Title: Radiation Biology
1Radiation Biology
2Biologic Effects
- Many factors determine the biologic response to
radiation exposure - Radiosensitivity and complexity of the biologic
system determine the type of response from a
given exposure - Usually complex organisms exhibit more
sophisticated repair mechanisms - Some responses appear instantaneously, others
weeks to decades
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 814.
3Classification of Bio Effects
- Biologic effects of radiation exposure can be
classified as either stochastic or deterministic
(non-stochastic) - Stochastic Effect
- The probability of the effect, rather than its
severity, ? with dose - Radiation-induced cancer and genetic effects
- Basic assumption risk ? with dose and no
threshold - Injury to a few cells or even a single cell can
theoretically result in manifestation of disease - The principal health risk from low-dose radiation
4Classification of Bio Effects
- Deterministic or Non-stochastic Effect
- Predominant biologic effect is cell killing
resulting in degenerative changes to the exposed
tissue - Severity of the effect, rather than its
probability, ? with dose - Require much higher dose to produce an effect
- Threshold dose below which the effect is not seen
- Cataracts, erythyma, fibrosis, and hematopoietic
damage are some deterministic effects - Dx radiology only observed in some lengthy,
fluoroscopically guided interventional procedures
5Interaction of Radiation with Tissue
- Ionizing radiation energy deposited randomly and
rapidly (lt 10-10 sec) via excitation, ionization
thermal heating - Interactions producing biologic changes
classified as either direct or indirect - Direct
- Critical targets (e.g., DNA, RNA or protein)
directly ionized or excited - Indirect
- Radiation interacts within the medium (e.g.,
cytoplasm) creating reactive chemical species
(free radicals) which in turn interact with the a
critical target macromolecule
6Interaction of Radiation with Tissue
- Vast majority of interactions are indirect (body
70 - 85 water) - Results in an unstable ion pair, H2O, H2O-
- Dissociate into another ion and a free radical
(lifetime is less than 10-5) - H2O ? H OH
- H2O- ? H OH-
- Combine w/ other free radicals to form molecules
such as hydrogen peroxide (H2O2) ? highly toxic
to cell - Oxygen enhances free radical damage via
production of reactive oxygen species (e.g., H
O2 ? HO2)
7Interaction of Radiation with Tissue
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 816.
8Linear Energy Transfer
- Biological effect dependent on the dose, dose
rate, environmental conditions, radiosensitivity
and the spatial distribution of energy deposition
- Linear Energy Transfer (LET)
- Amount of energy deposited per unit length
(eV/cm) - LET ? q2/KE
- Describes the energy deposition density which
largely determines the biologic consequence of
radiation exposure - High LET radiation a2, p, and other heavy ions
- Low LET radiation
- Electrons (e-, ß- and ß)
- EM radiation (x-rays or g-rays)
- High LET gtgt damaging than low LET radiation
9Relative Biological Effectiveness (RBE)
- Although all ionizing radiation capable of
producing a specific biological effect, the
magnitude/dose differs - Compare dose required to produce the same
specific biologic response as a reference
radiation dose (typically 250 kVp x-rays)
Relative Biological Effectiveness (RBE) - Essential in establishing radiation weighting
factors (wR) - X-rays/gamma rays/electrons LET 2 keV/µm wR
1 - Protons (lt 2MeV) LET 20 keV/µm wR 5-10
- Neutrons (E dep.) LET 4-20 keV/µm wR 5-20
- Alpha Particle LET 40 keV/µm wR 20
- H (equivalent dose, Sv) D (absorbed dose, Gy)
wR
10LET vs. RBE
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 817.
11Cellular Targets
- Radiation-sensitive targets are located in the
nucleus and not the cytoplasm of the cell - Cell death may occur if key macromolecules (e.g.,
DNA) which have no replacement are damaged or
destroyed - Considerable evidence that damage to DNA is the
primary cause of radiation-induced cell death - Concept of key or critical targets has led to a
model of radiation-induced cellular damage termed
target theory in which critical targets may be
inactivated by one or more ionization events
(hits)
12Radiation Effects on DNA
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 819.
