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Doses to the Embryo and Fetus from Intakes of Radionuclides by the Mother
2. DEVELOPMENT OF THE EMBRYO AND FETUS (31) The terminology used to describe the development of the conceptus from conception to term is variable in the literature. From studies in radiobiology, where the effects of in utero exposure to ionising radiation have been studied, three main phases of development may be considered: a pre-implantation period, an embryonic period of major organogenesis, and a fetal period of predominantly organ growth. Table 2.1 and Fig. 2.1 summarise the duration of these periods in different animal species. Table 2.2 gives more details for the rat, guinea pig, baboon, and human that are relevant to the development of biokinetic and dosimetric models. The stages of development are described below with emphasis, for the later stages of gestation, on tissue and organ systems of principal concern for internal dosimetry related to intakes of radionuclides. For the purposes of this report doses are calculated for the pre-implantation period and embryonic period combined and the subsequent fetal period. More comprehensive information on the development of the embryo and fetus can be found in Moore and Persaud, 1998; Browder et al, 1991; and O’Rahilly and Mu¨ller, 1992. 2.1. Fertilisation to gastrulation (32) Ovulation in humans generally occurs around the midpoint of the menstrual cycle, rarely earlier than ten days after the first day of the preceding menstrual cycle. Thus, fertilisation of the ovum by a spermatozoon to form the single cell zygote that eventually gives rise to a new individual typically occurs around 2 weeks into the menstrual cycle. Fertilisation takes place in the uterine tube and is followed by a series of cell divisions although no increase in volume of the embryo occurs at this early stage. When the embryo comprises around 16 cells, called blastomeres, a further
Table 2.1. Approximate time of the beginning and end of the major developmental periods in some mammalian species.a Species
Hamster Mouse Rat Rabbit Guinea-pig Dog Baboon Man a b c
Pre-implantation
Embryonic period of major organogenesis
Fetal period of organ growth
(days)
%b
(days)
%
(days)
%
0-5 0-5 0-7 0-5 0-8 0-17 0-9 0-8
31 26 33 16 13 27 5 3
6-12 6-13 8-15 6-15 9-25 18-30 10-49 9-56c
44 42 38 32 27 21 23 18
13-16 14-19 16-21 16-31 26-63 31-63 50-175 57-266c
25 32 29 52 60 52 72 79
Based on UNSCEAR (1977) Percentage of period of gestation Values adopted in this report 29
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Fig. 2.1. Timing of major developmental periods in some mammalian species (data from Table 2.1).
Table 2.2. Approximate times of development of various organs and embryonic structures in the rat, guinea-pig, baboon, and human. Days after conception Rat Germ layer differentiation and development of fetal membranes 5-10 Period of yolk sac haemopoiesis 9-13 10-11 Appearance of embryonic livera Onset of liver haemopoiesis 11 Onset of thyroid function 10 Onset of ossification 16 Onset of marrow haemopoiesis 10-17 Onset of brain developmentb 10
Guinea-pig Baboon Human 6-13 13-35 16 20 16 25 25-26 16
7-15 < 22 27 30 29 45-47 60 25
7-21 19-63 28 42 28 56 70-77 25
Data based on Metcalf and Moore, 1971; Kelemen et al., 1979; Harman and Saffry, 1934; Moore and Persaud, 1998; Scott, 1937; Strong, 1926; Nishimura and Shiota, 1977; Davignon et al., 1980; Dobbing and Sand, 1970; Enders et al., 1997; Evans and Sack, 1973; Hearn et al., 1994; Hendrickx and Houston, 1971; Hendrickx et al., 1970; Hendrickx and Peterson, 1997; Santoloya-Fargas et al., 1997. a First liver diverticula b Appearance of the first three brain vesicles 30
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stage of differentiation called compaction occurs. The embryonic cells form close cell contacts, and clearly delineated cell borders disappear to form the first embryonic ‘tissue’. This developmental stage is called the morula. Around 4 days after conception, when all blastomeres have passed through the 5th cell cycle, a broadening of the morula starts at the centre, leading to cavitation and formation of the blastocyst (Fig. 2.1). (33) During the early development of the embryo, and the formation of the early blastocyst, it is surrounded by the zona pellucida which is important for the exchange of nutrients and excretory products with maternal tissues via uterine secretions (Boyd and Hamilton, 1970). Animal studies suggest that up to the 4 to 8 cell stage, each cell, or blastomere, remains pluripotent and could, on its own, complete full development to form a new organism. This pluripotency appears to be lost around the point when the first cells lose their contact with the zona pellucida and migrate into the inner part of the developing embryo. From these cells the ‘inner cell mass’ is formed which develops later into the embryonic and extra-embryonic germ cell layers. The outer cells form a structure termed the trophoblast (Fig. 2.2). (34) Through these early developmental stages, the embryo has migrated along the uterine tube and enters the uterus approximately at the stage of the early morula. The implantation of the embryo into the uterine lining starts after the release of the blastocyst from within the zona pellucida and involves several stages: apposition of the blastocyst to the endometrial epithelium; penetration of the uterine epithelium; invasion into the tissues underlying the epithelium; and invasion of the maternal vascular system. These processes give rise to the early placental structures (Fig. 2.2 and 2.3). The whole period encompassing fertilisation and completion of implantation takes about 2 weeks. The timing of this initial period is very similar in most mammalian species (Table 2.1).
Fig. 2.2. Diagrammatic summary of the ovarian cycle, fertilisation, and human development during the first week. Developmental stage 1 begins with fertilisation and ends when the zygote forms. Stage 2 (days 2 to 3) comprises the early stages of cleavage (from 2 to about 16 cells or the morula). Stage 3 (days 4 to 5) consists of the free unattached blastocyst. Stage 4 (days 5 to 6) is represented by the blastocyst attaching to the centre of the posterior wall of the uterus, the usual site of implantation. O’Rahilly and Mu¨ller, 1992. 31
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Fig. 2.3. Development of the embryo during the first week. The last three drawings show three hypothetical steps in initial implantations. BV, blood vessel; ICM, inner cell mass. O’Rahilly and Mu¨ller, 1992.
(35) After embedding in the epithelial lining of the uterus, the implanted embryo becomes closely surrounded by maternal tissue, the progressive erosion of this tissue constituting a source of nourishment (Figs. 2.4 and 2.5). The outer layer of trophoblast cells has differentiated into the cytotrophoblast and syncytiotrophoblast and has invaded into maternal vessels. Differentiation of the trophoblast forms microvillus-lined clefts and lacunae. Maternal blood then begins to circulate through the communicating lacunae in order to nourish the embryo. (36) Further embryonic development is characterised by a rapid increase in embryonic mass and commences around 3 weeks after conception. The inner cell mass first differentiates into two primary germ layers: the outer ectoderm and inner endoderm. At this stage, two cavities develop, separated by the circular disk of the bilaminar embryo (Fig. 2.6). The cavities are the yolk sac, lined with extra-embryonic endoderm spreading from the embryonic endoderm, and the amniotic cavity, lined with extra-embryonic ectoderm. Ectodermal cells within the embryo then begin
Fig. 2.4. Implantation. The blastocyst becomes attached to the endometrium and then ‘invades’ that layer. The trophoblast, at first solid, soon develops lacunae, which communicate with uterine vessels. AC, amniotic cavity; BV, blood vessel. Asterisk, extra-embryonic mesoblast. O’Rahilly and Mu¨ller, 1992. 32
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Fig. 2.5. Developmental adnexa (fetal membranes). A, chorionic vesicle in utero at 3 1=2 weeks. B, embryo in utero at 8 weeks showing the diminution of the uterine cavity. O’Rahilly and Mu¨ller, 1992.
further proliferation and differentiation forming an elevation into the amniotic cavity called the primitive streak. From this region, proliferating cells push between the layers of ectoderm and endoderm to form the third germ layer of embryonic mesoderm (Hinrichsen, 1990; Carlson, 1994). The process of germ layer formation, termed gastrulation, is essentially complete by 21 days after conception (Fig. 2.6). 2.2. Formation of tissues and organ systems (37) Although the morphological appearance of the embryo during the first 3 weeks of development after conception does not seem very structured, the pattern of the basic body plan is already established during this time. Thus, the dorsal ectodermal cells proliferate and differentiate to form the neural plate, which develops into the neural tube, which comprises the nervous system. The mesodermal germ layer develops, for example, into the circulatory system and the heart and the endodermal layer forms the digestive system (Section 2.2.1). By the end of the 4th week of gestation the embryo, which is still only about 4 mm long, has established the basis of most of the maturing organ systems. The limbs are still absent and the urogenital system has developed only the early traces of the embryonic kidneys. The period of organogenesis (organ formation) may be considered to last up to about the end of the second month (56 days of gestation), at which time the developing embryo still weighs less than about 10 g (Moore and Persaud, 1998). (38) There is no distinct change of developmental process between organogenesis and the subsequent fetal period with major organogenesis occuring between about 4 and 14 weeks after conception (ICRP, 1996). All organ systems start their development during organogenesis and this continues during the fetal period. From about the 8th week, the developing organism is clearly recognisable as having human characteristics. 33
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Fig. 2.6. Development of the extra-embryonic membranes and embryo in the human. Note the folding of the embryo within the amniotic cavity and the folding of the yolk sac within the embryo (E,F). From Browder et al., 1991.
Further growth, development, and maturation of the fetal organs and systems continue to birth at around 38 weeks after conception (taken to be 266 days). Progressive differentiation, histogenesis, and growth are the characteristic processes that take place during the fetal period. The human fetus, as with most other mammalian species, is contained in the amniotic fluid where it is surrounded by fetal membranes and nourished via the placenta through the umbilical cord (Figs. 2.7 and 2.8), see Section 2.3. Between the end of the embryonic period, taken for this report to be at 56 days post conception and birth the mass of the fetus increases about five hundred-fold, with a birth weight of about 3.5 kg (Table 2.3). (39) The subsequent sections describe the development of the tissue and organ systems that are most relevant to the development of biokinetic models for the fetus. 34
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Fig. 2.7. Fetuses in utero and their membranes. A, in trimester 2, B, in trimester 3. O’Rahilly and Mu¨ller, 1992.
