Considerations Regarding the Unintended Radiation Exposure of the Embryo, Fetus, or Nursing Child (Ncrp Commentary)

NCRP COMMENTARY No. 9

CONSIDERATIONS REGARDING THE UNINTENDED RADIATION EXPOSURE OF THE EMBRYO, FETUS OR NURSING CHILD

Issued May 1,1994

National Council on Radiation Protection and Measurements 7910 Woodmont Avenue I Bethesda, Maryland 20814-3095

LEGAL NOTICE This Commentary was prepared by the National Council on Radiation Protection and Measurements (NCRP). The Council strives to provide accurate, complete and useful information in its documents. However, neither the NCRP, the members of NCRP, other persons contributing to or assisting in the preparation of this Commentary, nor any person acting on the behalf of any of these parties: (a) makes any warranty or representation, express or implied, with respect to the accuracy, completeness or usefulness of the information contained in this Commentary, or that the use of any information, method or process disclosed in this Commentary may not infringe on privately owned rights; or (b) assumes any liability with respect to the use of, or for damages resulting from the use of any information, method or process disclosed in this Commentary, under the Civil Rights Act of 1964, Section 701 et seq. a s amended 42 U.S.C.Section 2000e et seq. (Title VII) or any other statutory or colntnon law theory governing liability.

Library of Congress Cataloging-in-Publication D a t a

Considerations regarding the unintended radiation exposure of the embryo, fetus or nursing child. p. cm. (NCRP commentary ; no. 9) Includes bibliographical references. ISBN 0-292600-36-3 1.Fetus-Effect of radiation on. 2. Human embryo-Effect of radiation on. 3. Radioisotopes in obstetrics-safety measures. 4. Breast feeding-Health aspects. I. National Council on Radiation Protection and Measurements. 11. Series. PNLM: 1. Radiation Dosage-in infancy & childhood. 2. Embryoradiation effects. 3. Fetus-radiation effects. WN 650 C755 19941 RG627.6.R33C66 1994 618.3'2-dc20 DNLMIDLC for Library of Congress 94-18566

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CIP

Copyright O National Council on Radiation Protection and Measurements 1994 All rights reserved. This publication is protected by copyright. No part of this publication may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotation in critical articles or reviews.

Preface NCRP Commentary No. 7, Misadministration of Radioactive Material in MedicineScientific Background, dealt with the misadministration of radioactive material in medicine. Subsequently, the U.S. Nuclear Regulatory Commission asked the NCRP to address those special problems that could occur in the case of radiation exposure of the embryo, fetus or nursing child resulting from the administration of radioactive material in medicine. The treatment of these special problems is the subject of this Commentary. The Board of Directors established a n ad hoc committee to perform this work. Serving on the Committee were: W a r r e n K. Sinclair, Chairman National Council on Radiation Protection and Measurements Bethesda, Maryland

Members

S. J a m e s A d e l s t e i n Karvard Medical School Boston, Massachusetts

R o b e r t L. B r e n t Alfred I. duPont Institute Wilmington, Delaware

Consultant R i c h a r d L. L a F o n t a i n e National Naval Medical Center Bethesda, Maryland

NCRP Secretariat William M. B e c k n e r , Staff Assistant Cindy L. O'Brien, Editorial Assistant The Council wishes to express its appreciation to the Committee for their time and effort devoted to the preparation of this Commentary. Charles B. Meinhold President, NCRP Bethesda, Maryland January 14, 1994

Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

...

111

1

2 Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

3 . Exposure of the Embryo. Fetus or Nursing Child . . . . . . . . . . . . . . . . . . . . 3.1 Embryo or Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1 Specification of the Dose to the Embryo or Fetus . . . . . . . . . . . . . . . . . . 3.1.2 Radiological Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3 Brachytherapy to the Mother . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4 Teletherapy to the Mother . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5 Dose to the Fetal Thyroid During 1311. 1 2 3 ~or 9 9 m ~Administration c ... 3.2 NursingChild . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1 Radioactive Pharmaceuticals Administered to the Mother . . . . . . . . . . . 3.2.2 Brachytherapy to the Mother . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 3 3 3 3 5 7 8 8 8

.

