1. Hereditary Effects of Radiation
CHAPTER 11
Hereditary Effects of Radiation

2. GERM-CELL PRODUCTION AND RADIATION EFFECTS ON FERTILITY
In the male, doses as Iowa 0 15 Gy (15 rad) result in oligospermia (diminished sperm count) after a latent period of about 6 weeks.
Doses above 0.5 Gy (50 rad) result in azoospermia (absence of living spermatozoa) and therefore temporary sterility.
Recovery time depends on dose.
Permanent sterility in the male requires a single dose in excess of 6 Gy (600 rad)

3. GERM-CELL PRODUCTION AND RADIATION EFFECTS ON FERTILITY
In the male, fractionated doses cause more gonadal damage than a single dose.
Permanent sterility can result from a dose of 25 to 3 Gy ( rad) in a fractionated regime over 2 to 4 weeks
In the female, radiation is highly effective in inducing permanent ovarian failure, with a marked age dependence on the dose required.
The dose required for permanent sterility in the female varies from 12 Gy (1,200 rad) prepubertal to 2 Gy (200 rad) premenopausa I.

4. The induction of sterility in males does not produce significant changes in hormone balance, libido, or physical capability, but in the female leads to pronounced hormonal changes comparable to natural menopause.
Exposure of a population can cause adverse health effects in the descendants as a consequence of mutations induced in germ cells These used to be called "genetic" effects but are now more often called "hereditary" effects.

5. Hereditary diseases
Hereditary diseases are classified into three principal categories :
Mendelian
chromosomal
and multifactorial
Radiation does not produce new, unique mutations but increases the incidence of the same mutations that occur spontaneously.

6. Hereditary diseases
Exposure of a population to radiation can cause adverse health effects in the descendants as a consequence of mutations induced in the germ cells.
Hereditary diseases, also known as genetic diseases,' may result when mutations occurring in the germ cells of parents are transmitted to progeny
most cancers result from mutations in somatic cells.

7. It is a commonly held view that radiation produces bizarre mutations or monsters that may be recognized readily This is not true. Radiation increases the incidence of the same mutations that occur spontaneously in a given population. The study of radiation-induced hereditary effects is difficult because the
mutations produced by the radiation must be identified on a statistical basis in the presence of a high natural incidence of the same mutations.

8. Mendelian DISEASE
Mendelian diseases are those caused by mutations in single genes located on either the autosomes or the sex chromosomes.
The mutation may be a change in the structure of DNA, which may involve either the base composition, the sequence, or both.
sickle-cell anemia results from the substitution of only one base.
the relationship between mutation and Mendelian disease is simple and predictable.

9. Mendelian DISEASE Mendelian diseases are subdivided into:
autosomal dominant
autosomal recessive
and X-linked conditions
depending on which chromosome the mutant genes are located on and the pattern of trans­mission.

10. dominant
A dominant gene mutation is expressed in the first generation after its occurrence.
More than 700 such conditions have been identified with certainty and an additional 700 or more are less well established.
Some examples :
polydactyl,
achondroplasia
Huntington's chorea.

11. recessive mutations
require that the gene be present in duplicate to produce the trait, which means that the mutant gene must be inherited from each parent;
many generations may pass before it is expressed.
If one copy of the gene is mutant and the other is normal, the individual is not affected.
Some examples :
sickle-cell anemia
cystic fibrosis
Tay-Sachs disease.

12. X-linked recessive diseases
X-linked recessive diseases are caused by mutations in genes located on the X-chromosome.
The Y chromosome contains far fewer genes than the X.
Because males have only one X chromosome, all males having a mutation in the X chromosome show the effect of mutation: like dominant mutations.
Since females have two X chromosomes, they need two mutant genes to show the effect of an X-linked recessive mutation.
The best known examples of sex-linked disorders are hemophilia, color blind­ness, and a severe form of muscular dystrophy,

13. The three types of Mendelian diseases are summarized as follows:
Autosomal dominant: The disease is due to a mutation in a single gene on one chromosome.
Autosomal recessive: The disease is due to a defec­tive copy of the same gene from each parent.
Sex-linked: Males have one X chromosome, so one mutation can cause the disease; females have two
Xs, so two mutant genes are needed to cause the disease.