2.2.1. Epithelia and mesenchyme (40) Exposed surfaces of the body, internally and externally, are covered by one or more layers of closely packed cells, called epithelia. The ectoderm gives rise to the epithelia covering the external surfaces of the body. These include the epithelium of the skin and its derivatives, including hair, nails and glands, the epithelium of the cornea and conjunctiva, and parts of the epithelial lining of the mouth. The endoderm forms the lining epithelia of the gastrointestinal tract, respiratory tract, urinary bladder, and ducts associated with the liver and pancreas. (41) Mesoderm gives rise to the cells of connective or mesenchymal tissues, including muscle,heart, blood, and lymphatic vessels, as well as tendons, cartilage, and bone, characterised by their extracellular matrices. Mesoderm also differentiates to provide epithelial linings (usually called mesothelium) within the pericardial, pleural, and peritoneal cavity and the urogenital tract including the kidney tubules. 2.2.2. Cartilage, bone, and bone marrow (42) At sites of cartilage formation, mesenchymal cells become closely packed, become chondroblasts, and secrete extracellular material containing differing amounts of collagen fibres. Where cartilage is the precursor of bone, the shape of the 35
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Fig. 2.8. Schematic drawing of a section through a mature placenta, showing: (1) the relation of the villous chorion (fetal part of placenta) to the decidua basalis (maternal part of placenta), (2) the fetal placental circulation, and (3) the maternal placental circulation. Maternal blood flows into the intervillous space in funnel-shaped spurts from the spiral arteries, and exchanges occur with the fetal blood as the maternal blood flows around the branch villi. It is through the branch villi that the main exchange of material between the mother and embryo/fetus occurs. The inflowing arterial blood pushes venous blood out of the intervillous space into the endometrial veins, which are scattered over the entire surface of the decidua basalis. The umbilical arteries carry poorly oxygenated fetal blood to the placenta and the umbilical vein carries oxygenated blood to the fetus. The cotyledons are separated from each other by placental septa, projections of the decidua basalis. Each cotyledon consists of two or more main stem villi and their many branches. In this drawing only one stem villus is shown in each cotyledon, but the stumps of those that have been removed are indicated. (Moore and Persaud, 1998).
cartilage closely resembles that of the bone to be formed. Enlarged chondroblasts in a central region secrete alkaline phosphatase leading to local calcification of the matrix. These cells then die leaving spaces that are invaded by osteoblasts, which lay down layers or lamellae of bone. This process continues in both directions from the central region with calcified cartilage being replaced by bone lamellae and new cartilage being formed at the ends. As the lamellae are formed, some cells remain between the layers, now called osteocytes, connected by processes running through canaliculi in the bone matrix. As well as bone formation, bone growth and remodelling requires considerable removal or resorption, which is performed by osteoclasts. Cavities formed within bone become filled with the haemopoietic tissue of the 36
ICRP Publication 88 Table 2.3. Mass of selected fetal tissues at various times of development. Mass (g) Organ
8 wk
10 wk
15 wk
20 wk
25 wk
30 wk
38 wk
Brain Breast Stomach wall Colon Kidneys Liver Lungs Gonads Red marrow Bone surface Skin Spleen Oesophagus Thyroid Bladder wall Total body
3.7 0.0002 0.010 0.013 0.022 0.19 0.081 0.0005 0.065 0.023 0.19 0.00049 0.0082 0.011 0.0047 4.8
6.4 0.0007 0.043 0.054 0.12 0.81 0.53 0.0022 0.28 0.10 0.80 0.0035 0.041 0.022 0.020 21
22 0.0054 0.33 0.40 1.2 6.1 4.9 0.017 2.2 0.76 6.0 0.069 0.39 0.077 0.15 160
59 0.016 0.93 1.2 3.5 17 13 0.047 6.5 2.2 17 0.36 1.3 0.18 0.42 480
118 0.031 1.9 2.3 7 35 22 0.095 13 4.4 34 1.1 2.8 0.36 0.84 1000
192 0.052 3.1 3.9 12 59 32 0.16 23 7.3 57 2.7 5.1 0.63 1.4 1700
352 0.11 6.4 8.0 23 120 51 0.33 47 15 119 9.1 11 1.3 2.9 3500
red bone marrow, also of mesenchymal origin. Bone growth and ossification are particularly rapid during the first weeks of the fetal period (Carlson, 1994). At the beginning of the 9th week, the head constitutes almost half of the human fetus. Subsequently, body length increases rapidly and has approximately doubled by the end of the 12th week. (43) Blood cell formation (haemopoiesis) starts in the yolk sac during the 3rd week post conception. Blood islands are formed in the mesoderm of the yolk sac. These contain pluripotential stem cells that can develop into all types of cells found in blood. At about 4 weeks after conception, the primordium of the liver arises from the embryonic foregut and by around 5 to 6 weeks after conception haemopoiesis has been established in the liver (Kelemen et al., 1979); this may involve transfer of stem cells from the yolk sac (Metcalf and Moore, 1971). Around 6 to 8 weeks after conception, liver haemopoiesis takes over almost completely from the yolk sac and is the main source of blood cells. Haemopoiesis in the liver continues until the early neonatal period, although its contribution begins to decline in the 6th month after conception. At this time the bone marrow becomes active and is subsequently the predominant site of blood cell formation. The erythrocytes produced in the yolk sac are large, nucleated cells. The erythrocytes from the liver are non-nucleated cells but they are still larger than the erythrocytes produced postnatally (Carlson, 1994). (44) Species-specific characteristics become most evident during the fetal growth period. Guinea pigs have a longer period of fetal development than other rodents (Table 2.1) and are considered to be a better model for skeletal development in the human fetus than small rodents. At birth, the rat skeleton is thought to show the 37
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same degree of development as a 3-month-old human fetus (Strong, 1926). Skeletal maturation in guinea pigs in late gestation may be greater than in humans. 2.2.3. Gastrointestinal tract, liver, respiratory tract (45) The primitive gut is first formed when the head and tail folds of the developing embryo enclose part of the cavity of the yolk sac (Fig. 2.6). The communication with the rest of the yolk sac becomes progressively narrower and subsequently disappears. (46) The anterior portion of the gut (the foregut) eventually forms part of the mouth, including the tongue, the pharynx, thyroid, oesophagus, stomach, duodenum, liver, pancreas, and the respiratory system. The jejunum, ileum and large intestine, and parts of the urogenital system are formed from the mid- and hind-gut. The digestive tube of the gut is lined with endodermal epithelium. The muscles and connective tissues of the digestive organs, as well as the peritoneum that covers them, are derived from mesoderm. (47) The earliest evidence of the liver is an endodermal outgrowth from the gut in the region that will become the duodenum, known as the hepatic diverticulum. The liver bud grows into the surrounding mesoderm and develops into highly branched cords of cells. The distal cords become the functional cells of the liver and the cords closest to the gut become the hepatic ducts. Outgrowths from the hepatic diverticulum develop into the primordia of the gall bladder and pancreas. (48) The first indication of lung formation is the appearance of a midventral furrow in the floor of the pharyngeal endoderm in the anterior portion of the tube. As the groove deepens, it constricts and becomes separate from the gut apart from a small opening at the anterior end, which will become the glottis. The tracheal outgrowth lengthens caudally and bifurcates to form the two lobes of the lungs. The lobes grow into the surrounding mesenchyme, branching repeatedly to form the bronchial tree. 2.2.4. Thyroid (49) An unpaired primordium of the thyroid gland starts to develop from the pharyngeal endoderm around the 4th week after conception. This structure elongates to the thyroid diverticulum. During further growth it bifurcates to form the thyroid gland itself which consists of two main lobes connected by an isthmus. At about the 7th week post conception the thyroid has reached its final location. From the 8th to about the 13th week after conception the precolloid stage develops. A high mitotic activity is seen in the tissue, which continues during the period of early colloid formation. At around the 10th week after conception follicles with colloid material become evident reflecting the beginning of accumulation of iodine from the blood. A few weeks later the thyroid gland begins to synthesise iodinated thyroglobulin and by late in the 4th month all iodinated precursors and hormones can be detected. During this period the uptake of iodine into the developing thyroid progressively increases (Hinrichsen, 1990). It may be assumed for the purposes of developing biokinetic models that thyroid function, and hence accumulation of iodine, commences at about the end of the 11th week after conception. 38
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2.2.5. Nervous system (50) Ectodermal tissue destined to give rise to the central nervous system can be identified in the human embryo as early as the 16th day after conception. This tissue develops into the neural plate, which folds to form the neural tube. At the same time, anterior expansion occurs and the three major divisions of the brain, the prosencephalon, mesencephalon, and rhombencephalon, can be seen by 20 days after conception. The caudal neural tube forms the spinal cord, which gradually gains in length as the embryo grows. The primitive forebrain, the prosencephalon, is the precursor of the cerebral hemispheres. (51) Two basic cell types make up the nervous system: the neurons and the glial cells. Neuronal cells typically develop short processes called dendrites, designed to receive nervous impulses from other cells, and usually one longer process, the axon, for the transmission of impulses. Neuroglia cells play an active role in neuron migration, act as support cells and specialise as sheaths around axons, as oligo-dendrocytes within the central nervous system and as Schwann cells in the peripheral nervous system. (52) In the spinal cord, virtually all cell division and differentiation is complete by the 8th week after conception and relatively little cell migration occurs after this time. However, the development of the brain continues throughout the fetal period. It has become common practice when assessing radiation effects on the brain to consider four stages of development: (i)
In the first period (fertilisation to the 7th week) the precursors of the neurons and neuroglia have emerged and are mitotically active. (ii) In the second period from 8 to 15 weeks inclusive, a rapid increase in the number of neurons occurs; they migrate to their ultimate developmental and functional sites in the cerebral cortex and lose their capacity to divide, becoming perennial cells. Synaptic contacts with other neurons start to develop. This is the most sensitive period of brain development. (iii) In the third period (16–25 weeks), differentiation in situ accelerates, synaptogenesis that began about the eighth week increases. (iv) The fourth period (26 weeks to term) is one of continued cellular differentiation and synaptogenesis of the cerebrum, with, at the same time, accelerated growth and development of the cerebellum. Further details are given in Publication 49 (ICRP, 1986), UNSCEAR (1986, 1993), Konermann (1987) and Muirhead et al. (1993). (53) Radiation doses to the developing brain from incorporated radionuclides are given in this report for the most sensitive 8 to 15 week period (inclusive). This is taken to cover the period from 50 to 105 days after conception. 2.2.6. Excretory pathways (54) Three successive sets of excretory organs develop in human embryos: the pronephros (fore kidney), the mesonephros (mid kidney) and the metanephros (hind kidney) (Moore and Persaud, 1998). The pronephros is a nonfunctional structure appearing 39