4 The Risks Attributable to Radiation Exposures of the Embryo.

Fetus or Nursing Child . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Deterministic Effects and Threshold Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1 Deterministic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2 Threshold Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Stochastic Effects .Cancer Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Stochastic Effects . Induction of Heritable Effects . . . . . . . . . . . . . . . . . . . . . . 4.5 Dose Rate Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

9 9 9 9 10 11 11 12

5 Recommendations and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14

TheNCRP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19

NCRP Commentaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21

1. Introduction In Commentary No. 7, Misadministration of Radioactive Material in Medicine - Scientific Background (NCRP, 1991), the National Council on Radiation Protection and Measurements (NCRP) reviewed the misadministration of radioactive material in medicine. In that commentary, the number a n d variety of nuclear medicine procedures performed in the United States, administered activities and the resulting radiation doses were reviewed. Information on the reported frequency and nature of misadministrations was also summarized, a s were the possible deterministic and stochastic effects that might occur a s a result of the use in medicine of pharmaceuticals containing radioactive material. In addition, the basis for developing reporting requirements for the unintended administration of radioactive material to patients was also provided. The purpose of this Commentary is: (1) to draw special attention to problems in the protection of the embryo, fetus and nursing child that might result from the use, both externally and internally, of radioactive material in the medical diagnosis and treatment of the mother, a n d (2) to assist the Nuclear Regulatory Commission (NRC) in developing requirements appropriate to dealing with the unintended exposure of the embryo, fetus or nursing child a s a result of such procedures. The sensitivity of humans during these stages of life justlfy separate consideration beyond t h a t already grven for adults i n NCRP Commentary No. 7 (NCRP, 1991). Over six million diagnostic nuclear medicine examinations were performed in the United States in 1980 (NCRP, 1989). Women under the age of 45 comprised up to 15 percent of the persons receiving these examinations. Therefore, the nuclear medicine physician h a s to be constantly alert for the patient who may be pregnant or breast feeding. Thls is not only because these procedures may present some risk to the patient or to the embryo, fetus or nursing child, but also because the patient should be informed of these risks before the procedure is performed. Radiotherapeutic procedures are most likely to be applied to older persons, but not exclusively so. Furthermore, it is estimated t h a t among pregnant women in the United States, some 3,500 new cases of cancer can be expected each year (Donegan, 1983). Thus, when radiopharmaceutical, brachytherapy or external beam procedures a r e to be undertaken on women of childbearing age, the possibility of pregnancy or that a child is being nursed must be considered, and steps taken to minimize exposure to the embryo, fetus or nursing child.

2. Objective I t is the responsibility of the prescribing physician to explain all treatment (nuclear medicine, brachytherapy and teletherapy) procedures and diagnostic tests to the patient, and especially any procedure that may present a significant risk. Prior to initiating the procedure, it is important to determine whether the patient is or could be pregnant or breast feeding, and then to consider the consequences of the radiation exposure associated with the treatment. Evaluation of the radiation exposure to the embryo, fetus or nursing child should constitute part of the riskhenefit analysis employed in making a decision about the mother's therapeutic or diagnostic medical program. In most instances, the physician will have determined the pregnancy or nursing status of the patient and will have discussed with the patient the fact that the planned radiation procedure is necessary for her mehcal care. The physician will have discussed the radiation exposure involved and its associated risk [generally quite small, see Table 2.5 of NCRP Commentary No. 7 (NCRP, 1991) for some common nuclear medicine procedures], and therefore, given the proper indications, the procedure should be undertaken. Since a correct diagnosis and proper treatment is usually essential for a healthy pregnancy, the risktbenefit analysis will most often indicate that the procedure should be performed (Brent, 1989; Brent and Gorson, 1972; NCRP, 1977a). However, there are some instances where the procedure is clearly contra-indicated. An unintended exposure occurs if either (1) a pregnant woman or breast-feeding mother is given a medical procedure involving radioactive material without the prescribing physician's knowledge that the patient is pregnant or breast feeding or (2) the patient is known to be pregnant or nursing, but a misadministration occurs. Then, the magnitude of the exposure of the embryo, fetus or nursing child must be determined promptly in order to maintain a complete record and to comply with the requirements of the licensing authority. An objective of this Commentary is to suggest levels of radiation exposure to the embryo, fetus or nursing child which the NCRP considers should necessitate some action.