14. MULTIFACTORIAL
Characteristics of multifactorial diseases include the following:
Known to have a genetic component
Transmission pattern not simple Mendelian
Congenital abnormalities: cleft lip with or with­ out cleft palate; neural tube defects
Adult onset: diabetes, essential hypertension, coronary heart disease
Interaction with environmental factors

15. RADIATION-INDUCED HEREDITARY EFFECTS IN FRUIT FLIES
As early as 1927, Muller reported that exposure to x-rays could cause readily observable mutations in the fruit fly, Drosophila melaliogaster.
These included a change of eye color from red to white, the ebony mutant with its jet-black color,the "vestigial wing" mutant, and the easiest of all to observe, the recessive lethal mutation.

16. In the 1950s, hereditary changes were considered the principal hazard of exposure to ionizing radiation.
There were three reasons for this:
A low doubling dose (5-150 R) for mutations was estimated from fruit fly experiments.
(The doubling dose is the dose required to double the spontaneous mutation rate.)
Based again in the fruit fly, it was thought that hereditary effects were cumulative; that is, a little radiation now, some next week, and some next year all added up and contributed to the genetic load carried by the human race.
In the 1950s, little was known of the carcino­genic potential of low doses of radiation. An ex­cess incidence of leukemia was evident in the Japanese survivors of the A-bomb attacks, but the much larger number of solid cancers did not appear until many years later.

17. RADIATION-INDUCED HEREDITARY EFFECTS IN MICE
The extensive studies included the irradiation of both male and female mice with a range of doses, dose rates, and fractionation patterns.
Five major conclusions are pertinent to the radiologist:
The radiosensitivity of different mutations varies by a significant factor of about 35, so that it is only possible to speak in terms of average muta­tion rates.
In the mouse, there is a substantial dose-rate ef­fect, so that spreading the radiation dose over a period of time results in fewer mutations for a given dose than in an acute exposure.

18. Essentially all of the radiation-induced hered­itary data come from experiments with male mice.
The hereditary consequences of a given dose can be reduced greatly if a time interval is al­lowed between irradiation and conception.
The estimate of the doubling dose favored by the Committee on the Biological Effects of Ionizing Radiation (BEIR V) and the United Nations Sci­entific Committee on the Effects of Atomic Ra­diation (UNSCEAR 88) is I Gy (100 rad) based on low dose-rate exposure.

19. In the megamouse project, seven specific locus mutations were used to study radiation-induced hereditary effects. This photo shows three of the mutations, which involve changes of coat color. (Courtesy of Dr William L. Russell, Oak Ridge National Laboratory.)

20. Mutation in mice as a function of dose ,delivered at high and low dose rate

21. RADIATION-INDUCED HEREDITARY EFFECTS IN HUMANS
To estimate the risk of hereditary effects in the human population due to exposure to radiation, two basic pieces of data are needed:
first, the baseline spontaneous mutation rate, which is known for humans,
second, the doubling dose, which can only come from mouse experiments (1 Gy, or 100 rad).

23. Two correction factors are needed:
(1) to allow that not all mutations lead to a disease- this is the mutation component (MC), which varies for different classes of hereditary diseases;
(2) to allow for the fact that the seven specific locus mutations used in the mouse experiments are not representative of inducible hereditary diseases in the human because they are all nonessential for the survival of the animal or cell.

24. Table 11.4
The UNSCEAR 2001 estimates of hereditary risks for the first generation and first two gen­ erations of an irradiated population are listed in Table 11.4.

25. The risk of autosomal dominant and X-linked diseases for the first generation after irradiation is on the order of 750 to 1,500 cases progeny per gray of chronic low-LET radiation (compared to the baseline of 16,500 cases per million).
The risk of autosomal recessive diseases is essentially zero (compared to the baseline of7,500 per million).
The risk of chronic diseases is on the order of 250 to 1,200 cases per million (compared to the baseline of 650,000 per million).
The risk of multisystem developmental or congenital abnormalities may be of the order of about 2,000 cases per million.
Note that the total risk per gray is only about to 0.64% of the baseline risk of 738,000 per million live births-that is, a relatively small proportion.

26. MUTATIONS IN THE CHILDREN OF THE A-BOMB SURVIVORS
Children of the atomic-bomb survivors have been studied for a number of indicators:
congenital defects
gender ratio
physical development
survival, cytogenetic abnormalities
malignant disease and
electrophoretic variants of blood proteins
A recent paper estimated the doubling dose to be about 2 Sv (200 rem), with a lower limit of 1 Sv (100 rem) and an upper limit that is indeterminate because the increase in mutations is not statistically significant.

27. Thanks for your attention…