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at about the fourth week as a cluster of cells in the cervical region. The mesonephros develops late in the fourth week and may function as an interim kidney until the permanent kidneys (metanephri) are established. The mesonephros is functional in other mammalian species (e.g. rabbit, cat, and pig). The metanephri begin to develop in the fifth week and start to function by about the eighth week. Urine formation continues through fetal life. Takeuchi et al. (1994) have reported ultrasonic measurements of urine flow in normal fetuses to increase from about 6 ml h1 at 21 weeks to about 36 ml h1 at 38 weeks. 2.3. Placenta, extra-embryonic membranes, and yolk sac (55) The extra-embryonic membranes in the mammal form well ahead of the embryo, reflecting the fact that the mammalian embryo is dependent on the mother for all its needs and must develop an exchange system with the maternal blood supply before embryonic development can proceed very far (Fig. 2.6). (56) The need for nutrition and excretion of waste products exists from the moment of fertilisation to birth, and the structures developed to cope with the increasing and changing demands arising from the growth of the fetus. The chorio-allantoic placenta has developed in many species as a highly specific and complex structure for coping with the needs of the fetus. Humans have one version of the chorio-allantoic placenta as described by Wegst (1987) and Wegst and Davis (1992). The placenta either partly or wholly fulfills a number of functions that, after birth, are carried out by organs and tissues of the newborn. These include: gaseous exchange; excretion; resorption; synthesis of hormones and other molecules, and breakdown of metabolites. (57) The close apposition of maternal cells to fetal cells begins with implantation occurring two to three days after the blastocyst enters the uterus or six days after fertilisation. The implantation of the blastocyst is mediated by cell surface changes that also initiate production of human chorionic gonadotrophin, causing the corpus luteum to produce progesterone, critical to the maintenance of the pregnancy. The blastocyst sinks into the epithelial lining and is surrounded by maternal endometrium called decidua. The erosion into the maternal tissue causes haemorrhage and necrosis which, combined with the phagocytic ability of the trophoblast, constitutes a source of nourishment for the developing foreign cells. The increasing demands of the embryo, however, soon require the development of a more elaborate system. (58) From 13 to 21 days, the embryo begins the development of the chorionic villi which will eventually become the mature placenta, the major site of exchange for gases, nutrients, and waste products. The trophoblast differentiates into an inner layer or cytotrophoblast and an outer layer or syncytiotrophoblast. The cytotrophoblast consists of nucleated cells while the syncytiotrophoblast is a multinucleated mass that maintains the embryonic-maternal boundary. Pools of maternal blood form, which fuse into a network of lacunar spaces into which the cytotrophoblastic cells, surrounded by the syncytium, dip with finger-like projections. These projections are the primary villi of the chorionic placenta. (59) Simultaneously, a third cavity, the extra-embryonic coelom, forms around the embryonic structure with the exception of one portion near the embryonic disc. This 40
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portion, the connecting stalk, suspends the embryonic disc and yolk sac in the cavity. The cavity is lined with extra-embryonic somatic mesoderm covering the cytotrophoblastic cells. A layer of extra-embryonic splanchnic mesoderm surrounds the yolk sac. (60) The trophoblast and extra-embryonic somatic mesoderm form the chorion, which gives rise to the fetal part of the placenta. This is accomplished as the primary villi expand, developing into tree-like projections. The inner mesoderm layer forms a mesenchymatous tissue within the villi that differentiates into capillaries. By 22 days post conception, the capillaries within the villi, now called tertiary chorionic villi, coalesce into a network joining with vessels forming in the connecting stalk and from there with vessels in the embryo. The fetal circulation begins carrying nutrients, which are transferred to the fetal blood from the maternal blood in exchange for waste products. (61) Concurrently, the cytotrophoblast penetrates the syncytium and forms a complete shell attaching the chorionic sac to the maternal endometrium. The villi, which initially cover the entire chorionic sac at 5 weeks, regress to only one area by the 13th week. Here, they develop further elaborate projections dipping into maternal blood pools or cotyledons supplied by maternal arteries. These projections continue to develop through the fourth and fifth months of pregnancy, providing an ever increasing surface area for nutrient exchange and waste product removal in order to supply the demands of the growing fetus. By the end of the fourth month, the placenta and fetus each have masses of about 100 g. Thereafter, the fetal mass increases more rapidly with the placenta and fetal membranes weighing 500-600 g at birth compared with 3.5 kg for the newborn child (Moore and Persaud, 1998). (62) The mature placenta functions over the last four months of pregnancy (Fig. 2.8). It is lobular in nature, consisting of the fetal cotyledons. The intervillous spaces within the cotyledon become smaller as the surface area of the villi increase with continued development. The syncytium develops ‘sprouts’, which project into the intervillous space to form terminal villi, and which in turn fill with cytotrophoblasts, mesoderm, and the fetal blood vessels. Then the process repeats itself, leading to a branch and tree-like structure of the villi. In this way there are continuously developing villi with the terminal ends consisting only of a layer of syncytium. (63) As the pregnancy progresses, the barrier between the maternal and fetal blood decreases. The diameter of the villi decreases, the fetal capillary diameter increases, the connective tissue in the villous structure decreases, and the cytotrophoblasts become discontinuous, leaving only a shell of syncytium covered with microvilli. In the cotyledons, spiral arteries inject maternal blood into the intervillous space at high pressure. It flows toward the chorionic plate and then reflects back to the basal plate where it enters the venous system. This results in a counterflow pattern in many parts of the villous structure, which facilitates transfer of nutrients and waste products from maternal to fetal blood streams. The final villous structure presents an enormous fetal surface directly in contact with the maternal blood to maximise transport. The surface area of the placenta increases from around 5 m2 at 28 weeks after conception to almost 11 m2 at term. At the end of pregnancy the barrier membrane has reduced from approximately 0.025 mm in the first trimester, to 41
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approximately 0.002 mm or less at term (Wegst, 1987). The fetal blood flow through the placenta is higher than 100 ml per minute per kg fetal tissue. This means that during the late fetal period the fetus pumps its total blood volume once per minute through the placenta. Gases are transferred by diffusion. The waste products urea and bilirubin also diffuse freely through the placental barrier. Facilitated diffusion is an important mechanism for the transfer of glucose into the fetus and of lactate from the fetus to the mother. Electrolytes, including sodium, potassium, calcium, iron, chlorine and phosphate ions are actively transported. This is also the case for vitamins and hormones of low molecular weight. Various other substances of higher molecular weight can be transported by endocytotic and exocytotic processes. (64) The shape, as well as the structure, of placentas vary from species to species. There are structural and functional differences in chorioallantoic placentas, even between closely related species, and also variations with the stage of gestation (Steven, 1975). For example, rats, mice, and guinea pigs have a haemochorial placenta as in humans. However, the structure is haemotrichorial in rats and mice and haemomonochorial in humans and guinea pigs, referring to the number of layers of trophoblast cells between maternal and fetal blood supplies. The structural similarity of the placenta in humans and guinea pigs does not imply necessarily that they are functionally similar since differences in blood flow, surface area for exchange, as well as mechanisms of transfer could dominate (Hagerman and Villee, 1960; Steven, 1975; Wegst, 1987). (65) The yolk sac in the human does not contain food reserves but is an example of a developmental process that recapitulates evolutionary history. It may have an early nutritive role but is vestigial during later development (Moore and Persaud, 1998). The origin of haemopoietic stem cells in the yolk sac is discussed above. Primordial germ cells are also formed in the yolk sac and subsequently migrate to the embryo (Ham and Cormack, 1979). In rodents, the yolk sac continues to have a nutritive role throughout gestation, complimentary to that of the placenta (Wislocki et al., 1946; Anderson and Leissring, 1961), reflecting considerable differences between rodents and humans in membrane configuration. (66) In rodents, the yolk sac folds during development to envelop the embryo. Blood islands in the internal mesodermal layer of the yolk sac coalesce to form the vitelline circulation. The outer endodermal layer actively takes up nutrients which pass from maternal blood through Reichert’s membrane into a cavity surrounding the embryo (yolk cavity). In humans, the yolk sac does not fold around the embryo but is folded internally to form part of the gut (see Section 2.2.3) and a vestigial structure within the umbilical cord. (67) From the time of the rapid growth of the human embryo from 3 weeks post conception, it becomes folded within the amnion. Throughout subsequent embryonic and fetal development, protection is afforded by the amniotic fluid which fills the amniotic cavity. External to the amnion is the chorion, essentially trophoblast with an internal mesenchymal layer. As the embryo grows and the placenta develops, the layer of maternal decidua encapsulating the embryo within the uterine cavity thins and loses its blood supply. The chorionic villi in this region are eventually lost and are then confined to the placental disk (Fig. 2.5). 42
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2.4. Modelling fetal organ development (68) An extensive compilation of biometric data for the prenatal period has been published by Guihard-Costa and Larroche (1995). Their objective was to establish a set of normalised curves for clinical measures used to characterise fetal growth and development. Their analysis involved nearly 5,000 fetuses, some studied postmortem and others by ultrasound. The biometric measures of principal value in developing a three-dimensional model of the fetal anatomy for dosimetric computations included the postmortem measures of body and brain masses, crown-to-rump length, crownto-heel length, foot length, and head circumference; and ultrasound measures of the femur length, abdominal transverse diameter, biparietal diameter, and fronto-occipital diameter. (69) Guihard-Costa and Larroche (1995) reported the postmortem measurements of body mass for 496 fetuses that were judged to be of normal development. The fetal ages ranged from 10 to 42 weeks gestation, measured from the last normal menstrual period. For modelling purposes the data were fitted to a modified logistic function of fetal age relative to estimated time of fertilisation. Ages of gestation were converted to fetal ages by subtracting 2 weeks. (In assembling organ mass data some authors report menstrual ages that were converted here to fetal ages in the above manner.) Fetal body mass as a function of age is shown in Fig. 2.9. Values for masses of selected fetal tissues at various ages considered in the anatomical modelling are tabulated in Table 2.3.