Exposure of the Embryo, Fetus or Nursing Child 3.1 Embryo or Fetus

3.1.1 Specification of the Dose to the Embryo or Fetus Exposures of the embryo or fetus may occur as a result of diagnostic or therapeutic radiological procedures, and in some instances expose specific tissues and organs rather than the entire embryo or fetus. Some authors have suggested that early in pregnancy the dose to the ovary can be used as a surrogate for the dose to the embryo or fetus (Mettler and Moseley, 1985). At later stages of development (and perhaps early on a s well), it may be more appropriate to specify the dose to the embryo or fetus a s the same as for the uterus as recommended in NCRP Report No. 54 (NCRP, 1977a) and by the International Commission on Radiological Protection (ICRP, 1987). Specification of the dose to the uterus will be adequate for external exposure and often for internal exposure from radionuclides a s well. However, i n some instances, due to large individual organ doses (e.g., iodine in the fetal thyroid), it may be necessary to specify the dose to specific organs in the fetus. The dose to the uterus can be taken to be the dose to the whole body of the embryo or fetus and is, therefore, taken to be equivalent to the effective dose to the embryo or fetus (ICRP, 1991; NCRP, 1993). 3.1.2 Radiological Procedures Radiological procedures a r e widely used i n medicine for diagnostic purposes, a n d many involve the use of radioactive material (NCRP, 1989; 1991). For typical diagnostic procedures, the doses to the uterus or gonads of the female a s well a s the gonads of the male a r e well documented and are given in Table 3.1 for some x-ray procedures and Table 3.2 for a few nuclear medicine procedures (ICRP, 1987; NCRP, 1989). Radioactive materials used for therapy in nuclear medicine frequently involve the administration of large amounts of radiopharmaceuticals in order to deliver the appropriate dose. Thus, in circumstances involving pregnancy, the doses to the embryo or fetus must be carefully calculated to assess the risk for the purpose of making a medical judgment. One result is t h a t the procedures may be delayed. Note the special case of the administration of iodine isotopes discussed in Section 3.1.5. 3.1.3 Brachytherapy to the Mother Brachytherapy is a special therapeutic application of radioactive material and i t refers to the treatment of localized malignancies with implanted sealed radioactive sources. Due to the rapid fall off of dose outside of the treatment volume, high doses can be delivered to the volume of tissue of interest while sparing surrounding normal tissue. Brachytherapy is not widely used compared with external beam therapy. However, external beam therapy may be combined with brachytherapy in order to treat areas outside the implant site which may be a t risk for microscopic disease. Brachytherapy implants are classified a s either intracavitary or interstitial and can be temporary or permanent.

4

/

3. EXPOSURE OF THE EMBRYO, FETUS OR NURSING

CHILD

TABLE3.1 - Doses to the gorrads from typical x-ray procedure^.^ Procedure Chest Head and neck Cervical spine Lumbar spine Upper extremities Lower extremities Abdomen Upper G.I. tract Barium enema Gallbladder Intravenous pyelogram

Dose (mGy) Male

Female

0.01

0.01

---b

---

---

---

2.1

5.9

aNCRP Report No. 100, Table 3.22 (NCRP, 1989). b(---) indicates less than 0.01 mGy.

Intracavitary implants are most often performed for gynecologic malignancies, but may also be used in the esophagus, nasopharynx, trachea or bronchus. Typical sites for interstitial implants are head and neck, breast and the extremities. The most commonly used brachytherapy sources in the United States are 1 3 7 ~for s temporary intracavitary implants, lg21rfor temporary interstitial and intracavitary implants, and125~ for permanent interstitial implants (Clarke and Martinez, 1990). The majority of intracavitary implants are performed using manual afterloading techniques, although the number of implants performed using high- and low-dose rate automated remote afterloaders is increasing (AAPM, 1993).

TABLE3.2 - Doses to the adult gonads and uterus from typical nuclear medicirte procedure^.^

Procedure

Brain Bone Lung Thyroid Renal Abscess/tumor

Radiopharmaceutical

9 9 ~DTPA c 9 9 m ~phosphate c 99mTc(MAA) 9 9 m O4 ~ ~

9 9 m ~DTPA c 6 7 ~citrate a

Administered Activity

740 MBq 740 MBq 185 MBq 185 MBq 740 MBq 111 MBq

aNCRP Report No. 100, Table 4.17 (NCRP, 1989). b~~~~ Publication No. 53 (ICRP, 1987).