13Cellular Radiosensitivity
- Studied through radiation-induced cell death
(loss of reproductive integrity) - Useful in assessing the relative biologic impact
of various types of radiation and exposure
conditions - Cellular inability to form colonies as a function
of radiation exposure ? cell survival curves - Three parameters defining response to radiation
n, Dq and D0
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 822.
14Cell Survival Cures n
- n Extrapolation number - found by extrapolating
the linear portion of the curve back through the
y-axis Represents either the number of targets in
a cell that must be hit once by a radiation
event to inactivate the cell or the number of
hits required on a single critical target to
inactivate the cell - For mammalian cells 2,10
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 822.
15Cell Survival Curves D0
- D0 Mean lethal dose
- Radiosensitivity of the cell population under
study - Dose producing a 63 (1-e-1) reduction in viable
cell number slope ?y/?x .63/D0
(e 2.72 e-1 0.37) - ? reciprocal linear region slope
- Radioresistant cell D0 gt radiosensitive cell D0
- ? D0 ? lesser survival/dose
- Mammalian cells 1Gy,2Gy
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 822.
16Cell Survival Curves Dq
- Dq Quasithreshold dose (Dq D0 logen)
- Width of the shoulder region and a measure of
sublethal damage - Irradiated cells remain viable until enough hits
received to inactivate the critical target or
targets - Clear evidence that for low-LET radiation, damage
produced by a single radiation interaction with
cellular critical target(s) is insufficient to
produce reproductive death
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 822.
17Factors Affecting Cellular Radiosensitivity
- Conditional factors - physical or chemicals
factors that exist previous to and/or at
irradiation - Dose rate
- LET
- Fractionation
- Presence of oxygen
- Inherent factors - biologic factors
characteristic of the cell - Mitotic rate
- Degree of differentiation
- Cell cycle phase
18Conditional Factors-Dose Rate
Which has highest D0?
Which has highest n?
Which has highest Dq?
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 823.
19Conditional Factors-LET
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 824.
20Conditional Factors-Fractionation
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 825.
21Conditional Factors-Presence of Oxygen
- Increases cell damage by inhibiting
- Free radical recombination to form harmless
chemical species - Repair of damage caused by free radicals
- Oxygen enhancement ratio (OER) ratio of dose
producing a given biologic response in the
absence of oxygen to that in the presence of
oxygen - Mammalian cells
- Low-LET 2,3
- High-LET 1,2
22Conditional Factors- Oxygen
Conditional Factors - Oxygen
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p.
23Inherent Factors Law of Bergonie Tribondeau
- Radiosensitivity greatest for cells with
- High mitotic rate
- Long mitotic future
- Undifferentiated
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 826.
24Inherent Factors-Cell Cycle Phase
- Cells are most sensitive to radiation during
mitosis (M phase) and RNA synthesis (G2 phase) - Less sensitive during the preparatory period for
DNA synthesis (G1 phase) - Least sensitive during DNA synthesis (S phase)
- During mitosis (M), the metaphase is the most
sensitive
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 827.
