seven million) occurs in the embryo where the ovum, surrounded by a single cell layer, is known as a primordial follicle and after the foetal stage they no longer divide.
However, most of them soon degenerate so that less than two million are present in the two ovaries at birth, and only 300,000 at puberty. Then, during all the reprod­uctive years of the female, only about 450 of these follicles develop enough to expel their ova; the remainder degene­rate.
Therefore, in the adult there are no stem cells but there are three types of follicles: immature, nearly mature, and mature.
Once again, from radiation therapy experi­ence, it has been found that a dose of about 0.5 Gy may cause temporary sterility in some indivi­duals, but a single dose of about 4 Gy or a fracti­onated dose of 15 Gy over 10 days will cause permanent sterility.
In contrast to the effect in males, though, pronounced hormonal changes comparable to those associated with the natural menopause accompany radiat­ion­-in­duced steril­isation in females.

Radiat­ion­-Pr­oduced Mutations

It is a common miscon­ception of the lay population that exposure to radiation can produce bizarre and even horrific mutants in future genera­tions. In reality, however, radiation does not result in genetic effects that are new or unique but rather increases the freque­ncies of the same mutations that already occur sponta­neously or naturally.
Since radiat­ion­-pr­oduced mutations are identical in nature to those that occur sponta­neo­usly, you can appreciate that their study is partic­ularly difficult and experi­mental sample sizes must be large in order to confid­ently detect those attributed to radiation as distinct from those that would otherwise appear.
Animal Studies
Estimation of hereditary risk is based almost entirely on the results of animal invest­iga­tions. In an enormous biological experiment involving up to seven million mice (known as the ‘Megamouse project’), the develo­pment of hereditary effects from radiation were observed and evaluated.
Radiat­ion­-in­duced genetic changes, like mutations from any other agent, may be a conseq­uence of a gene mutation or chromo­somal changes. Mutation incidence has no threshold and is a linear function of dose; if the dose is doubled, the number of mutations is doubled.
This has led to the concept of the doubling dose, which is the dose of radiation required to double the sponta­neous mutation rate, that is, the dose of radiation that would produce a number of mutations equal to the sponta­neous or background level. Results from the mouse data support an approx­imate doubling dose of 1 Gy.
Human Studies
Although many epidem­iol­ogical invest­iga­tions have been undertaken in humans, they have failed to demons­trate radiat­ion­-in­duced genetic effects. However, mutations of human cells have been identified in culture.
The largest population studied carefully for genetic effects is the survivors of the A-bomb attacks on Hiroshima and Nagasaki. Several genetic indicators have been studied for many decades in children born to the survivors. These include:
1. stillb­irths, major congenital defects, early death;
2. childhood mortality; and
3. sex chromosome abnorm­ali­ties.
Parents of children studied came from both cities and from low (0.01 to 0.09 Gy) and high (more than 1 Gy) dose groups. Indivi­duals from outside the cities were studied as controls. Though no genetic indicator has been found to be statis­tically signif­icant, the average doubling dose has been estimated to be 1.56 Sv.
In spite of this, numerical values of hereditary risk are currently based on a doubling dose of 1 Gy (equiv­alent dose of 1 Sv) and the ICRP estimate for radiat­ion­-in­duced hereditary disorders is 0.6 × 10−2 per sievert (that is, 0.6 percent per sievert). By way of compar­ison, it is estimated that the natural sponta­neous mutation rate in humans is approx­imately 10 percent.

Effect of Radiation on the Embryo and Foetus

Although the increased risk of cancer­-in­duction is of concern, the possib­ility of develo­pmental effects is equally important.
Experi­ments in Animals
It is clear that moderate doses of radiation can have an enormous effect on the developing embryo.
The principal factors are the dose, dose rate and the stage of gestation. Most data have been obtained from experi­mental animals, predom­inantly mouse, where we have:
1. reprod­uction in quantity;
2. relatively short gestation periods;
3. accurate radiation doses; and
4. specific times of concep­tion.
The in utero develo­pment period can be accurately divided into three stages; namely preimp­lan­tation, organo­genesis and the foetal stage.
Preimp­lan­tation: he time from fertil­isation to when the embryo attaches to the wall of the uterus.
It is the most sensitive stage for lethal effects of radiation.
However, during the first few divisions the cells are undiff­ere­ntiated and lack predet­erm­ination for a particular organ system. If radiation were to kill some cells at this stage, the remaining cells could survive and continue the embryonic reprod­uction normally; the only effect would be a delay in develo­pment.
Conseq­uently, there is either a radiat­ion­-in­duced sponta­neous abortion (if all cells are killed) or the embryo survives and grows normally in utero and afterwards (if at least one cell survives). This is referred to as an all-or­-no­thing effect.
Organo­genesis: period during which the major organs are developed.
The principal effect of radiation is the production of a variety of congenital abnorm­alities of a structural nature.
The Foetal Stage: the growth of the structures already formed takes place.
Functional changes have been observed on the haemat­opo­ietic system, liver, kidney and gonads following irradi­ation. Much higher doses of radiation are required to produce death during this period than at other stages of develo­pment.
Experience in Humans
Once again, our knowledge mainly comes from studies of bomb survivors and from early medical exposures which were mainly therap­eutic irradi­ations.
At any given time, there will be a certain percentage of the female population who are pregnant. From a statis­tical point of view, the stage of these pregna­ncies should be distri­buted roughly uniformly throughout the typical nine-month gestation period.
Conseq­uently, there ought to be approx­imately as many females who are only one day pregnant, or who are 100 days pregnant, or who are just one day from giving birth, etcetera.
In the bomb survivors who were irradiated in utero, too few persons have been identified who were younger than four weeks gestat­ional age at the time the bomb was dropped. Additi­onally, no birth defects were found as a result of irradi­ation before 15 days of gestat­ional age.
These results are consistent with animal experi­ments which demons­trated the ‘all-o­r-n­othing effect’, that is, either death of the embryo or normal develo­pment.
In humans, the principal effects of irradi­ation in utero are small head size (micro­cep­haly) and mental retard­ation.
These results are ultimately used to extrap­olate to very low doses to give recomm­end­ations regarding dose limits for radiation workers (female) and the role of radiation tests in pregnancy.