Dose (mGy) Male, (gonads) 2.2 3.7 0.4 0.4 2.2 7.2

Female (gonads) 4.4 4.4

0.4 1.1 4.4 8.4

uterusb 5.8 4.5 0.4

--5.8 8.8

3.1 EMBRYO OR FETUS

1 5

Intracavitary therapy for treatment of the cervix or uterus is generally combined with external beam irradiation in all but early stage disease. In a pregnant patient, this would involve direct exposure of the embryo or fetus to a n unacceptably high dose resulting in lack of embryo implantation, fetal death or severe developmental abnormalities (Dekaban, 1968). Gynecological malignancies in pregnant women are generally managed in one of two ways: (1) the pregnancy is terminated through therapeutic abortion or a n abortion is caused a s a result of having irradiated the malignancy or (2) when appropriate, a third trimester pregnancy will be carried to maturity with treatment delayed until after delivery (Marcial, 1989; Wharton and Rutledge, 1980). Published cases of cervical brachytherapy implants during pregnancy without concomitant external beam treatments have reported very large fetal doses, e.g., 6,800 mGy average dose (Kallinger and Granninger, 1979) a n d 1,800 to 3,000 mGy brain dose (Mulvihillet al., 1991), with large dose gradients within the fetus. Brachytherapy to other parts of the body would involve exposure of the embryo or fetus to doses which will vary considerably depending on implant site, radionuclide, implant duration, gestational age and anatomical variations between patients. Standard brachytherapy calculation methodologies can be used to calculate doses for implants close to the embryo or fetus,e.g., cervical implants, but are generally valid only to distances of clinical interest, i.e., 10 to 15 cm from the source (Sakelliouet al., 1992). Methods for calculating brachytherapy doses a t extended distances of 20 to 50 cm a r e not widely employed i n clinical practice. For the purposes of this Commentary, fetal dose estimates from brachytherapy sources a t extended distances are approximated using the medical internal radiation dose (MIRD) methodology (Loevinger and Berman, 1975). The MIRD absorbed fraction method has been used to calculate brachytherapy doses to tissue a t extended distances i n a large multiinstitutional epidemiology study of second tumors following radiotherapy for cancer of the uterine cervix (Boice et al., 1988). Comparison of the calculated brachytherapy doses for t h a t study with anthropomorphic phantom measurements have demonstrated agreement within +20 percent of the selected dose, except a t large distances (uterus to brain) where agreement was 250 percent (Stovall et al., 1989). Table 3.3 gives doses from brachytherapy implants for certain frequently treated tissue sites outside the pelvic region. Doses to the adult female ovaries and uterus resulting from these procedures were calculated using the computer program MIRDOSE (Version 2) available from Oak Ridge Associated Universities (ORAU, 1984). The selected source organ was the available MIRDOSE organ closest to the implant site with the ovaries or uterus a s target organs to estimate fetal dose. The doses differ little between the ovary and uterus. For the examples cited, the estimated fetal doses range from less t h a n 1 mGy to about 14 mGy.

3.1.4 Teletherapy to the Mother Teletherapy treatment to the mother, e.g., using a 6 0 ~ unit, o would result i n embryonic or fetal doses which vary with treatment site, prescribed dose, gestational age, anatomical variations between patients, and the treatment unit and specific set up used. If the embryo or fetus is within the treatment volume, the fetal dose will approximate the prescribed treatment dose, typically i n the range of 30 to 60 Gy. If the embryo or fetus is not within the

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3. EXPOSURE OF THE EMBRYO, FETUS OR NURSING CHILD

TABLE3.3 - Estimated doses to the ovaries and uterus from typical brachytherapy procedures

(outside the pelvic region). Procedure Head and neckC Base of tongueC NasopharynxC Pancreas6 ~reast~

Radioisotope 1 2 5 ~seeds lg21, seeds 137~ tubes s 125~ seeds lg21rseeds

Implant Source Implant Strength Duration (pGy m2 h-' )a 32d 181e 57af 32d 181e

Permanent 48 h 10 h

Permanent 48 h

Tumor Dose (GY) 160 20 12 160 20

Dose ( r n ~ ~ ) ~ Ovaries Uterus 1.9E-03 2.6 2.6 8.6 10.4

1.6E-03 2.5 2.5 6.8 13.5

a h r kerma rate at 1 m. b~alculatedfrom MIRDOSE program (ORAU, 1984). WIRD source organ (site of implant): thyroid. d ~ i f t seeds, y 0.5 mCi activity per seed. eFifty seeds, 0.5 mg-Fta-equivper seed. f ~ o u tubes, r 20 mg-Ra-equiv per tube. WIRD source organ: pancreas. h~~~~ source organ: breast. treatment volume, the dose will be a function of the peripheral dose distribution of the treatment set up a n d unit (McParland a n d Fair, 1992). The peripheral dose is comprised of two principal components: (1) internal scatter from the patient a n d (2) leakage and scatter from the treatment unit head (Francois et al., 1988; ICRP, 1985). The relative contributions from these two components will vary depending on the aforementioned factors, but typically will be of the same order of magnitude for teletherapy treatments with60Co units (Fraass and van de Geijn, 1983). Because of the many variables contributing to the peripheral dose, distribution calculations and/or dose simulations must be performed to determine the actual dose to the embryo or fetus. Published d a t a on fetal doses from treatment of the mother with teletherapy are typically a function of prescribed dose and distance from the center or edge of the treatment field to the embryo a n d fetus (e.g.,Denoix, 1970; Sampiere, 1980). Published fetal or ovarian dose estimates for a variety of radiotherapeutic techniques are Listed i n Table 3.4. These dose estimates a r e reasonably consistent by treatment site a n d demonstrate the much higher fetal dose expected from teletherapy relative to brachytherapy for treatment performed outside the pelvic region. I n the case of irradiation of the breast, the estimated distance of the fetus from the treatment field center is approximately 40 cm in early pregnancy and perhaps only 10 cm late i n pregnancy when the fetal dose wdl be more nonuniform (Wallack et al., 1983). The average fetal dose from teletherapy treatment of the mother's breast will range from about 200 mGy to approximately 4,000 mGy (see Table 3.4). The fetal dose from 6 0 ~ teletherapy o can be reduced to some extent by shielding the patient's abdominal and/or pelvic region from treatment head leakage a n d scatter (Sampiere, 1980). However, internally generated scattered radiation generally cannot be shielded and, depending on the treatment site a n d irradiated volume, may contribute the greater fraction of fetal dose (ICRP, 1985; Villafana, 1973).