25Davis Notes-Radiation Biology
- 4. The quasi-threshold dose (Dq) for cell line C
is - A. 500
- B. 700
- C. 1,000
- D. 1,500
- E. impossible to determine from this data
26Huda 2nd Edition-Chapter 10-Radiation Biology
- 1. Radiological LD50 is the radiation dose that
kills - (A) 50 of exposed cells
- (B) 50 exposed cells
- (C) All exposed cells within 50 days
- (D) e-50 of exposed cells
- (E) e/50 of exposed cells
27Huda 2nd Edition-Chapter 10-Radiation Biology
- 10. Stochastic effects of radiation
- (A) Can be recognized as caused by radiation
- (B) Have a dose-dependent severity
- (C) Have a threshold of 50 mSv/year
- (D) Include carcinogenesis
- (E) Involve cell killing
28Huda 2nd Edition-Chapter 10-Radiation Biology
- 5. The LET of x-rays is
- (A) Between 0.3 and 3 keV/µm
- (B) Cannot be defined for energies greater than 2
MeV - (C) Greater than the LET for alpha particles
- (E) Low energy threshold
- (D) Independent of relative biological
effectiveness (RBE)
29Huda 2nd Edition-Chapter 10-Radiation Biology
- 4. Which is not true of the interaction of
ionizing radiation with tissues? - (A) Cellular DNA is a key target
- (B) Direct action is more frequent than indirect
action - (D) Ions can dissociate into free radicals
- (E) It can produce chromosome aberrations
- (C) Indirect action causes most of the biological
damage
30Huda 2nd Edition-Chapter 10-Radiation Biology
- 3. Which cells are considered to be the least
radiosensitive? - (A) Bone marrow cells
- (B) Lymphoid tissues
- (C) Neuronal cells
- (D) Skin cells
- (E) Spermatids
31Huda 2nd Edition-Chapter 10-Radiation Biology
- 2. The cell division stage most sensitive to
radiation is - (A) Anaphase
- (B) Interphase
- (C) Metaphase
- (D) Prophase
- (E) Telophase
32Organ Systems Response Regenerization and Repair
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 828.
33Organ Systems Response Skin
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 830.
34Organ Systems Response Reproductive System
- Gonads are very radiosensitive
- Females
- Temporary sterility 1.5 Gy (150 rad) acute dose
- Permanent sterility 6.0 Gy (600 rad) acute dose
- reported for doses as low as 3.2 Gy
- Males
- Temporary sterility 2.5 Gy (250 rad) acute dose
- reported for doses as low as 1.5 Gy
- Permanent sterility 5.0 Gy (500 rad) acute dose
- Reduced fertility 20-50 mGy/wk (2-5 rad/wk) when
total dose gt 2.5 Gy
35Organ Systems Response Ocular Effects
- Eye lens contains a population of radiosensitive
cells - Cataract magnitude and probability of occurrence
? to the dose - Acute doses
- 2 Gy (200 rad) cataracts in a small percentage
of people exposed - gt 7 Gy (700 rad 700 cGy) always produce
cataracts - Protracted exposure
- 2 months 4 Gy threshold
- 4 months 5.5 Gy threshold
- Unlike senile cataracts that typically develop in
the anterior pole of the lens radiation-induced
cataracts begin with a small opacity in the
posterior pole and migrate anteriorly
36Acute Radiation Syndrome
- Characteristic clinical response when whole body
(or large part thereof) is subjected to a large
acute external radiation exposure - Organism response quite distinct from isolated
local radiation injuries such as epilation or
skin ulcerations - Combination of subsyndromes occurring in stages
over hours to weeks as the injury to various
tissues and organs is expressed - In order of their occurrence with increasing
radiation dose - Hematopoietic syndrome
- Gastrointestinal syndrome
- Neurovascular syndrome
37ARS Sequence of Events
- Prodromal symptoms typically begin within 6 hours
of exposure - No symptoms during the latent period, which may
last up to 6 weeks for dose lt 1 Gy - Manifest illness stage onset of organ system
damage clinical expression which can last 2-3 wks
- Most difficult to manage from a therapeutic
standpoint - Treatment during the first 6-8 wks essential to
optimize recovery - Higher risk of cancer and genetic abnormalities
in future progeny if patient survives
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., pp. 832-3.
38Acute Radiation Syndrome Interrelationships
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 836.