Fig. 2.9. Fetal body mass as a function of age. The Figure is based on the compilation of biometric data published by Guihard-Costa and Larroche (1995). For ages t less than 16 weeks, the curve is given by m(t)=4.7434+2.0145 (t-8)+2.9696 (t-8)2 and at all other ages as m(t)=127 e0.08764t/[1+80.553 e0.25189t]. 43
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(70) Organ masses reported in the literature are derived from autopsy data. Recent advances in ultrasound make it possible, however, to derive organ volumes from ultrasound images. The data reported in the literature are typically expressed relative to body mass rather than by fetal age. (71) Guihard-Costa and Larroche (1995) measured the mass of the brain in 291 samples weighed prior to fixation and 432 samples that were fixed for 4 to 10 weeks. The masses of the brain given in Table 2.3 were based on these data. (72) Fetal thyroid masses have been reported by Costa (1986), Aboul-Khair et al. (1966), Evans et al. (1967), and Ares et al. (1995). These data were fitted to a power function as shown in Fig. 2.10. The fitting procedure required that the value at birth corresponded to the mass of the thyroid in the newborn (1.3 g). The masses of the thyroid in Table 2.3 were derived from the functional fit shown in Fig. 2.10. (73) The masses of fetal organs, other than the brain and thyroid, were obtained from autopsies and have been reported in the literature by Jackson (1909), Widdowson and Dickerson (1964), Hudson (1965), Trotter and Peterson (1968), Potter and Craig (1975), Burdi et al. (1981), and Shepard et al. (1988). Luecke et al. (1995) analysed the data using an allometric relationship with total body mass. The allometric parameters of Luecke et al. (1995) were adjusted such that the organ and tissue masses at birth corresponded to the values in the newborn. The organ masses for the adrenals, bone, red marrow, heart, kidneys, liver, lungs, pancreas, spleen, and thymus that are tabulated in Table 2.3 were derived in this manner. The masses for all other organs
Fig. 2.10. Fetal thyroid mass as a function of age. Data are from: (*) Aboul-Khair et al (1996); (*) Evans et al (1967); (&) Ares et al (1995); and (&) Costa (1986). The curve that expresses the thyroid mass m as a function of age t is m(t) = 0.0204 t3.0389. 44
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mT (excluding brain and thyroid) in Table 2.3 at times, t, were derived by scaling their mass in the newborn as a power function of body mass; that is as mT ðtÞ ¼ ½
mT newborn m0:9714 ðtÞ TB m0:9714 TB
ð2:1Þ
where mTB(t) is the mass of the total body of the fetus at the age, t, of interest and the value of the exponential corresponds to the average value of Luecke et al. (1995). (74) The biometric data of Guihard-Costa and Larroche (1995) and the organ mass data discussed above were used by Ulanovsky and Eckerman (1998) and Eckerman et al. (to be published) to formulate a series of anatomical models, corresponding to the various ages given in Table 2.3, for the developing fetus. 2.5. Newborn child (75) The newborn child at birth weighs about 3.5 kg. The transition from an intrauterine to extrauterine existence requires substantial changes, especially in the cardiovascular and respiratory systems. The body as a whole grows particularly rapidly during infancy and the birth weight is usually trebled in about the first year of life. The mass of the newborn child and of its organs and tissues used in the calculation of dose coefficients are given in Table 2.3. 2.6. References for Development of embryo/fetus Aboul-Khair, S.A., Buchanan, T.J., Crooks, J., et al. (1966) Structural and functional development of the human foetal thyroid. Clin. Sci. 31, 415–424. Anderson, J.W., Leissring, J.J. (1961) The transfer of serum proteins from mother to young in the guinea pig II. Histochemistry of tissues involved in prenatal transfer. Amer. J. Anat. 109, 157–174. Ares, S., Pastor, I., Quero, J., Morreale de Escobar, G. (1995) Thyroid gland volume as measured by ultrasonography in preterm infants. Acta Paediatr. 84, 58–62. Boyd, J.D., Hamilton, J.W. (1970) The Human Placenta. Cambridge Ltd, W. Heffer and Sons. Browder, L.W., Erickson, C.A., Jeffery, W.R. (1991) Developmental Biology. Saunder Co, Philadelphia. Burdi, A.R., Barr, M., Babler, W.J. (1981) Organ weight patterns in human fetal development. Hum. Biol. 53, 355–366. Carlson, B.M. (1994) Human Embryology and Developmental Biology. Mosby. St, Louis. Costa, A. (1986) Development of thyroid function between VI–IX months of fetal life in humans. J. Endo. Invest. 9, 273–280. Davignon, R.W., Parker, R.M., Hendrickx, A.G. (1980) Staging of the early embryonic brain in the baboon (Papio cynocephalus) and rhesus monkey (Macaca mulatta). Anat. Embryol. 159, 317–334. Dobbing, J., Sand, J. (1970) Growth and development of the brain and spinal cord of the guinea pig. Brain Res. 17, 115–127. Eckerman, K.F., Ulanovsky, A.V., Kerr, G.D. Electron and Photon Absorbed Fractions in the Developing Fetus. ORNL/TM Report (to be published). Enders, A.C., Lantz, K.C., Peterson, P.E., et al. (1997) From blastocyst to placenta: the morphology of implantation in the baboon. Hum. Reprod. Update 3, 561–573. Evans, H.E., Sack, W.O. (1973) Prenatal development of domestic and laboratory mammals: growth curves, external features and selected references. Anat. Histol. Embryol. 2, 11–21. Evans, T.C., Kretzschmar, R.M., Hodges, R.E., et al. (1967) Radioiodine uptake studies of the human fetal thyroid. J. Nucl. Med. 8, 157–165. 45
ICRP Publication 88 Guihard-Costa, A.M., Larroche, J.C. (1995) Fetal biometry: Growth charts for practical use in fetopathology and antenatal ultrasonography. Fetal Diagn. Ther. 10, 215–278. Hagerman, D.D., Villee, C.A. (1960) Transport functions of the placenta. Physiology Reviews 40, 313– 330. Ham, A.W., Cormack, D.H. (1979) Histology, 8th Edition. J.B. Lippincott Company, Philadelphia. p. 977. Harman, M.T., Saffry, O.B. (1934) The skeletal development of the anterior limb of the guinea-pig, cavia cobaya cuva, from the 25-day embryo to the 161-day postnatal guinea-pig. Amer. J. Anat. 54, 315–327. Hearn, J.P., Hendrickx, A.G., Webley, G.E., et al. (1994) Normal and abnormal embryo-fetal development in mammals. In: Lamming, E.E. (Ed.), Marshall’s Physiology of Reproduction, Vol. III. Part I. Chapman and Hall, London, pp. 535–676. Hendrickx, A.G., Houston, M.C. (1971) Comparative reproduction of non-human primates. In: Hafez, E.S.E. (Ed.), Prenatal and Postnatal Development. Springfield: Charles C, Thomas, pp. 334–381. Hendrickx, A.G., Houston, M.C., Kraemer, D.C., et al. (1970) Embryology of the Baboon. University of Chicago Press, Chicago. Hendrickx, A.G., Peterson, P.E. (1997) Perspectives on the use of the baboon in embryology and teratology research. Hum. Reprod. Update 3, 575–592. Hinrichsen, K.V. (1990) Human-Embryologie. Springer-Verlag, Berlin. Hudson, G. (1965) Organ size of human foetal bone marrow. Nature 205, 96–97. ICRP (1986) Developmental effects of irradiation on the brain of the embryo and fetus. ICRP Publication 49. Annals of the ICRP 16 (4). ICRP (1996) Radiological protection and safety in medicine. ICRP Publication 73. Annals of the ICRP 26 (2). Jackson, C.M. (1909) On the prenatal growth of the human body and relative growth of various organs and parts. Amer. J. Anat. 9, 119–165. Kelemen, E., Calvo, W., Fliedner, T.M. (1979) Atlas of Human Haemopoietic Development. SpringerVerlag, Berlin. Konermann, G. (1987) Postimplantation defects in development following ionizing irradiation. Adv. Radiat. Biol. 13, 91–167. Luecke, R.H., Wolsilait, W.D., Young, J.F. (1995) Mathematical representation of organ growth in the human embryo/fetus. J. BioMed. Computing 39, 337–341. Metcalf, D., Moore, M.A.S. (1971) Haemopoietic Cells. Embryonic Aspects of Haemopoiesis. American Elsevier, New York, pp. 172–267. Moore, K.L., Persaud, T.V.N. (1998) The Developing Human, 6th ed. W. B. Saunders Company, London. Muirhead, C.R., Cox, R., Stather, J.W., et al. (1993) Estimates of late radiation risks to the UK population. Docs. NRPB 4 (4), 15–157. Nishimura, H., Shiota, K. (1977) Summary of comparative embryology and teratology. In: Wilson, J.G., Fraser, F.C. (Eds.), Handbook of Teratology. Vol. 3. Comparative and Maternal and Epidemiologic aspects. Plenum Press, New York, pp. 119–154. O’Rahilly, R., Mu¨ller, F. (1992) Human Embryology and Teratology. Wiley-Liss, New York. Potter, E.L., Craig, J.M. (1975) Rate of antenatal growth. In: Pathology of the Fetus and Infant. Year Book Medical Publishers, Chicago, pp. 15–25. Santoloya-Forgas, J., Vengalil, S., Meyer, W., et al. (1997) Transvaginal ultrasonographic (TVS) evaluation of baboon gestation from 37–62 days postconception. Amer. J. Primatol 43, 323–328. Scott, M.R. (1937) The embryology of the guinea-pig. A table of normal development. Amer. J. Anat 60, 397–432. Shepard, T.H., Shi, M., Fellingham, G.W., et al. (1988) Organ weight standards for human fetuses. Pediatr. Pathol 8, 513–524. Steven, D.H. (1975) Comparative Placentation—Essays in Structure and Function. Academic Press, London. Strong, R.M. (1926) The order, time and rate of ossification of the albino rat skeleton. Amer. J. Anat. 36, 313–335. 46
ICRP Publication 88 Takeuchi, H., Koyanagi, T., Yoshizato, T., et al. (1994) Fetal urine production at different gestational ages: correlation to various compromised fetuses in utero. Early Hum. Develop. 40, 1–11. Trotter, M., Peterson, R.R. (1968) Weight of bone in the fetus—A preliminary report. Growth 32, 83–90. Ulanovsky, A.V., Eckerman, K.F. (1998) Absorbed fractions for electron and photon emissions in the developing thyroid: fetus to five year old. Radiat. Prot. Dosim. 79 (1–4), 419–424. UNSCEAR (1977) United Nations Scientific Committee on the Effects of Atomic Radiation. 1977 Report to the General Assembly, with annexes. Sources and Effects of Ionizing Radiation. United Nations, New York. UNSCEAR (1986) United Nations Scientific Committee on the Effects of Atomic Radiation. 1986 Report to the General Assembly, with annexes. Genetic and Somatic Effects of Ionizing Radiation. United Nations, New York. UNSCEAR (1993) United Nations Scientific Committee on the Effects of Atomic Radiation. 1993 Report to the General Assembly, with annexes. Sources and Effects of Ionizing Radiations. United Nations, New York. Wegst, A.V. (1987) Physiology of transfer. In: Gerber, G.B. (Ed.), Me´tivier, H., Smith, H. (Eds): Agerelated Factors in Radionuclide Metabolism and Dosimetry. Martinus Nihjhoff for the Commission of the European Communities. Dordrecht, EUR 10556, pp. 293–301. Wegst, A.V., Davis, J.M. (1992) Anatomy and physiology of the embryo, fetus and placenta. In: Agedependent Factors in the Biokinetics and Dosimetry of Radionuclides. Radiat. Prot. Dosim. 41 (2–4), 103–110. Widdowson, E.M., Dickerson, J.W.T. (1964) Growth and composition of the fetus and newborn. In: Mineral Metabolism, Part 2A. Academic Press. New York. Wislocki, G.B., Dean, H.B., Dempsey, E.W. (1946) Histochemistry of the rodents placenta. Amer. J. Anat 78, 281–346.