3.1 EMBRYO OR FETUS

TABLE3.4 - Estirnated fetal or ovariar~doses from Treatment Site Breasta BreastC BreastC Breasta Mediastinume Mehastinumg ~ediastinum~ Para-aortice

'OCO

/

7

teletherapy procedures.

Distance to Fetus

Treatment Dose (Gy)

Fetal Dose (mGy)

40 cmb 20 cmd 5 cmd 10 cmb 30 cmd 28 cmb 25 cmd 10 cmd

50 45 45 50 44 40 40 36

200 300 1,800 4,000 190f 244 300 830f

aWallack et al. (1983). b ~ i s t a n c efrom center of treatment field to fetus. 'Denoix (1970). d ~ i s t a n c efrom edge of treatment field to fetus. eNiroomand-Rad and Cumberlin (1993). h e a s u r e d ovarian dose. gVillafana (1973). h ~ a m p i e r e(1980).

3.1.5 Dose to the Fetal Thyroid During l3'I, Iz3I or 99'nTcAdministration A special case in which the fetus may be affected by the administration of a c. radiopharmaceutical to the mother is in thyroid studies using 1311, 1 2 3 ~or 9 9 m ~ Radioiodine readily crosses the placenta and the human thyroid b e g n s to accumulate iodine by about the 10th to 13th week of gestation (NCRP, 1977b), and possibly earlier (Jacobson a n d Brent, 1959; Otis and Brent, 1954). Accumulations are hlgher t h a n i n the adult and typically the dose for 13'1 to the fetal thyroid will be 7 to 200 mGy per 37 kBq over 10 to 22 weeks of gestational age (Mettler a n d Moseley, 1985). Doses for 1 2 3 ~would be about one percent of these values. I n the case of 9 9 m ~ cwhich , also crosses the placenta rapidly, the dose to the fetal thyroid is only about 37 pGy per 37 kBq (Mettler and Moseley, 1985). I n the current radiation protection system (ICRP, 1991; NCRP, 1993) the weighting factor for the thyroid is 0.05, and therefore, the magnitudes of the effective dose to the embryo, fetus or nursing child will be approximately 20 times less than the doses to the thyroid given above. The assumption is made t h a t the tissue weighting factor is applicable to the embryo or fetus a s for all postnatal ages (ICRP, 1991). In a diagnostic administration of, e.g., 185 kBq of 13'1, the effective dose to the fetus from exposure to the thyroid could be a s high a s 100 mGy. Such exposure should be avoided by using 1 2 3 ~or 9 9 m ~ cif, the test is essential. A much more serious situation could arise if the mother were to need treatment for hyperthyroidism (involving perhaps 370 MBq 1311) or thyroid cancer (involving perhaps 3,700 MBq 1311). Clearly the fetal dose would be so large t h a t the treatment should not be undertaken while the mother is pregnant. Therefore, the administration of radioactive isotopes of iodine to the mother should be considered a special case due to the likely preferential uptake by the embryo, fetus or nursing child.