Exposure to Medical Radiation

In humans, the relati­onship between microc­ephaly and x-irra­diation of the pelvis was recognised from early radiation therapy experi­ence. Additi­onally, several other defects were also reported and although the number of cases studied is small and the radiation doses not known with any certainty.
Cancer in childhood after irradi­ation in utero
An associ­ation between exposure to diagnostic irradi­ation in utero and the subsequent develo­pment of childhood cancer or leukaemia has been suggested.
Several invest­iga­tions have demons­trated a very slight increase in cancer incidence in children exposed to radiation.
Of 7649 children who developed leukaemia or cancer, 1141 had been irradiated in utero, whereas in an identical number of control children (no cancer) only 774 had been irradiated in utero.
Although this suggests an associ­ation between irradi­ation and childhood cancer, you can see that this study also provides confli­cting results. For example, many children (6508 in fact) who did develop cancer had not been irradiated in utero and 774 who had been irradiated did not develop cancer. Conseq­uently, these results and others have stirred lengthy debate about whether or not the relati­onship is one of cause and effect, or simply a correl­ation dependent on other health­-re­lated issues.
Although, this debate is still ongoing it is obvious that careful consid­eration must be given to evaluate the possible benefits versus the potential risks involved in any radiol­ogical procedure involving foetal irradi­ation.

Factors Influe­ncing Effects and Risks

Dose
The amount of dose delivered is also important in determ­ining the likelihood and severity of effects. At doses under 0.1 Gy there is unlikely to be any signif­icant effect on organo­genesis or foetal develo­pment as the threshold for these problems is not reached.
hen doses climb above this level in the organo­genesis period, it is recomm­ended that women be councilled over the potential for congenital abnorm­alities induced by radiation.
Depending on your religious or ethical viewpo­ints, it is also recomm­ended that therap­eutic abortion of the pregnancy be discussed with women who are irradiated in the organo­genesis period.
The likelihood of stochastic effects is related to the exposed dose in a linear fashion.
Limits of data on humans
There is no evidence in humans that radiation increases the rate of death during the implan­tation period. This data must be interp­reted from animal studies.
There is no compelling evidence that exposure during organo­genesis leads to signif­icant abnorm­alities from human studies. Data is interp­reted from animal studies.
Data on exposures after embryo­genesis is limited to survivors of the atomic bombs; and is limited to evidence of microc­ephaly and mental retard­ation.
Gestat­ional Age
The gestat­ional age is the most important factor in determ­ining what kind of effect will occur.
Before implan­tation has occurred, the most likely effects are loss of the embryo (dose dependent) or no effect. It seems that the cells at the preimp­lan­tation stage are capable of differ­ent­iating into any of the required cells for develo­pment to occur, and the loss of a signif­icant number of these cells leads to demise of the embryo.
Organo­genesis occurs between implan­tation and the commen­cement of the foetal stage. During this period the precursors of all major organs are formed. Damage to these progne­nitor cells may lead to severe develo­pment abnorm­alities (such as failure of organ formation or structural defects).
The foetal stage (from about 6 weeks after concep­tion) is more resistant to serious abnorm­alities or prenatal death. Animal studies suggest a high rate of growth retard­ation. Human evidence suggests microc­ephaly, growth retard­ation and mental retard­ation are more common, partic­ularly in the early foetal period.
Irradi­ation in all periods can increase the rate of childhood cancer, which is more dose dependent.

Pregnancy and the Radiation Worker

Once pregnancy has been declared, the conceptus should be protected by applying a supple­mentary equiva­len­t-dose limit to the surface of the worker's abdomen of 2 mSv for the remainder of the pregnancy.
This will ensure that the foetus does not receive a dose in excess of the 1 mSv limit applicable to members of the general public.
Typically, the annual occupa­tional radiation dose received by radiation therapy techno­logists is of the order of 200 µSv. Conseq­uently, there is usually no reason from a radiation safety point of view that should restrict such a person from working until the full term of the pregnancy
However, it is approp­riate that the pregnant worker be excluded from any employment activity that carries a signif­icant probab­ility of high accidental doses.
For example, radiation workers would routinely be excluded from high-dose brachy­therapy applic­ations, fluoro­scopy and radiop­har­mac­eut­icals work.
In terms of radiation protec­tion, a second badge dosimeter for the abdomen needs to be issued, and the two badges need to be checked on a monthly basis (instead of once every 3 months) throughout the term of pregnancy. Lead abdomen shielding is also available for a pregnant radiation worker.