Eric J Hall Chapter

1. HERITABLE EFFECTS OF
RADIATION
By
Dr.Ayush Garg

2. GERM CELL PRODUCTION AND RADIATION
EFFECTS ON FERTILITY

3. BASICS OF GENETICS
• CHROMOSOME
- Contains long threadlike structures called DNA
- Carries all the information that specifies a
particular human with his/her individual
characteristics
- 22 pair of autosomes + 1 pair of allosomes

4. DNA
• Double helix
• Organic bases
• Sugar-phosphate backbone

5. • Gene – Finite segment of DNA specified by an
exact sequence of bases.
• Locus – Position of a gene
• Human genome – DNA of chromosomes +
DNA of mitochondria.
• 6 billion base pairs of DNA.
• Total no of protein encoding genes – 25,000 to
50000/haploid set of chromosomes.

6. MUTATION
• Any change in chromosomes, their genes, and
their DNA.
• Include an array of changes in DNA, such as
deletion, rearrangement, breakage in the
sugar-phosphate backbone, and base
alterations.

7. HERITABLE EFFECTS OF RADIATION
• Adverse health effects in descendants due to
mutations induced in germ cells.
• Radiation does not produce new unique
mutations, but increases the incidence of the
same mutations that occur spontaneously.
• Information on the genetic effects of radiation
comes almost entirely from animal
experiments.

9. HERITABLE DISEASES
Mendelian
Chromosomal
Multifactorial

11. MENDELIAN INHERITANCE
• Autosomal Dominant
• Autosomal Recessive
• X-linked
Mendelian Diseases

12. Autosomal Dominant
• Expressed in the first generation after its
occurrence.
• Eg’s - Polydactyly, achondroplasia, Marfan’s
syndrome and Huntington's chorea.

13. Autosomal Recessive
• Require that the gene be present in duplicate
to produce the trait
• Mutant gene must be inherited from each
parent
• Eg’s - Sickle-cell anemia, cystic fibrosis, and
Tay-Sachs disease.

14. X-Linked
• Mutations in genes located on the X-
chromosome.
• Eg’s - Hemophilia, color blindness, and a
severe form of muscular dystrophy

15. • 67% are caused predominantly by point
mutations (base-pair changes in the
DNA)
• 22% by both point mutations and DNA
deletions within genes (i.e., they are
intragenic)
• 13% by intragenic deletions and large
multilocus deletions.

16. CHROMOSOMAL CHANGES
• Abnormalities either in the structure of the
chromosomes or in the number of
chromosomes
• Down's syndrome
• 40% of the spontaneous abortions
• 6% of stillbirths
• Radiation is much more effective at breaking
chromosomes than in causing errors in
chromosome distribution.

17. MULTIFACTORIAL
• Known to have a genetic component
• Transmission pattern not simple Mendelian
• Congenital abnormalities: cleft lip with or
without cleft palate; neural tube defects
• Adult onset: diabetes, essential hypertension,
coronary heart disease
• Interaction with environmental factors

18. RADIATION-INDUCED HEREDITARY
EFFECTS IN FRUIT FLIES
• 1927 – Müller - exposure to x-rays could cause
readily observable mutations in the fruit fly,
Drosophila melanogaster.
• Included a change of eye color from red to
white, the ebony mutant with its jet-black
color, the “vestigial wing” mutant, and the
recessive lethal mutation.

19. • Hereditary changes were considered the
principal hazard of exposure to ionizing
radiation because
– A low doubling dose (5-150 R) for mutations
– Hereditary effects were cumulative
– Little was known of the carcinogenic potential of
low doses of radiation.
• The doubling dose is the dose required to
double the spontaneous mutation rate.

20. RADIATION-INDUCED HEREDITARY
EFFECTS IN MICE
• Russell and Russell - Oak Ridge National
Laboratory
• To determine specific locus mutation rates in
the mouse
• Megamouse project - 7 million mice
• An inbred mouse strain was chosen in which
seven specific mutations occur, 6 involving
change of coat color & 1 as stunted ear.