39Epidemiologic Investigations of Radiation Induced
Cancer
- Dose-response relationships for cancer induction
at high dose and dose rate have been well
established - Not so for low dose exposures like those
resulting from diagnostic and occupational
exposures - Very difficult to detect a small increase in the
cancer rate due to radiation - Natural incidence of many forms of cancer is high
- Latent period for most cancers is long
- To rule out simple statistical fluctuations, a
very large irradiated population is required
40Difficulties in Quantifying Low Dose Risk
- If excess risk proportional to dose, then large
studies are required for low absorbed dose to
maintain statistical precision and power the
necessary sample power increases approximately as
the inverse square of dose - This relationship reflects a decline in the
signal (radiation risk) to noise (natural
background risk) ratio as dose decreases. - 500 persons needed to quantify the effect of a
1,000 mSv dose - 50,000 for a 100 mSv dose
- 5 million for a 10 mSv dose (a single body CT
7.5 mSv)
SS c/D2
National Research Council (1995) Radiation Dose
Reconstruction for Epidemiologic Uses. Natl.
Acad. Press
41What is the Evidence?
- Major epidemiological investigations that form
the basis of current cancer dose-response
estimates in human populations - Atomic-bomb survivors (Japan) life span study
(LSS) - Anklyosing spondylitis (UK)
- Postpartum mastitis study (New York)
- Radium dial painters (Tritium)
- Thorotrast (radioactive Thorium x-ray contrast
agent) - Massachusetts tuberculosis patients (multiple
chest fluoroscopy) - Stanford University Hodgkins disease patients
(x-ray therapy)
42Risk Estimation Models Dose-Response Curves
- Dose-response models predict cancer risk from
exposure to low levels of ionizing radiation ?
dose-response curves - Linear, non-threshold (LNT)
- Effect aDose
- Linear-quadratic, non-threshold
- Effect aDose ßDose2
- a/ß 1Gy-10Gy
- appears linear for low dose
- appears quadratic (non-linear) for higher dose
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 844.
43Risk Estimation Models-Risk Models
- Multiplicative risk model after a latent period,
the excess risk is a multiple of the natural
age-specific cancer risk for the population in
question - Additive risk model fixed or constant increase
in risk unrelated to the spontaneous age-specific
cancer risk at the time of exposure - Latency periods
- Leukemia 10 yrs average
- Solid tumors 25 yrs average
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 845.
44Risk Estimation Models-Risk Expression
- Relative Risk
- Ratio of the cancer incidence in the exposed
population to that in the general (unexposed)
population - RR of 1.2 would indicate 20 increase over the
spontaneous rate - Excess relative risk is simply RR - 1
- Absolute Risk
- Expressed as the number of excess
radiation-induced cancers per 104 people/Sv-yr - For a cancer with a radiation-induced risk of 4
per 10,000 person/Sv-yr and a latency period of
20 years, the risk of developing cancer from a
dose of 0.1 Sv (13x body CT dose) within the
next 40 years would be - (40-20) or 20 years x 0.1 Sv x 4 per 10,000
person/Sv-yr - 8 per 10,000 or 0.08
45Radiation Standards Organizations
- Independent bodies of experts evaluate
information on radiation health effects - BIER - National Academy of Sciences/National
Research Council Committee on the Biological
Effects of Ionizing Radiation - UNSCEAR - United Nations Scientific Committee on
the Effects of Radiation - RERF - Radiation Effects Research Foundation
- Experts draw upon this collective knowledge to
develop recommendations for systems of radiation
protection - NCRP National Council on Radiation Protection
and Measurements - ICRP International Commission on Radiological
Protection - Radiation protection regulatory framework
- NRC Nuclear Regulatory Commission
- EPA - Environmental Protection Agency
46BEIR V Risk Estimates
- BEIR published a report in 1990 entitled, The
Health Effects of Exposure to Low Levels of
Ionizing Radiation or the BEIR V report - Single best estimate of radiation-induced
mortality at low exposure levels is 4 per Sv
(0.04 per rem) for a working population (ICRP -
5 per Sv for the whole population - takes
children into account) - The single best estimate of radiation-induced
mortality at high doses applied at high dose rate
is 8 per Sv (0.08 per rem) - The BEIR V Committee believed that the LNT
dose-response model was best for all cancers
except leukemia and bone cancer for those
malignancies, a linear-quadratic model was
recommended - According to the LNT model, an exposure of 10,000
people to 10 mSv would result in approximately 4
cancer deaths in addition to the 2,200 (22)
normally expected in the general population
47ACRP 60 Risk Estimates
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 847.