8

3. EXPOSURE O F THE EMBRYO, FETUS OR NURSING CHILD

3.2 Nursing Child 3.2.1 Radioactive Pharmaceuticals Administered to the Mother If the mother has received a radiopharmaceutical, the nursing child may be exposed, either a s a result of transfer of the material to the child by the mother's milk or by exposure to the radiation from the mother's body. I n the first case, the transferred amount will depend on the concentration of the radionuclide i n the milk. Unless the rahonuclide concentrates to a high degree i n the mother's milk, the concentration resulting initially i n the child must be appreciably less t h a n i n the mother, but may eventually reach the concentration of t h a t of the mother. Since the dose to the mother from radiopharmaceuticals rarely exceeds a few mGy, the dose to the child is likely to be substantially less. Again, the special case of l3'1, especially a t therapeutic levels, must be considered. Diagnostic tests should be c than 13'1, and 13'1 therapy is inadvisable, unless undertaken with either 1 2 3 ~or 9 9 m ~rather breast feeding is terminated. I n the second case, external exposure of the child from radionuclides in the mother, estimates need to be made of the dose to the child while nursing. If the radionuclide is uniformly distributed,e.g., a 1 3 7 ~ s - l i kgamma-ray e emitting radionuclide, the dose rate a t the mean distance of the c h l d (about 10 cm) is about one-fifth of the maximum dose rate i n the mother's body. Thus the dose r a t e to the child would be approximately equal to the mother's whole-body dose rate divided by five. Assuming the fraction of time the child spends nursing is approximately one-tenth, the total dose to the child would be approximately one-fiftieth of t h a t received by the mother. Since few diagnostic nuclear medicine procedures give wholebody or effective doses of more than a few mGy to the mother, the dose to the nursing child is not llkely to exceed 1 mGy. The mother should, however, be advised to hold the child a s little a s possible during the exposure period. 3.2.2 Brachytherapy to the Mother

An entirely different situation applies i n the much less likely event t h a t the mother is to receive brachytherapy. Each individual situation has to be evaluated separately. I n the case of temporary implants,e.g., intracavitary sources i n the uterus and/or cervix or a n interstitial lg21r implant, the mother will be hospitalized and under the supervision of a physician. Depending on the implant site and radionuclide, dose rates in close proximity to the mother can exceed several mGy per hour (Papin et al., 1990). Since temporary implants a r e routinely for 24 to 72 h only, contact between the mother and infant should be avoided during this period, as was previously recommended in NCRP Report No. 37 (NCRP, 1970). In the case of permanent implants,e.g., 1 2 5 ~in the head a n d neck region, the patient will generally be released from the hospital within several days following the implant a n d must therefore receive specific radiation safety instructions to minimize dose to other persons, in particular the infant during breast feeding. Radionuclides used for permanent implants emit radiation of low energy which is easily attenuated; therefore, except for implants close to the body surface, minimal external dose results. In the case of implants close to the surface, shields can be fashioned from thin lead sheet or other attenuating material to reduce the external radiation exposure from the mother during her contact with the child.

4. The Risks Attributable to Radiation Exposures of the Embryo, Fetus or Nursing Child 4.1 I n t r o d u c t i o n The criteria t h a t are utilized to perform the riskhenefit analysis of the exposure of the embryo, fetus or nursing child a s a result of radiological procedures to the mother, depend on the consideration of deterministic effects, stochastic effects, including genetic effects, and, in turn, i n considering these, the effect of dose r a t e must be examined. Each of these is discussed i n more detail below.

4.2 D e t e r m i n i s t i c E f f e c t s and T h r e s h o l d D o s e s 4.2.1 Deterministic Effects

A wide variety of anomalies can be produced i n the human embryo or fetus following irradiation. [For a detailed discussion see Table 8.3, Mettler and Moseley (1985).] All of these anomalies a r e temporally related to the stage of pregnancy. Thus, the timing of the exposure relative to the stage of pregnancy is critical to the nature of the anomalies produced. I n the early stages, mainly during the first two weeks, resorption of the embryo is the most llkely result, i.e.,the pregnancy is terminated. Later (two to four weeks postconception and longer), gross malformations may result. Growth retardation may result from exposures from two weeks postconception until term, the severity depending on the stage of development and the radiation dose. Growth retardation can be produced most readily i n mid-gestation (Rugh et al., 1964). After seven to eight weeks, the embryo has developed into a fetus and neurological development begins. The risk of mental retardation depends on dose and is greatest i n the period from 8 to 15 weeks, still present a t 16 to 25 weeks and h a s a much lower risk or may be absent before or after these periods (Otake and Schull, 1984), a s noted i n NCRP Report No. 116 (NCRP, 1993). In the most sensitive period there is also a reduction in intelligence scores, of the order of 21 to 29 points per Gy a t 1 Gy (NCRP, 1993; Otake et al., 1988; Schull et al., 1988). Small head size can also result from radiation exposure, but it is not directly associated with mental retardation and although the majority of cases cluster in the 8 to 15 week period (NCRP, 1993), some also occur in the 0 to 7 week period when mental retardation has not been observed (Otake and Schull, 1993). Sterility, cataracts and neuropathology can also occur a s a result of exposure during fetal life (up to 40 weeks). The timing of these induced anomalies is represented in Table 4.1, see Brent (1983), Dekaban (1968) and Mettler and Moseley (1985).