23. • Five major conclusions
1. The radiosensitivity of different mutations varies
by a significant factor of about 35
2. Dose rate effect was evident.
– Chronic dose exposure induces fewer mutations
– Acute dose exposure induces more mutation
– This is in contrast with Drosophila
3. The oocytes are exquisitely radiosensitive.
4. The genetic effects of a given radiation dose can
be reduced greatly if a time interval is allowed
between exposure and conception.
5. The estimate of the doubling dose adopted by
BEIR V and UNSCEAR 88 is 1 Gy.

24. RADIATION-INDUCED HEREDITARY
EFFECTS IN HUMANS
• Two basic pieces of data are needed:
–Base-line spontaneous mutation rate in
humans – 738,000 per million.
–Doubling Dose (1 Gy, or 100 rad).

25. RADIATION AND SEX CELLS
• Resistant
– Post-spermatogonial cells
• Sensitive
– Stem cells
• Temporary sterility
– 15 rad (0.15 Gy)
– 40 rad/year (0.4 Gy/yr)
• Permanent sterility
– 350-600 rad (3.5 to 6 Gy)
– 200 rad/yr (2 Gy/yr)
• No significant hormonal
imbalance
• Resistant
– Post-oogonial cells
• Sensitive
– follicles
• Permanent sterility
– 250-600 rad (2.5 to 6 Gy)
– 20 rad/yr (0.2 Gy/yr)
Pronounced hormonal
imbalance
Males Females

26. Two Correction Factors
• Not all mutations lead to disease.
• The mutation component (MC):
– 0.3 for autosomal dominant.
– 0.0 for autosomal recessive.
– 0.01-0.02 for chronic multifactorial.
• The 7 specific locus mouse mutations are not
representative; they are genes not essential for
viability. Only a small proportion of human genes,
when mutated, would result in live births.

28. 1. Assuming an average life
expectancy of 75 years, with
mean reproductive age stopping
at 30 years
2. The risk coefficients for a total
population of all ages will be
30/75, that is, 40% of that for a
reproductive population.
3. This rounds out at 0.2% per
sievert.
4. For a working population, the age
range is only from 18 to 30 years
because of the fact that no one is
allowed to be a radiation worker
before the age of 18 and the
reproductive cycle is assumed to
end at the age of 30
5. Consequently, the risk coefficients
will be 12/75, or 16% of that for a
reproductive population, which
rounds out at 0.1% per sievert.

29. Hereditary Effects of Radiation - Human
• Children of the survivors of Hiroshima and
Nagasaki have been studied for untoward
pregnancy outcomes, death of live-born
children, sex chromosome abnormalities,
electrophoretic variants of blood proteins.
• Though no genetic indication is statistically
significant, the average doubling dose is 156
rem (1.56 Sv).

30. MUTATIONS IN THE CHILDREN OF THE
A-BOMB SURVIVORS

31. CHANGING CONCERNS FOR RISKS
• Dose limit of radiation workers reduced to
50mSv per year(by ICRP in 1956)
• The level of concern regarding genetic effects
has declined steadily – as a consequence the
percentage of radiation detriment attributed
to the genetic component in view of ICRP has
declined from 100% in 1955 to 4% in 2007
• The level of concern involving radiation
carcinogenesis has increased as more and
more solid tumours have appeared in the
Japanese A-bomb survivors

33. EPIGENETICS
• Changes in gene expression that takes place
without a change in the DNA sequence
• The changes result from mainly these
molecular modifications
- DNA methylation which takes place at the
carbon – 5 position of cytosine in CpG
dinucleotides
- Changes to chromatin packaging of DNA by
post translational histone modifications

34. • Pre natal and early postnatal environmental
factors can result in altered epigenetic
programming and subsequent changes in the
risk of developing disease later in life
• Environmental changes studied include
nutritional supplements, xenobiotic chemicals
and exposure to ionizing radiation

35. • Radiation studies showed that exposure of
adult mice led to transgenerational genome
instability in the offspring resulting from a
significant loss of DNA methylation in somatic
tissue.
• In addition there is some evidence from
animal studies that epigenetic alterations may
be inherited trans- generationally thereby
affecting the health of future generations