47
Table 2.1. Approximate time of the beginning and end of the major developmental periods in some mammalian species.a Species
Hamster Mouse Rat Rabbit Guinea-pig Dog Baboon Man a b c
Pre-implantation
Embryonic period of major organogenesis
Fetal period of organ growth
(days)
%b
(days)
%
(days)
%
0-5 0-5 0-7 0-5 0-8 0-17 0-9 0-8
31 26 33 16 13 27 5 3
6-12 6-13 8-15 6-15 9-25 18-30 10-49 9-56c
44 42 38 32 27 21 23 18
13-16 14-19 16-21 16-31 26-63 31-63 50-175 57-266c
25 32 29 52 60 52 72 79
Based on UNSCEAR (1977) Percentage of period of gestation Values adopted in this report 29
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Fig. 2.1. Timing of major developmental periods in some mammalian species (data from Table 2.1).
Table 2.2. Approximate times of development of various organs and embryonic structures in the rat, guinea-pig, baboon, and human. Days after conception Rat Germ layer differentiation and development of fetal membranes 5-10 Period of yolk sac haemopoiesis 9-13 10-11 Appearance of embryonic livera Onset of liver haemopoiesis 11 Onset of thyroid function 10 Onset of ossification 16 Onset of marrow haemopoiesis 10-17 Onset of brain developmentb 10
Guinea-pig Baboon Human 6-13 13-35 16 20 16 25 25-26 16
7-15 < 22 27 30 29 45-47 60 25
7-21 19-63 28 42 28 56 70-77 25
Data based on Metcalf and Moore, 1971; Kelemen et al., 1979; Harman and Saffry, 1934; Moore and Persaud, 1998; Scott, 1937; Strong, 1926; Nishimura and Shiota, 1977; Davignon et al., 1980; Dobbing and Sand, 1970; Enders et al., 1997; Evans and Sack, 1973; Hearn et al., 1994; Hendrickx and Houston, 1971; Hendrickx et al., 1970; Hendrickx and Peterson, 1997; Santoloya-Fargas et al., 1997. a First liver diverticula b Appearance of the first three brain vesicles 30
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stage of differentiation called compaction occurs. The embryonic cells form close cell contacts, and clearly delineated cell borders disappear to form the first embryonic ‘tissue’. This developmental stage is called the morula. Around 4 days after conception, when all blastomeres have passed through the 5th cell cycle, a broadening of the morula starts at the centre, leading to cavitation and formation of the blastocyst (Fig. 2.1). (33) During the early development of the embryo, and the formation of the early blastocyst, it is surrounded by the zona pellucida which is important for the exchange of nutrients and excretory products with maternal tissues via uterine secretions (Boyd and Hamilton, 1970). Animal studies suggest that up to the 4 to 8 cell stage, each cell, or blastomere, remains pluripotent and could, on its own, complete full development to form a new organism. This pluripotency appears to be lost around the point when the first cells lose their contact with the zona pellucida and migrate into the inner part of the developing embryo. From these cells the ‘inner cell mass’ is formed which develops later into the embryonic and extra-embryonic germ cell layers. The outer cells form a structure termed the trophoblast (Fig. 2.2). (34) Through these early developmental stages, the embryo has migrated along the uterine tube and enters the uterus approximately at the stage of the early morula. The implantation of the embryo into the uterine lining starts after the release of the blastocyst from within the zona pellucida and involves several stages: apposition of the blastocyst to the endometrial epithelium; penetration of the uterine epithelium; invasion into the tissues underlying the epithelium; and invasion of the maternal vascular system. These processes give rise to the early placental structures (Fig. 2.2 and 2.3). The whole period encompassing fertilisation and completion of implantation takes about 2 weeks. The timing of this initial period is very similar in most mammalian species (Table 2.1).
Fig. 2.2. Diagrammatic summary of the ovarian cycle, fertilisation, and human development during the first week. Developmental stage 1 begins with fertilisation and ends when the zygote forms. Stage 2 (days 2 to 3) comprises the early stages of cleavage (from 2 to about 16 cells or the morula). Stage 3 (days 4 to 5) consists of the free unattached blastocyst. Stage 4 (days 5 to 6) is represented by the blastocyst attaching to the centre of the posterior wall of the uterus, the usual site of implantation. O’Rahilly and Mu¨ller, 1992. 31
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Fig. 2.3. Development of the embryo during the first week. The last three drawings show three hypothetical steps in initial implantations. BV, blood vessel; ICM, inner cell mass. O’Rahilly and Mu¨ller, 1992.
(35) After embedding in the epithelial lining of the uterus, the implanted embryo becomes closely surrounded by maternal tissue, the progressive erosion of this tissue constituting a source of nourishment (Figs. 2.4 and 2.5). The outer layer of trophoblast cells has differentiated into the cytotrophoblast and syncytiotrophoblast and has invaded into maternal vessels. Differentiation of the trophoblast forms microvillus-lined clefts and lacunae. Maternal blood then begins to circulate through the communicating lacunae in order to nourish the embryo. (36) Further embryonic development is characterised by a rapid increase in embryonic mass and commences around 3 weeks after conception. The inner cell mass first differentiates into two primary germ layers: the outer ectoderm and inner endoderm. At this stage, two cavities develop, separated by the circular disk of the bilaminar embryo (Fig. 2.6). The cavities are the yolk sac, lined with extra-embryonic endoderm spreading from the embryonic endoderm, and the amniotic cavity, lined with extra-embryonic ectoderm. Ectodermal cells within the embryo then begin
Fig. 2.4. Implantation. The blastocyst becomes attached to the endometrium and then ‘invades’ that layer. The trophoblast, at first solid, soon develops lacunae, which communicate with uterine vessels. AC, amniotic cavity; BV, blood vessel. Asterisk, extra-embryonic mesoblast. O’Rahilly and Mu¨ller, 1992. 32
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Fig. 2.5. Developmental adnexa (fetal membranes). A, chorionic vesicle in utero at 3 1=2 weeks. B, embryo in utero at 8 weeks showing the diminution of the uterine cavity. O’Rahilly and Mu¨ller, 1992.
further proliferation and differentiation forming an elevation into the amniotic cavity called the primitive streak. From this region, proliferating cells push between the layers of ectoderm and endoderm to form the third germ layer of embryonic mesoderm (Hinrichsen, 1990; Carlson, 1994). The process of germ layer formation, termed gastrulation, is essentially complete by 21 days after conception (Fig. 2.6). 2.2. Formation of tissues and organ systems (37) Although the morphological appearance of the embryo during the first 3 weeks of development after conception does not seem very structured, the pattern of the basic body plan is already established during this time. Thus, the dorsal ectodermal cells proliferate and differentiate to form the neural plate, which develops into the neural tube, which comprises the nervous system. The mesodermal germ layer develops, for example, into the circulatory system and the heart and the endodermal layer forms the digestive system (Section 2.2.1). By the end of the 4th week of gestation the embryo, which is still only about 4 mm long, has established the basis of most of the maturing organ systems. The limbs are still absent and the urogenital system has developed only the early traces of the embryonic kidneys. The period of organogenesis (organ formation) may be considered to last up to about the end of the second month (56 days of gestation), at which time the developing embryo still weighs less than about 10 g (Moore and Persaud, 1998). (38) There is no distinct change of developmental process between organogenesis and the subsequent fetal period with major organogenesis occuring between about 4 and 14 weeks after conception (ICRP, 1996). All organ systems start their development during organogenesis and this continues during the fetal period. From about the 8th week, the developing organism is clearly recognisable as having human characteristics. 33
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Fig. 2.6. Development of the extra-embryonic membranes and embryo in the human. Note the folding of the embryo within the amniotic cavity and the folding of the yolk sac within the embryo (E,F). From Browder et al., 1991.
Further growth, development, and maturation of the fetal organs and systems continue to birth at around 38 weeks after conception (taken to be 266 days). Progressive differentiation, histogenesis, and growth are the characteristic processes that take place during the fetal period. The human fetus, as with most other mammalian species, is contained in the amniotic fluid where it is surrounded by fetal membranes and nourished via the placenta through the umbilical cord (Figs. 2.7 and 2.8), see Section 2.3. Between the end of the embryonic period, taken for this report to be at 56 days post conception and birth the mass of the fetus increases about five hundred-fold, with a birth weight of about 3.5 kg (Table 2.3). (39) The subsequent sections describe the development of the tissue and organ systems that are most relevant to the development of biokinetic models for the fetus. 34
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Fig. 2.7. Fetuses in utero and their membranes. A, in trimester 2, B, in trimester 3. O’Rahilly and Mu¨ller, 1992.