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4. RISKS ATTRIBUTABLE TO RADIATION EXPOSURES

TABLE4.1 - Te~nporalrelatior~shipof possible effects of radiatio~~ d u r i ~ p~ rge g i ~ a ~ ~ c y . ~ Stage of Development PreImplantation EarlyLate implantation Organogenesis

Fetal

Days Since Conception (gestation)

Lethality (resorption) Gross malformations Growth retardation (at term) Growth retardation (as adult) Sterility Cataracts Neuropathology Mental retardation Small head sizeC I& Carcinogenesis

aAdapted from Brent (1983) and Mettler and Moseley (1985). b~ffects listed in thls Table have been identified mainly in animals (but some also in humans) at dose levels of about 1 Gy and are listed a s a function of the comparable human gestation period. Key: +++ occurs with high incidence; ++ readily apparent effect; + demonstrated effect; 2 questionable effect; -no observed incidence. 'Otake and Schull (1993). 4.2.2 Threshold Doses

The effects described in Table 4.1 have been observed after fetal exposures of 1 Gy or more, a n d some may also occur after smaller doses (NCRP, 1991; UNSCEAR, 1986). Since the effects a r e mainly deterministic in character, except for carcinogenesis, they a r e likely to have thresholds, i.e., a dose level below w h c h no effect occurs, but above which the effect a n d the harm increase a s the dose increases. Both human and animal studies indicate t h a t the threshold doses of low-LET ionizing radiation for occurrence of developmental effects, such a s malformations and growth retardation, may be i n the range of 100 to 200 mGy for acute exposure to the whole body, i.e., effective dose (UNSCEAR, 1986). For mental retardation the d a t a from the atomic-bomb survivors are consistent with either linearity or with a threshold of 100 to 200 mGy, a n d perhaps a s high a s 400 mGy, depending on whether Down syndrome cases are excluded from the original data (NCRP, 1993). For small head size, a distinct phenomenon, the threshold may perhaps be a s low a s 50 mGy for acute exposure (NCRP, 1991). These thresholds, which are invariably substantially higher for protracted exposure, have been determined both in animal experiments a t the most sensitive periods of organogenesis and brain development (Brent et a,l., 1986; 1987; Jensh a n d Brent, 1986; 1987; 1988a; 198813; Jensh et al., 1987) and from human exposures resulting i n mental retardation (Otake a n d Schull, 1984; Schull, 1991).

4.4 STOCHASTIC EFFECTS - INDUCTION OF HERITABLE EFFECTS

1 11

Deterministic effects have not been seen a t doses less than 1 Gy in children in the following organs a n d tissues; brain, thyroid, ovary, eye, musculoskeletal system, cardiovascular system, lung, breast, digestive system, kidney and probably in bone marrow (UNSCEAR, 1993a). There is not, in most cases, enough information t o determine actual thresholds. One exception may be the testes in which testicular function may be compromised a t doses a s low a s 0.5 Gy. Thresholds exist for cataract in the eye of adults a t 2.5 Gy acute exposure, 10 Gy fractionated exposure and have been seen in children a t 2.5 Gy (UNSCEAR, 1993a). Although the nursing child could be more sensitive t h a n "young children" i t seems very unlikely t h a t any deterministic effects would occur in the nursing child a t less t h a n 200 mGy a n d probably not even a t somewhat higher doses.

4.3 Stochastic Effects

- Cancer Induction

The magnitude of the risk of childhood cancer following in utero exposure is uncertain in t h a t both negative and positive studies have been reported. An early report of Stewart et al. (1958) a n d later reports on the same study (e.g., Bithell, 1989; Muirhead and Kneale, 1989), which suggested a high sensitivity of the fetus to the leukemogenic effect of irradiation, has not been corroborated by the Japanese survivor experience i n which there has been no measurable increase in childhood cancer, although it is supported to a degree by some other studies [for a discussion of this issue see UNSCEAR (1986) a n d more recently UNSCEAR (1994)l. Those who were exposed in utero to the atomic bomb may have a n increased risk of adult cancer. This appeared to be about the same risk as t h a t of young children exposed to radiation (Yoshimoto et al., 1988). However, the most recent follow-up i n this study found no further cancer cases during the latest evaluation period and the net risk of adult cancer from exposure in utero no longer appears to be significantly elevated (Yoshimoto et al., 1992). Animal experiments have not reported a greater sensitivity of the embryo or fetus to the carcinogenic effects of irradiation t h a n i n young animals, on the contrary, susceptibility to tumor induction was lower rather t h a n higher (UNSCEAR, 1986). A reasonable assumption is t h a t the embryo or fetus is a s susceptible to the carcinogenic effects of radiation a s the young child, i.e., the risks are numerically about the same, viz 10 x lom2 SV-' (NCRP, 1993). No detailed information is available on whether the carcinogenic SV-l, risk occurs a t all periods of gestation. This level of carcinogenic risk, i.e., 10 x is assumed also to apply t o the nursing child.