36. IMPRINTED GENES
• Expression is from only one parental allele
with the other allele silenced – this leads to a
non mendelian germ line inherited form of
gene regulation that involves heritable DNA
methylation and histone modification
• Expression of an imprinted gene in the
present generation depends on the
environment that it experienced in the
previous generation

37. EFFECTS OF RADIATION ON THE
EMBRYO AND FETUS

38. Commonly used measurements for
ionizing radiation and their units
(Nuclear Wastelands, Makhijani et al., eds., Cambridge: MIT Press, 1995)
Units Description equivalent
Rem
(roentgen equivalent man)
A unit of equivalent absorbed
dose of radiation with relative
biological effectiveness
rem = rad x Q
Sievert (Sv) A unit of equivalent absorbed
dose equal to 100 rem.
1 Sv = 100 rem
Sv = Gy x Q
Rad
(radiation absorbed dose)
A unit of absorbed dose of
radiation. Rad is a measure of
the amount of energy deposited
in tissue
1 rad = 100
erg/gram
Gray (Gy) A unit of absorbed radiation
dose equal to 100 rad. Gray is a
measure of deposition of energy
in tissue
1 Gy = 100 rad

39. Health impact of high-dose radiation
from a nuclear disaster
• Cell death
– Alter DNA of normal cells
– Uncontrolled cell divisions
– Induce cancer
• Damage organs
– Acute radiation sickness (coagulopathy, immunity
disorders)
– Diarrhea
– Fever, burns, coordination & equilibrium disturbances

40. Ionizing radiation from Natural source

41. Ionizing radiation from Natural source
(World Nuclear Association)

42. Effects of
Prenatal Radiation
Exposure

43. Effects of radiation in pregnancy
• Pregnancy loss
• Malformation
• Neurobehavioral abnormalities
• Fetal growth restriction
--- deterministic effect
--- Threshold or NOAEL (No-Adverse-Effect Level)
• Cancer
--- Stochastic effect
--- More radiation, greater the chance of the disease
--- No defined threshold

44. Effects of radiation in pregnancy
- Deterministic effect
• Radiation dose, the trimester of the pregnancy
Ex) Pregnancy loss
• During the 1st 2 weeks after conception, 100-200mGy
(10-20 rad)
• Shortly thereafter, 250-500 mGy (25-50 rad)
• 18weeks, 5000mGy (500 rad)
• At term, 20, 000mGy (2000rad)

45. Effect
Most sensitive period
after conception(d)
Threshold dose at effect was observed (mGy)
Absolute
incidence
Animal studies Human studies
Perinatal death
Preimplantation
Postimplantation
0-8 50-100
250
ND ND
Growth retardation 8-56 10 200 ND
Organ malformation 14-56 250 250 ND
Small head size 14-105 100 No threshold observed 0.05-0.1%
Severe mental
retardation
56-105 ND 100 0.04%
Reduction of IQ 56-105 ND 100 ND
Childhood cancer 0-77 No threshold No threshold 0.017%
Fetal Effects from
Low-level Radiation Exposure
(Wagner LK, 1997)

46. Radiation and mental retardation
• 8-15 weeks,
: Risk of impaired CNS
development > 5 times than
16~25 weeks
• < 8 weeks, or > 25
weeks
– No increased risk of
mental retardation

47. OVERVIEW OF RADIATION EFFECTS
ON THE EMBRYO AND FETUS
Lethal Effects
Malformations
Growth
disturbances and
growth
retardation,
without
malformations

48. LETHAL EFFECTS
• These are induced by radiation before or
immediately after implantation of the embryo
into the uterine wall or are induced after
increasingly higher doses during all stages of
intrauterine development, to be expressed
either before birth (prenatal death) or at
about the time of birth (neonatal death).

49. MALFORMATIONS
• These are characteristic of the period of major
organogenesis in which the main body
structures are formed, and especially of the
most active phase of cell multiplication in the
relevant structures.

50. GROWTH DISTURBANCES AND GROWTH
RETARDATION, WITHOUT MALFORMATIONS
• These are induced at all stages of
development but particularly in the latter part
of pregnancy.
• The principal factors of importance are the
dose and the stage of gestation at which it is
delivered.