2.2.1. Epithelia and mesenchyme (40) Exposed surfaces of the body, internally and externally, are covered by one or more layers of closely packed cells, called epithelia. The ectoderm gives rise to the epithelia covering the external surfaces of the body. These include the epithelium of the skin and its derivatives, including hair, nails and glands, the epithelium of the cornea and conjunctiva, and parts of the epithelial lining of the mouth. The endoderm forms the lining epithelia of the gastrointestinal tract, respiratory tract, urinary bladder, and ducts associated with the liver and pancreas. (41) Mesoderm gives rise to the cells of connective or mesenchymal tissues, including muscle,heart, blood, and lymphatic vessels, as well as tendons, cartilage, and bone, characterised by their extracellular matrices. Mesoderm also differentiates to provide epithelial linings (usually called mesothelium) within the pericardial, pleural, and peritoneal cavity and the urogenital tract including the kidney tubules. 2.2.2. Cartilage, bone, and bone marrow (42) At sites of cartilage formation, mesenchymal cells become closely packed, become chondroblasts, and secrete extracellular material containing differing amounts of collagen fibres. Where cartilage is the precursor of bone, the shape of the 35
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Fig. 2.8. Schematic drawing of a section through a mature placenta, showing: (1) the relation of the villous chorion (fetal part of placenta) to the decidua basalis (maternal part of placenta), (2) the fetal placental circulation, and (3) the maternal placental circulation. Maternal blood flows into the intervillous space in funnel-shaped spurts from the spiral arteries, and exchanges occur with the fetal blood as the maternal blood flows around the branch villi. It is through the branch villi that the main exchange of material between the mother and embryo/fetus occurs. The inflowing arterial blood pushes venous blood out of the intervillous space into the endometrial veins, which are scattered over the entire surface of the decidua basalis. The umbilical arteries carry poorly oxygenated fetal blood to the placenta and the umbilical vein carries oxygenated blood to the fetus. The cotyledons are separated from each other by placental septa, projections of the decidua basalis. Each cotyledon consists of two or more main stem villi and their many branches. In this drawing only one stem villus is shown in each cotyledon, but the stumps of those that have been removed are indicated. (Moore and Persaud, 1998).
cartilage closely resembles that of the bone to be formed. Enlarged chondroblasts in a central region secrete alkaline phosphatase leading to local calcification of the matrix. These cells then die leaving spaces that are invaded by osteoblasts, which lay down layers or lamellae of bone. This process continues in both directions from the central region with calcified cartilage being replaced by bone lamellae and new cartilage being formed at the ends. As the lamellae are formed, some cells remain between the layers, now called osteocytes, connected by processes running through canaliculi in the bone matrix. As well as bone formation, bone growth and remodelling requires considerable removal or resorption, which is performed by osteoclasts. Cavities formed within bone become filled with the haemopoietic tissue of the 36
ICRP Publication 88 Table 2.3. Mass of selected fetal tissues at various times of development. Mass (g) Organ
8 wk
10 wk
15 wk
20 wk
25 wk
30 wk
38 wk
Brain Breast Stomach wall Colon Kidneys Liver Lungs Gonads Red marrow Bone surface Skin Spleen Oesophagus Thyroid Bladder wall Total body
3.7 0.0002 0.010 0.013 0.022 0.19 0.081 0.0005 0.065 0.023 0.19 0.00049 0.0082 0.011 0.0047 4.8
6.4 0.0007 0.043 0.054 0.12 0.81 0.53 0.0022 0.28 0.10 0.80 0.0035 0.041 0.022 0.020 21
22 0.0054 0.33 0.40 1.2 6.1 4.9 0.017 2.2 0.76 6.0 0.069 0.39 0.077 0.15 160
59 0.016 0.93 1.2 3.5 17 13 0.047 6.5 2.2 17 0.36 1.3 0.18 0.42 480
118 0.031 1.9 2.3 7 35 22 0.095 13 4.4 34 1.1 2.8 0.36 0.84 1000
192 0.052 3.1 3.9 12 59 32 0.16 23 7.3 57 2.7 5.1 0.63 1.4 1700
352 0.11 6.4 8.0 23 120 51 0.33 47 15 119 9.1 11 1.3 2.9 3500
red bone marrow, also of mesenchymal origin. Bone growth and ossification are particularly rapid during the first weeks of the fetal period (Carlson, 1994). At the beginning of the 9th week, the head constitutes almost half of the human fetus. Subsequently, body length increases rapidly and has approximately doubled by the end of the 12th week. (43) Blood cell formation (haemopoiesis) starts in the yolk sac during the 3rd week post conception. Blood islands are formed in the mesoderm of the yolk sac. These contain pluripotential stem cells that can develop into all types of cells found in blood. At about 4 weeks after conception, the primordium of the liver arises from the embryonic foregut and by around 5 to 6 weeks after conception haemopoiesis has been established in the liver (Kelemen et al., 1979); this may involve transfer of stem cells from the yolk sac (Metcalf and Moore, 1971). Around 6 to 8 weeks after conception, liver haemopoiesis takes over almost completely from the yolk sac and is the main source of blood cells. Haemopoiesis in the liver continues until the early neonatal period, although its contribution begins to decline in the 6th month after conception. At this time the bone marrow becomes active and is subsequently the predominant site of blood cell formation. The erythrocytes produced in the yolk sac are large, nucleated cells. The erythrocytes from the liver are non-nucleated cells but they are still larger than the erythrocytes produced postnatally (Carlson, 1994). (44) Species-specific characteristics become most evident during the fetal growth period. Guinea pigs have a longer period of fetal development than other rodents (Table 2.1) and are considered to be a better model for skeletal development in the human fetus than small rodents. At birth, the rat skeleton is thought to show the 37
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same degree of development as a 3-month-old human fetus (Strong, 1926). Skeletal maturation in guinea pigs in late gestation may be greater than in humans. 2.2.3. Gastrointestinal tract, liver, respiratory tract (45) The primitive gut is first formed when the head and tail folds of the developing embryo enclose part of the cavity of the yolk sac (Fig. 2.6). The communication with the rest of the yolk sac becomes progressively narrower and subsequently disappears. (46) The anterior portion of the gut (the foregut) eventually forms part of the mouth, including the tongue, the pharynx, thyroid, oesophagus, stomach, duodenum, liver, pancreas, and the respiratory system. The jejunum, ileum and large intestine, and parts of the urogenital system are formed from the mid- and hind-gut. The digestive tube of the gut is lined with endodermal epithelium. The muscles and connective tissues of the digestive organs, as well as the peritoneum that covers them, are derived from mesoderm. (47) The earliest evidence of the liver is an endodermal outgrowth from the gut in the region that will become the duodenum, known as the hepatic diverticulum. The liver bud grows into the surrounding mesoderm and develops into highly branched cords of cells. The distal cords become the functional cells of the liver and the cords closest to the gut become the hepatic ducts. Outgrowths from the hepatic diverticulum develop into the primordia of the gall bladder and pancreas. (48) The first indication of lung formation is the appearance of a midventral furrow in the floor of the pharyngeal endoderm in the anterior portion of the tube. As the groove deepens, it constricts and becomes separate from the gut apart from a small opening at the anterior end, which will become the glottis. The tracheal outgrowth lengthens caudally and bifurcates to form the two lobes of the lungs. The lobes grow into the surrounding mesenchyme, branching repeatedly to form the bronchial tree. 2.2.4. Thyroid (49) An unpaired primordium of the thyroid gland starts to develop from the pharyngeal endoderm around the 4th week after conception. This structure elongates to the thyroid diverticulum. During further growth it bifurcates to form the thyroid gland itself which consists of two main lobes connected by an isthmus. At about the 7th week post conception the thyroid has reached its final location. From the 8th to about the 13th week after conception the precolloid stage develops. A high mitotic activity is seen in the tissue, which continues during the period of early colloid formation. At around the 10th week after conception follicles with colloid material become evident reflecting the beginning of accumulation of iodine from the blood. A few weeks later the thyroid gland begins to synthesise iodinated thyroglobulin and by late in the 4th month all iodinated precursors and hormones can be detected. During this period the uptake of iodine into the developing thyroid progressively increases (Hinrichsen, 1990). It may be assumed for the purposes of developing biokinetic models that thyroid function, and hence accumulation of iodine, commences at about the end of the 11th week after conception. 38
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2.2.5. Nervous system (50) Ectodermal tissue destined to give rise to the central nervous system can be identified in the human embryo as early as the 16th day after conception. This tissue develops into the neural plate, which folds to form the neural tube. At the same time, anterior expansion occurs and the three major divisions of the brain, the prosencephalon, mesencephalon, and rhombencephalon, can be seen by 20 days after conception. The caudal neural tube forms the spinal cord, which gradually gains in length as the embryo grows. The primitive forebrain, the prosencephalon, is the precursor of the cerebral hemispheres. (51) Two basic cell types make up the nervous system: the neurons and the glial cells. Neuronal cells typically develop short processes called dendrites, designed to receive nervous impulses from other cells, and usually one longer process, the axon, for the transmission of impulses. Neuroglia cells play an active role in neuron migration, act as support cells and specialise as sheaths around axons, as oligo-dendrocytes within the central nervous system and as Schwann cells in the peripheral nervous system. (52) In the spinal cord, virtually all cell division and differentiation is complete by the 8th week after conception and relatively little cell migration occurs after this time. However, the development of the brain continues throughout the fetal period. It has become common practice when assessing radiation effects on the brain to consider four stages of development: (i)
In the first period (fertilisation to the 7th week) the precursors of the neurons and neuroglia have emerged and are mitotically active. (ii) In the second period from 8 to 15 weeks inclusive, a rapid increase in the number of neurons occurs; they migrate to their ultimate developmental and functional sites in the cerebral cortex and lose their capacity to divide, becoming perennial cells. Synaptic contacts with other neurons start to develop. This is the most sensitive period of brain development. (iii) In the third period (16–25 weeks), differentiation in situ accelerates, synaptogenesis that began about the eighth week increases. (iv) The fourth period (26 weeks to term) is one of continued cellular differentiation and synaptogenesis of the cerebrum, with, at the same time, accelerated growth and development of the cerebellum. Further details are given in Publication 49 (ICRP, 1986), UNSCEAR (1986, 1993), Konermann (1987) and Muirhead et al. (1993). (53) Radiation doses to the developing brain from incorporated radionuclides are given in this report for the most sensitive 8 to 15 week period (inclusive). This is taken to cover the period from 50 to 105 days after conception. 2.2.6. Excretory pathways (54) Three successive sets of excretory organs develop in human embryos: the pronephros (fore kidney), the mesonephros (mid kidney) and the metanephros (hind kidney) (Moore and Persaud, 1998). The pronephros is a nonfunctional structure appearing 39