48Specific Cancer Risk Estimates Leukemia
- Natural incidence in US population 1 in 104
(0.01) - 17 of total mortality from radiocarcinogenesis
- The incidence of leukemia greatly influenced by
age at the time of exposure - BEIR V nonlinear dose-response model predicting
excess life-time risk of 10 in 104 (0.1) after
exposure to 0.1 Gy (10 rad) - Average latent period 10 yrs
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 849.
49Specific Cancer Risk Estimates Thyroid Cancer
- 6-12 of total mortality from radiocarcinogenesis
- Females 3-5x greater risk than males
- Latency period
- Benign nodules 5-35 yrs
- Thyroid malignancies 10-35 yrs
- Dose-response curve LNT
- Associated mortality rate 5
- However, other responses such as hypothyroidism
and thyroiditis with thresholds - 2 Gy for external irradiation
- 50 Gy for internal radiation (radioactive
materials like 131I)
50Specific Cancer Risk Estimates Breast Cancer
- One of 8 US women at risk of developing breast
cancer - 180,000 new cases/yr
- 1 in 30 women die of breast cancer
- Low LET radiation risk age dependent, 50 times
greater for the 15 yo age group ( 0.3 per year)
after exposure of 0.1 Gy than those gt 55 yo - The risk estimates for women in the 25, 35 and 45
yo age groups are 0.05, 0.04 to 0.02
respectively (BEIR V) - Dose-response curve LNT w/ dose of 0.8 Gy
doubling the natural incidence - Latent period 10yrs,40yrs longer latencies
with younger women
51Increased Risk of Induced Breast Cancer Before 65
Years of Age per 25 mSv Breast Organ Dose for Age
at Exposure
52Comparisons of the Risks of Some Medical Exams
53Davis Notes- Radiation Biology
- 9. The overall fatal cancer risk per rad of whole
body low LET radiation of a population selected
at random would be on the order of - A. 104
- B. 102
- C. 10-4
- D. 10-6
- E. 106
- Risk 1 cSv (1 rad) 0.04/Sv 0.0004 4x10-4
54Genetic Effects in Humans
- Genetic effects the result of radiation exposure
to the gonads - Epidemiological investigations have failed to
demonstrate radiation-induced genetic effects - Current risk estimates are based on animal
experiments - For workers, the risk of severe hereditary
effects is 0.8 per Sv of gonadal radiation
according to the ICRP - For a whole population, the risk of severe
hereditary effects is 1.3 per Sv which is higher
because of the inclusion of children
55Radiation Effects In Utero
- Gestational period divided into 3 stages
- Relatively short preimplantation stage (day 0-9)
- Extended period of major organogenesis (day 9-56)
- Fetal growth stage (day 45 to term)
- Preimplantation conceptus extremely sensitive
and radiation damage can result in prenatal
death All-or-nothing response - Animal experiments have demonstrated an increase
in the spontaneous abortion rate after doses as
low as 50 to 100 mGy (5 to 10 rad)
56Critical Periods for Radiation-Induced Birth
Defects
pre-implantation
major organogenesis
fetal growth
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 855.
57Relative Incidence of Radiation-Induced Health
Effects at Various Stages in Fetal Development
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 860.