4.4 Stochastic Effects

- Induction

of Heritable Effects

Recent evaluations of the effects of radiation in utero [ICRP, 1991 (Annex B); UNSCEAR, 19861 and of hereditary effects (UNSCEAR, 1993b) make no specific mention of hereditary effects i n the next generation following in utero exposure. Therefore, the risk of genetic effects after such exposure is conjectural. Given t h a t the h u m a n female h a s all of her ova present a t birth, the female embryo or fetus might be a s susceptible to subsequent genetic effects a s the reproductive adult. In both the male a n d female embryo or fetus, the long time between the induction of a n effect after in utero exposure a n d the expression of any genetic

12 /

4. RISKS ATTRIBUTABLE TO RADIATION EXPOSURES

damage allows a prolonged opportunity for loss of damaged cells altogether or for their repair. Thus, i t seems reasonable to assume that the embryo, fetus and nursing child are a s sensitive to the induction of hereditary effects as the adult. In this case, the level of induction possible is 1 x Sv-' (ICRP, 1991), about one-tenth of the risk of induced cancer. However, this risk is derived from animal studies and no human study has shown such effects.

4.5 Dose R a t e Effects At the low radiation doses that might be received by the embryo or fetus as a result of medical procedures on the mother, i.e., below the threshold dose for any deterministic effect, dose rate is unimportant because it will not influence the response, even though a t higher doses it may be an important factor.' Furthermore, the radiation dose from radiopharmaceuticals and brachytherapy implants is normally protracted and the dose for teletherapy is fractionated. Therefore, the dose from the procedures will be less effective than a similar acute dose. Accordingly, threshold levels for developmental effects, estimated from human and animal studies involving acute doses, may actually be higher, and in any event, not less, for some or all medically administered radioactive materials.

'A dose is considered low if it is below 200 mGy and a dose rate is low if below 0.1 mGy rain.' (UNSCEAR, 1993~).

5. Recommendations and Conclusions Given the various factors discussed in earlier sections, it seems clear that exposures resulting in doses to the whole body (i.e., effective dose ) of 100 mSv or less will not cause detectable deterministic effects in the embryo or fetus, with the possible exception of the induction of small head size with a threshold perhaps a s low a s 50 ~ S VAlso . ~no detectable deterministic effects would be expected in the nursing child. Stochastic effects, such a s cancer induction, should not exceed about one percent a t 100 mSv for the embryo, fetus or nursing child (NCRP, 1993). Therefore, setting requirements for action after radiation exposure of the embryo, fetus or nursing child a t some level below a n effective dose of 100 mSv to allow for a margin of safety, should enable all such incidents with the potential for harm to be dealt with appropriately. With regard to exposure of the embryo, fetus or nursing child during a medical procedure to t h e mother involving radioactive material, if the physician is aware t h a t the patient is pregnant or breast feeding and the riskhenefit has been fully discussed with the patient before t h e procedure is undertaken, no unintended exposure will have occurred. Unintended exposure of the embryo, fetus or nursing child a s a result of medical procedures to the mother involving radioactive material results when the physician is unaware of the patient's pregnancy, or t h a t she is breast or bottle feeding a t the time of the procedure or a misadministration h a s occurred. When the physician becomes aware of the situation after the fact, h e or she needs to have procedures available regarding appropriate action (see below). If the dose to the embryo, fetus or nursing child from a n unintended exposure is less than or equal to an effective dose of 50 mSv, there is no harm from deterministic effects and t h e risk of stochastic effects is less t h a n one percent. A full record of the exposure and circumstances a n d the doses involved must be developed so that procedures can be implemented to reduce t h e chance of future unintended exposures, but no action regarding the embryo, fetus or nursing child other t h a n assurance of the accuracy of the dose is warranted. If the dose to the embryo, fetus or nursing child from a n unintended exposure exceeds a n effective dose of 50 mSv, since the possibility of harm increases with the dose, i t is recommended t h a t action be instituted to assure t h a t the dose estimation is accurate, a n d in addition, t h a t expert medical evaluation, advice and follow-up be utilized on a case-by-case basis.

2~hroughoutthis text, absorbed doses of low-LET rahation, such as x and y rays, are specified in mGy. However, the effects described here are believed to apply to all radiations, consequently, the doses are given in equivalent whole-body doses to the fetus (i.e., effective dose) and speclfied in mSv.

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