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at about the fourth week as a cluster of cells in the cervical region. The mesonephros develops late in the fourth week and may function as an interim kidney until the permanent kidneys (metanephri) are established. The mesonephros is functional in other mammalian species (e.g. rabbit, cat, and pig). The metanephri begin to develop in the fifth week and start to function by about the eighth week. Urine formation continues through fetal life. Takeuchi et al. (1994) have reported ultrasonic measurements of urine flow in normal fetuses to increase from about 6 ml h1 at 21 weeks to about 36 ml h1 at 38 weeks. 2.3. Placenta, extra-embryonic membranes, and yolk sac (55) The extra-embryonic membranes in the mammal form well ahead of the embryo, reflecting the fact that the mammalian embryo is dependent on the mother for all its needs and must develop an exchange system with the maternal blood supply before embryonic development can proceed very far (Fig. 2.6). (56) The need for nutrition and excretion of waste products exists from the moment of fertilisation to birth, and the structures developed to cope with the increasing and changing demands arising from the growth of the fetus. The chorio-allantoic placenta has developed in many species as a highly specific and complex structure for coping with the needs of the fetus. Humans have one version of the chorio-allantoic placenta as described by Wegst (1987) and Wegst and Davis (1992). The placenta either partly or wholly fulfills a number of functions that, after birth, are carried out by organs and tissues of the newborn. These include: gaseous exchange; excretion; resorption; synthesis of hormones and other molecules, and breakdown of metabolites. (57) The close apposition of maternal cells to fetal cells begins with implantation occurring two to three days after the blastocyst enters the uterus or six days after fertilisation. The implantation of the blastocyst is mediated by cell surface changes that also initiate production of human chorionic gonadotrophin, causing the corpus luteum to produce progesterone, critical to the maintenance of the pregnancy. The blastocyst sinks into the epithelial lining and is surrounded by maternal endometrium called decidua. The erosion into the maternal tissue causes haemorrhage and necrosis which, combined with the phagocytic ability of the trophoblast, constitutes a source of nourishment for the developing foreign cells. The increasing demands of the embryo, however, soon require the development of a more elaborate system. (58) From 13 to 21 days, the embryo begins the development of the chorionic villi which will eventually become the mature placenta, the major site of exchange for gases, nutrients, and waste products. The trophoblast differentiates into an inner layer or cytotrophoblast and an outer layer or syncytiotrophoblast. The cytotrophoblast consists of nucleated cells while the syncytiotrophoblast is a multinucleated mass that maintains the embryonic-maternal boundary. Pools of maternal blood form, which fuse into a network of lacunar spaces into which the cytotrophoblastic cells, surrounded by the syncytium, dip with finger-like projections. These projections are the primary villi of the chorionic placenta. (59) Simultaneously, a third cavity, the extra-embryonic coelom, forms around the embryonic structure with the exception of one portion near the embryonic disc. This 40
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portion, the connecting stalk, suspends the embryonic disc and yolk sac in the cavity. The cavity is lined with extra-embryonic somatic mesoderm covering the cytotrophoblastic cells. A layer of extra-embryonic splanchnic mesoderm surrounds the yolk sac. (60) The trophoblast and extra-embryonic somatic mesoderm form the chorion, which gives rise to the fetal part of the placenta. This is accomplished as the primary villi expand, developing into tree-like projections. The inner mesoderm layer forms a mesenchymatous tissue within the villi that differentiates into capillaries. By 22 days post conception, the capillaries within the villi, now called tertiary chorionic villi, coalesce into a network joining with vessels forming in the connecting stalk and from there with vessels in the embryo. The fetal circulation begins carrying nutrients, which are transferred to the fetal blood from the maternal blood in exchange for waste products. (61) Concurrently, the cytotrophoblast penetrates the syncytium and forms a complete shell attaching the chorionic sac to the maternal endometrium. The villi, which initially cover the entire chorionic sac at 5 weeks, regress to only one area by the 13th week. Here, they develop further elaborate projections dipping into maternal blood pools or cotyledons supplied by maternal arteries. These projections continue to develop through the fourth and fifth months of pregnancy, providing an ever increasing surface area for nutrient exchange and waste product removal in order to supply the demands of the growing fetus. By the end of the fourth month, the placenta and fetus each have masses of about 100 g. Thereafter, the fetal mass increases more rapidly with the placenta and fetal membranes weighing 500-600 g at birth compared with 3.5 kg for the newborn child (Moore and Persaud, 1998). (62) The mature placenta functions over the last four months of pregnancy (Fig. 2.8). It is lobular in nature, consisting of the fetal cotyledons. The intervillous spaces within the cotyledon become smaller as the surface area of the villi increase with continued development. The syncytium develops ‘sprouts’, which project into the intervillous space to form terminal villi, and which in turn fill with cytotrophoblasts, mesoderm, and the fetal blood vessels. Then the process repeats itself, leading to a branch and tree-like structure of the villi. In this way there are continuously developing villi with the terminal ends consisting only of a layer of syncytium. (63) As the pregnancy progresses, the barrier between the maternal and fetal blood decreases. The diameter of the villi decreases, the fetal capillary diameter increases, the connective tissue in the villous structure decreases, and the cytotrophoblasts become discontinuous, leaving only a shell of syncytium covered with microvilli. In the cotyledons, spiral arteries inject maternal blood into the intervillous space at high pressure. It flows toward the chorionic plate and then reflects back to the basal plate where it enters the venous system. This results in a counterflow pattern in many parts of the villous structure, which facilitates transfer of nutrients and waste products from maternal to fetal blood streams. The final villous structure presents an enormous fetal surface directly in contact with the maternal blood to maximise transport. The surface area of the placenta increases from around 5 m2 at 28 weeks after conception to almost 11 m2 at term. At the end of pregnancy the barrier membrane has reduced from approximately 0.025 mm in the first trimester, to 41
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approximately 0.002 mm or less at term (Wegst, 1987). The fetal blood flow through the placenta is higher than 100 ml per minute per kg fetal tissue. This means that during the late fetal period the fetus pumps its total blood volume once per minute through the placenta. Gases are transferred by diffusion. The waste products urea and bilirubin also diffuse freely through the placental barrier. Facilitated diffusion is an important mechanism for the transfer of glucose into the fetus and of lactate from the fetus to the mother. Electrolytes, including sodium, potassium, calcium, iron, chlorine and phosphate ions are actively transported. This is also the case for vitamins and hormones of low molecular weight. Various other substances of higher molecular weight can be transported by endocytotic and exocytotic processes. (64) The shape, as well as the structure, of placentas vary from species to species. There are structural and functional differences in chorioallantoic placentas, even between closely related species, and also variations with the stage of gestation (Steven, 1975). For example, rats, mice, and guinea pigs have a haemochorial placenta as in humans. However, the structure is haemotrichorial in rats and mice and haemomonochorial in humans and guinea pigs, referring to the number of layers of trophoblast cells between maternal and fetal blood supplies. The structural similarity of the placenta in humans and guinea pigs does not imply necessarily that they are functionally similar since differences in blood flow, surface area for exchange, as well as mechanisms of transfer could dominate (Hagerman and Villee, 1960; Steven, 1975; Wegst, 1987). (65) The yolk sac in the human does not contain food reserves but is an example of a developmental process that recapitulates evolutionary history. It may have an early nutritive role but is vestigial during later development (Moore and Persaud, 1998). The origin of haemopoietic stem cells in the yolk sac is discussed above. Primordial germ cells are also formed in the yolk sac and subsequently migrate to the embryo (Ham and Cormack, 1979). In rodents, the yolk sac continues to have a nutritive role throughout gestation, complimentary to that of the placenta (Wislocki et al., 1946; Anderson and Leissring, 1961), reflecting considerable differences between rodents and humans in membrane configuration. (66) In rodents, the yolk sac folds during development to envelop the embryo. Blood islands in the internal mesodermal layer of the yolk sac coalesce to form the vitelline circulation. The outer endodermal layer actively takes up nutrients which pass from maternal blood through Reichert’s membrane into a cavity surrounding the embryo (yolk cavity). In humans, the yolk sac does not fold around the embryo but is folded internally to form part of the gut (see Section 2.2.3) and a vestigial structure within the umbilical cord. (67) From the time of the rapid growth of the human embryo from 3 weeks post conception, it becomes folded within the amnion. Throughout subsequent embryonic and fetal development, protection is afforded by the amniotic fluid which fills the amniotic cavity. External to the amnion is the chorion, essentially trophoblast with an internal mesenchymal layer. As the embryo grows and the placenta develops, the layer of maternal decidua encapsulating the embryo within the uterine cavity thins and loses its blood supply. The chorionic villi in this region are eventually lost and are then confined to the placental disk (Fig. 2.5). 42
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2.4. Modelling fetal organ development (68) An extensive compilation of biometric data for the prenatal period has been published by Guihard-Costa and Larroche (1995). Their objective was to establish a set of normalised curves for clinical measures used to characterise fetal growth and development. Their analysis involved nearly 5,000 fetuses, some studied postmortem and others by ultrasound. The biometric measures of principal value in developing a three-dimensional model of the fetal anatomy for dosimetric computations included the postmortem measures of body and brain masses, crown-to-rump length, crownto-heel length, foot length, and head circumference; and ultrasound measures of the femur length, abdominal transverse diameter, biparietal diameter, and fronto-occipital diameter. (69) Guihard-Costa and Larroche (1995) reported the postmortem measurements of body mass for 496 fetuses that were judged to be of normal development. The fetal ages ranged from 10 to 42 weeks gestation, measured from the last normal menstrual period. For modelling purposes the data were fitted to a modified logistic function of fetal age relative to estimated time of fertilisation. Ages of gestation were converted to fetal ages by subtracting 2 weeks. (In assembling organ mass data some authors report menstrual ages that were converted here to fetal ages in the above manner.) Fetal body mass as a function of age is shown in Fig. 2.9. Values for masses of selected fetal tissues at various ages considered in the anatomical modelling are tabulated in Table 2.3.