58Radiation Effects In Utero (2)
- Exposures gt 1 Gy associated with a high incidence
of CNS abnormalities - Growth retardation after in utero exposure 100
mGy demonstrated - Fetal doses generally are much less than 100 mGy
in most diagnostic and nuclear medicine
procedures and thought to carry negligible risk
compared with the spontaneous incidence of
congenital abnormalities (4-6) - A conservative estimate of the excess risk of
childhood cancer from in utero irradiation is
6 per Gy (0.06 per rad)
59Radiation Effects In Utero (3)
- Recommendations from Wagner are
- If radiation dose received during or prior to the
first two weeks post conception (lt 14 days) - Exposure to diagnostic radiation is not an
indication for therapeutic abortion - For patients exposed to radiation between the 2nd
and 8th weeks post-conception (days 14-56) - Therapeutic abortion based solely on radiation
exposure is not advised for dose less than 150
mGy (15 rad) - Dose exceeding 150 mGy (15 rad) may be an
indication for therapeutic abortion in the
presence of less severely compromising factors.
However, diagnostic studies rarely result in such
dose levels.
Wagner, et al. Exposure of the Pregnant Patient
to Diagnostic Radiation, pp. 166-7.
60Radiation Effects In Utero (4)
- For a conceptus exposed between the 8th and 15th
week post-conception (days 56-105) - Fetal dose below 50 mGy (5 rad)
- Radiation not a sufficient risk to justify
therapeutic abortion - Fetal dose between 50-150 mGy (5-15 rad)
- therapeutic abortion is not advisable on the
basis of the radiation risk alone - Fetal dose above 150 mGy (15 rad)
- In this time interval there is scientific
evidence that may support a recommendation for
therapeutic abortion based on the radiation
exposure. However, this does not mean an abortion
is necessarily recommended. Diagnostic studies
rarely result in such dose levels.
Wagner, et al. Exposure of the Pregnant Patient
to Diagnostic Radiation, pp. 166-7.
61Radiation Effects In Utero (5)
- Fetal dose at 150 mGy
- Up to a 6 probability the child could be
mentally retarded - Natural incidence 0.4
- Probability the child will develop cancer lt 3
- Natural incidence 1.4
- Probability of small head size 15 (but does
not necessarily affect normal mental function) - Natural incidence 4
- IQ may fall a few points short of its full
potential - Except for possible effects to individual organs
from radionuclide studies, no other risks have
been demonstrated. However, always practice ALARA!
Wagner, et al. Exposure of the Pregnant Patient
to Diagnostic Radiation, pp. 166-7.
62Effect of In Utero Risk Factors on Outcome
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 858.
63In Utero Irradiation Summary
c.f. Bushberg, et al. The Essential Physics of
Medical Imaging, 2nd ed., p. 860.
64Huda 2nd Edition-Chapter 10-Radiation Biology
- 15. When is gross malformation most likely to
occur? - (A) Early fetal period
- (B) Early organogenesis
- (C) Late fetal period
- (D) Late organogenesis
- (E) Preimplantation
65Huda 2nd Edition-Chapter 10-Radiation Biology
- 16. What threshold embryo/fetal dose
corresponds to a radiation risk smaller than
those normally encountered during pregnancy? - (A) Less than 10 mGy (1 rad)
- (B) 10 mGy (1 rad)
- (C) 30 mGy (3 rad)
- (D) 100 mGy (10 rad)
- (E) More than 100 mGy (10 rad)
66Davis Notes-Radiation Biology
- 6. A barium enema was performed on a 25 year-old
female who was determined to be three weeks
pregnant at the time of examination. As the
consulting radiologist, you should - A. Recommend a therapeutic abortion.
- B. Counsel the patient that the embryo is at a
significantly high risk for gross malformations
as a result of the radiation exposure however,
an abortion is not necessarily warranted. - C. Discuss the implications of the radiation
exposure with the hospitals legal department. - D. Do not discuss any potential effects of the
radiation exposure on the embryo because very
little is known about in utero radiation exposure
and your comment would be totally speculative and
unsubstantiated. - E. Explain to the referring physician and patient
that the radiation received by the embryo by this
diagnostic procedure is relatively small and that
the increase in risk is negligible compared to
the spontaneous incidence of congenital
abnormalities.