51. Russell and Russell divided the total developmental period in utero into three stages:

54. Preimplantation

55. Organogenesis

57. EXPERIENCE IN HUMANS

58. Survivors of the A-Bomb Attacks on
Hiroshima and Nagasaki Irradiated In Utero

59. Exposure to Medical Radiation
• Dekaban surveyed the literature for instances of
pelvic x-irradiation in pregnant women. Based on
the available data, the following generalizations
were proposed:
• 1. Large doses of radiation (2.5 Gy) delivered to
the human embryo before 2 to 3 weeks of
gestation are not likely to produce severe
abnormalities in most children born, although a
considerable number of the embryos may be
resorbed or aborted.

60. • 2.Irradiation between 4 and 11 weeks of gestation
would lead to severe abnormalities of many organs
in most children.
• 3.Irradiation between 11 and 16 weeks of gestation
may produce a few eye, skeletal, and genital organ
abnormalities; stunted growth, microcephaly, and
mental retardation are frequently present.

61. • 4. Irradiation of the fetus between
16 and 25 weeks of gestation may
lead to a mild degree of
microcephaly, mental retardation,
and stunting of growth.
• 5. Irradiation after 30 weeks of
gestation is not likely to produce
gross structural abnormalities
leading to a serious handicap in
early life but could cause functional
disabilities.

62. COMPARISON OF HUMAN AND
ANIMAL DATA

63. 63
Fetal Radiation Risk
• There are radiation-related risks throughout
pregnancy which are related to the stage of
pregnancy and absorbed dose
• Radiation risks are most significant during
organogenesis and in the early fetal period
somewhat less in the 2nd trimester and least in
the third trimester
Less Least
Most
risk

64. This table summarizes the lowest doses at
which effects on the embryo and fetus have
been observed.

65. CANCER IN CHILDHOOD
AFTER IRRADIATION IN
UTERO
The Oxford Survey of
Childhood Cancers,
published by Stewart and
Kneale in the 1950s,
suggested an association
between the risk of
cancer, principally
leukemia, up to 15 years
of age and exposure in
utero to diagnostic x-rays.
This was a retrospective
case-controlled study and
is summarized in this table

66. Radiation exposure on
infants and lactating women
• Direct exposure to radiation on breast
• Ingestion of radioactive pharmaceuticals
• Mammogram ---- breastfeeding (O)
• The highest radiation conc. in breast milk
– 3-4 hours after adm. of radioactive pharmaceuticals
– radiation absorbed by fetus < 3-10% of the total dose absorbed by a
woman
– But, no negligible dose !
– 1 Gy in infant :thyroid cancer(x10)
• CDC: if radioactive iodine ----stop breastfeeding !

67. Protection of pregnant women and
fetuses from radiation exposure
• Maintaining a safe distance
• Shielding one’s body from exposure
• Avoiding ingestion of food and water contaminated with
radioactive particles in the air, rain, or soil
• In disaster, minimize the exposure
• Lead-containing vest
• In radioactive pharmaceuticals, hydration + voiding!
• If safe protocol, < 1mSv /year

68. Probability of birth with no malformation
and no childhood cancer
Dose to conceptus
(mGy)
No malformation
(%)
No childhood
cancer(%)
No malformation
and No childhood
cancer (%)
0 96.00 99.93 95.93
0.5 95.999 99.926 95.928
1.0 95.998 99.921 95.922
2.5 95.995 99.908 95.91
5.0 95.99 99.89 95.88
10.0 95.98 99.84 95.83
50.0 95.90 99.51 95.43
100.0 95.80 99.07 94.91
(Wagner LK et al. 1982)

69. Thus…
• ICRP (The International Commission on Radiological Protection)
– < 100mGy (10 rad)
: Not medical ground for termination
• ACOG
– Threshold for medical concern ~ 50mGy (5 rad)
– > 1000mGy (100 rad)
: Serious risk to fetus’ CNS---severe mental retardation
– Single diagnostic radiation exposure? –10rad? 5 rad?

70. 70
Research on Pregnant Patients
• Radiation research
involving pregnant
patients should be
discouraged