Fig. 2.9. Fetal body mass as a function of age. The Figure is based on the compilation of biometric data published by Guihard-Costa and Larroche (1995). For ages t less than 16 weeks, the curve is given by m(t)=4.7434+2.0145 (t-8)+2.9696 (t-8)2 and at all other ages as m(t)=127 e0.08764t/[1+80.553 e0.25189t]. 43
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(70) Organ masses reported in the literature are derived from autopsy data. Recent advances in ultrasound make it possible, however, to derive organ volumes from ultrasound images. The data reported in the literature are typically expressed relative to body mass rather than by fetal age. (71) Guihard-Costa and Larroche (1995) measured the mass of the brain in 291 samples weighed prior to fixation and 432 samples that were fixed for 4 to 10 weeks. The masses of the brain given in Table 2.3 were based on these data. (72) Fetal thyroid masses have been reported by Costa (1986), Aboul-Khair et al. (1966), Evans et al. (1967), and Ares et al. (1995). These data were fitted to a power function as shown in Fig. 2.10. The fitting procedure required that the value at birth corresponded to the mass of the thyroid in the newborn (1.3 g). The masses of the thyroid in Table 2.3 were derived from the functional fit shown in Fig. 2.10. (73) The masses of fetal organs, other than the brain and thyroid, were obtained from autopsies and have been reported in the literature by Jackson (1909), Widdowson and Dickerson (1964), Hudson (1965), Trotter and Peterson (1968), Potter and Craig (1975), Burdi et al. (1981), and Shepard et al. (1988). Luecke et al. (1995) analysed the data using an allometric relationship with total body mass. The allometric parameters of Luecke et al. (1995) were adjusted such that the organ and tissue masses at birth corresponded to the values in the newborn. The organ masses for the adrenals, bone, red marrow, heart, kidneys, liver, lungs, pancreas, spleen, and thymus that are tabulated in Table 2.3 were derived in this manner. The masses for all other organs
Fig. 2.10. Fetal thyroid mass as a function of age. Data are from: (*) Aboul-Khair et al (1996); (*) Evans et al (1967); (&) Ares et al (1995); and (&) Costa (1986). The curve that expresses the thyroid mass m as a function of age t is m(t) = 0.0204 t3.0389. 44
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mT (excluding brain and thyroid) in Table 2.3 at times, t, were derived by scaling their mass in the newborn as a power function of body mass; that is as mT ðtÞ ¼ ½
mT newborn m0:9714 ðtÞ TB m0:9714 TB
ð2:1Þ
where mTB(t) is the mass of the total body of the fetus at the age, t, of interest and the value of the exponential corresponds to the average value of Luecke et al. (1995). (74) The biometric data of Guihard-Costa and Larroche (1995) and the organ mass data discussed above were used by Ulanovsky and Eckerman (1998) and Eckerman et al. (to be published) to formulate a series of anatomical models, corresponding to the various ages given in Table 2.3, for the developing fetus. 2.5. Newborn child (75) The newborn child at birth weighs about 3.5 kg. The transition from an intrauterine to extrauterine existence requires substantial changes, especially in the cardiovascular and respiratory systems. The body as a whole grows particularly rapidly during infancy and the birth weight is usually trebled in about the first year of life. The mass of the newborn child and of its organs and tissues used in the calculation of dose coefficients are given in Table 2.3. 2.6. References for Development of embryo/fetus Aboul-Khair, S.A., Buchanan, T.J., Crooks, J., et al. (1966) Structural and functional development of the human foetal thyroid. Clin. Sci. 31, 415–424. Anderson, J.W., Leissring, J.J. (1961) The transfer of serum proteins from mother to young in the guinea pig II. Histochemistry of tissues involved in prenatal transfer. Amer. J. Anat. 109, 157–174. Ares, S., Pastor, I., Quero, J., Morreale de Escobar, G. (1995) Thyroid gland volume as measured by ultrasonography in preterm infants. Acta Paediatr. 84, 58–62. Boyd, J.D., Hamilton, J.W. (1970) The Human Placenta. Cambridge Ltd, W. Heffer and Sons. Browder, L.W., Erickson, C.A., Jeffery, W.R. (1991) Developmental Biology. Saunder Co, Philadelphia. Burdi, A.R., Barr, M., Babler, W.J. (1981) Organ weight patterns in human fetal development. Hum. Biol. 53, 355–366. Carlson, B.M. (1994) Human Embryology and Developmental Biology. Mosby. St, Louis. Costa, A. (1986) Development of thyroid function between VI–IX months of fetal life in humans. J. Endo. Invest. 9, 273–280. Davignon, R.W., Parker, R.M., Hendrickx, A.G. (1980) Staging of the early embryonic brain in the baboon (Papio cynocephalus) and rhesus monkey (Macaca mulatta). Anat. Embryol. 159, 317–334. Dobbing, J., Sand, J. (1970) Growth and development of the brain and spinal cord of the guinea pig. Brain Res. 17, 115–127. Eckerman, K.F., Ulanovsky, A.V., Kerr, G.D. Electron and Photon Absorbed Fractions in the Developing Fetus. ORNL/TM Report (to be published). Enders, A.C., Lantz, K.C., Peterson, P.E., et al. (1997) From blastocyst to placenta: the morphology of implantation in the baboon. Hum. Reprod. Update 3, 561–573. Evans, H.E., Sack, W.O. (1973) Prenatal development of domestic and laboratory mammals: growth curves, external features and selected references. Anat. Histol. Embryol. 2, 11–21. Evans, T.C., Kretzschmar, R.M., Hodges, R.E., et al. (1967) Radioiodine uptake studies of the human fetal thyroid. J. Nucl. Med. 8, 157–165. 45
ICRP Publication 88 Guihard-Costa, A.M., Larroche, J.C. (1995) Fetal biometry: Growth charts for practical use in fetopathology and antenatal ultrasonography. Fetal Diagn. Ther. 10, 215–278. Hagerman, D.D., Villee, C.A. (1960) Transport functions of the placenta. Physiology Reviews 40, 313– 330. Ham, A.W., Cormack, D.H. (1979) Histology, 8th Edition. J.B. Lippincott Company, Philadelphia. p. 977. Harman, M.T., Saffry, O.B. (1934) The skeletal development of the anterior limb of the guinea-pig, cavia cobaya cuva, from the 25-day embryo to the 161-day postnatal guinea-pig. Amer. J. Anat. 54, 315–327. Hearn, J.P., Hendrickx, A.G., Webley, G.E., et al. (1994) Normal and abnormal embryo-fetal development in mammals. In: Lamming, E.E. (Ed.), Marshall’s Physiology of Reproduction, Vol. III. Part I. Chapman and Hall, London, pp. 535–676. Hendrickx, A.G., Houston, M.C. (1971) Comparative reproduction of non-human primates. In: Hafez, E.S.E. (Ed.), Prenatal and Postnatal Development. Springfield: Charles C, Thomas, pp. 334–381. Hendrickx, A.G., Houston, M.C., Kraemer, D.C., et al. (1970) Embryology of the Baboon. University of Chicago Press, Chicago. Hendrickx, A.G., Peterson, P.E. (1997) Perspectives on the use of the baboon in embryology and teratology research. Hum. Reprod. Update 3, 575–592. Hinrichsen, K.V. (1990) Human-Embryologie. Springer-Verlag, Berlin. Hudson, G. (1965) Organ size of human foetal bone marrow. Nature 205, 96–97. ICRP (1986) Developmental effects of irradiation on the brain of the embryo and fetus. ICRP Publication 49. Annals of the ICRP 16 (4). ICRP (1996) Radiological protection and safety in medicine. ICRP Publication 73. Annals of the ICRP 26 (2). Jackson, C.M. (1909) On the prenatal growth of the human body and relative growth of various organs and parts. Amer. J. Anat. 9, 119–165. Kelemen, E., Calvo, W., Fliedner, T.M. (1979) Atlas of Human Haemopoietic Development. SpringerVerlag, Berlin. Konermann, G. (1987) Postimplantation defects in development following ionizing irradiation. Adv. Radiat. Biol. 13, 91–167. Luecke, R.H., Wolsilait, W.D., Young, J.F. (1995) Mathematical representation of organ growth in the human embryo/fetus. J. BioMed. Computing 39, 337–341. Metcalf, D., Moore, M.A.S. (1971) Haemopoietic Cells. Embryonic Aspects of Haemopoiesis. American Elsevier, New York, pp. 172–267. Moore, K.L., Persaud, T.V.N. (1998) The Developing Human, 6th ed. W. B. Saunders Company, London. Muirhead, C.R., Cox, R., Stather, J.W., et al. (1993) Estimates of late radiation risks to the UK population. Docs. NRPB 4 (4), 15–157. Nishimura, H., Shiota, K. (1977) Summary of comparative embryology and teratology. In: Wilson, J.G., Fraser, F.C. (Eds.), Handbook of Teratology. Vol. 3. Comparative and Maternal and Epidemiologic aspects. Plenum Press, New York, pp. 119–154. O’Rahilly, R., Mu¨ller, F. (1992) Human Embryology and Teratology. Wiley-Liss, New York. Potter, E.L., Craig, J.M. (1975) Rate of antenatal growth. In: Pathology of the Fetus and Infant. Year Book Medical Publishers, Chicago, pp. 15–25. Santoloya-Forgas, J., Vengalil, S., Meyer, W., et al. (1997) Transvaginal ultrasonographic (TVS) evaluation of baboon gestation from 37–62 days postconception. Amer. J. Primatol 43, 323–328. Scott, M.R. (1937) The embryology of the guinea-pig. A table of normal development. Amer. J. Anat 60, 397–432. Shepard, T.H., Shi, M., Fellingham, G.W., et al. (1988) Organ weight standards for human fetuses. Pediatr. Pathol 8, 513–524. Steven, D.H. (1975) Comparative Placentation—Essays in Structure and Function. Academic Press, London. Strong, R.M. (1926) The order, time and rate of ossification of the albino rat skeleton. Amer. J. Anat. 36, 313–335. 46
ICRP Publication 88 Takeuchi, H., Koyanagi, T., Yoshizato, T., et al. (1994) Fetal urine production at different gestational ages: correlation to various compromised fetuses in utero. Early Hum. Develop. 40, 1–11. Trotter, M., Peterson, R.R. (1968) Weight of bone in the fetus—A preliminary report. Growth 32, 83–90. Ulanovsky, A.V., Eckerman, K.F. (1998) Absorbed fractions for electron and photon emissions in the developing thyroid: fetus to five year old. Radiat. Prot. Dosim. 79 (1–4), 419–424. UNSCEAR (1977) United Nations Scientific Committee on the Effects of Atomic Radiation. 1977 Report to the General Assembly, with annexes. Sources and Effects of Ionizing Radiation. United Nations, New York. UNSCEAR (1986) United Nations Scientific Committee on the Effects of Atomic Radiation. 1986 Report to the General Assembly, with annexes. Genetic and Somatic Effects of Ionizing Radiation. United Nations, New York. UNSCEAR (1993) United Nations Scientific Committee on the Effects of Atomic Radiation. 1993 Report to the General Assembly, with annexes. Sources and Effects of Ionizing Radiations. United Nations, New York. Wegst, A.V. (1987) Physiology of transfer. In: Gerber, G.B. (Ed.), Me´tivier, H., Smith, H. (Eds): Agerelated Factors in Radionuclide Metabolism and Dosimetry. Martinus Nihjhoff for the Commission of the European Communities. Dordrecht, EUR 10556, pp. 293–301. Wegst, A.V., Davis, J.M. (1992) Anatomy and physiology of the embryo, fetus and placenta. In: Agedependent Factors in the Biokinetics and Dosimetry of Radionuclides. Radiat. Prot. Dosim. 41 (2–4), 103–110. Widdowson, E.M., Dickerson, J.W.T. (1964) Growth and composition of the fetus and newborn. In: Mineral Metabolism, Part 2A. Academic Press. New York. Wislocki, G.B., Dean, H.B., Dempsey, E.W. (1946) Histochemistry of the rodents placenta. Amer. J. Anat 78, 281–346.
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