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Children and the unborn child

2. Biological susceptibility

2.1 Susceptible periods in human development

The nature and magnitude of chemically induced damage does not depend only on the substance and dose in question, but also on the condition of the tissue with which the substance comes into contact. A given substance administered at equal dose rates but at different time points in the gestational and postnatal periods may produce essentially different types of abnormalities or functional deficits while different substances administered at the same point in time can produce identical damages. Disturbances in the normal biological cycle can lead to the early loss of the conceptus and embryo-foetal damage (i.e. malformation and functional defects).

In utero and postnatal developmental susceptibility to xenobiotics may depend on a number of determinants, including

	the genotype of the individual.
	the developmental stage at exposure.
	the mechanism of action of the substance.
	the kinetics of the xenobiotics in the mother, the conceptus and the child.
	the dose-effect and dose-response relationships.

(Dencker & Eriksson 1998, Harris 1997, National Research Council 1993).

2.1.1 Human developmental stages

Knowledge on the normal reproductive cycle and developmental stages is important for understanding developmental toxic effects of chemical substances and their underlying modes of action. The terminology used for the various human developmental stages is given in Table 2.1. Milestones in early organ development are given in Table 2.2 and the periods of susceptibility for persistent malformations are given in Figure 2.1 (see Annex 1).

Germ cell formation and maturation

Germ cell formation and maturation in men and women occur at quite different stages in the life cycle. In both sexes, the primordial germ cells appear at an early stage in the embryo-foetal development. However, in the female foetus, the germ cells divide during foetal growth and thus, females are born with their total number of oocytes. No new ova are formed after birth. But the oocytes are not fully developed at term. In the fourth month of gestation, the primary oocyte is arrested in the first meiotic division and the second meiotic division is not taken place until the time of ovulation during the adult females reproductive life. In contrast, the male germ cell formation and subsequent maturation does not start until around puberty and continuous throughout life.

As cells are particularly sensitive to exogenous agents when dividing, this difference between men and women may indicate that the highest risk of causing mutations in germ cells occur in the fertile period for both sexes, but in addition, the female foetus may be at increased risk around the fourth month of gestation.
(Barbera 1997, LST 1989, Johnson et al. 1997).

Table 2.1
Stages in human development (from Larsen & Pascal 1998)

Preimplantation stage conception

At conception, the ovum is fertilised and during the next four days, the conceptus is conveyed through the oviducts to the uterine cavity. The movement of the conceptus may be affected by anatomical defects in the oviduct (malformation, formation of cicatricial tissue) and by disturbances in the woman's autonomic nervous system or hormone metabolism, particularly of sex hormones.

blastogenesis

During the transportation, the conceptus develops by cleavage to a blastocyst, a fluid filled vesicle. Around day 6 implantation of the blastocyst takes place. At first the blastocyst is fully dependent on the supply of nutrients via passive diffusion from surrounding secretions. It has been demonstrated that foreign substances can accumulate in the secretions within the blastocyst.
During the preimplantation period, the conceptus is in general considered refractory to exogenous insults in terms of induction of classical malformations, but exposure to certain agents may have the potential for inducing embryonic death and/or latent developmental defects (e.g. DDT, nicotine). A reasonable explanation for this is that a massive insult during this developmental stage will kill the conceptus, while, on the other hand, if only a few cells are damaged they will be replaced by other cells as the cells of the embryoblast still maintain a high degree of pluripotency (the potential to differentiate into various kinds of cells).
Although seldom in this developmental period, it has been possible to induce malformations by exposure of experimental animals to chemical substances (e.g. ethylene oxide, methylnitrosourea).
(Dencker & Eriksson 1998, LST 1989, Rogers & Kavlock 1996).

During the second and third week, gastrulation (formation of the three germ layers) and beginning of placental formation takes place. In mice, exposure to ethanol during gastrulation may lead to ocular, facial and neural malformations, which in many ways are similar to the foetal alcohol syndrome seen in human infants.

organogenesis

In humans, the organogenesis (used here with the same meaning as embryogenesis) occurs between approximately day 18 and 58 of gestation, ranging from the appearance of the neural plate to the closure of the palate shelves (Table 2.2). The period of organogenesis is considered to be the developmental phase most sensitive to exogenous induced classical malformations in single organs and/or syndromes of malformations. Within organogenesis, there are periods of maximal susceptibility for each forming structure (see Figure 2.1 in Annex 1). During this short period, the embryo undergoes rapid and dramatic changes and therefore, the nature of the embryo/ foetus as a target for toxicity is also changing. At week 3 of gestation, the human conceptus is in most ways indistinguishable from other vertebrate embryos. By weeks 8, the embryo is unmistakable human although the organs are not yet completely functional. The rapid changes of organogenesis require extensive cell proliferation, cell migration, cell to cell and cell to matrix interactions, and morphogenetic tissue remodelling. Differentiating cells in various organ precursors now start to develop susceptibility, for example, to xenobiotics affecting specific receptors. Loss of cells, whose function by now is often completely determined, can no longer be replaced by the surrounding cells and disturbances will result in permanent damage. Known human chemical teratogens, which are active mostly in this period, are e.g. cytostatics, thalidomide, and diethylstilbestrol.
(Dencker & Eriksson 1998, LST 1989, Harris 1997, Rogers & Kavlock 1996).

Foetal stage

Foetogenesis, the period from 9^th week of pregnancy and onwards, is characterised by tissue differentiation, growth and physiological maturation (histogenesis). Exposure to xenobiotics in this period (e.g. tetracycline, aspirin, warfarine, ethanol, lead, and methylmercury) is most likely to result in effects on growth and functional maturation and not considered resulting in major morphological malformations. The formation of the organs is not complete, but almost all the organs are present and grossly recognisable.
The further development proceeds during the foetal period to attain the requisite functionality before birth, including fine structural morphogenesis (e.g. outgrowth of renal tubules) as well as biochemical maturation (e.g. induction of tissue specific enzymes). Receptors and other molecular targets for substances affecting future functions are continuously developing, so that the foetus may be even more sensitive than the embryo to some pharmacological effects. Functional abnormalities of the central nervous system (CNS) and reproductive organs, including behavioural, mental and motor deficits and decreases in fertility are among the possible adverse outcomes. These manifestations are not necessarily apparent at birth. Until the 24^th-26^th week of pregnancy, the organ functions are not sufficiently developed to enable the foetus to survive outside the uterus and even at this time, the histogenesis is not yet complete in all organs. In the 36^th week of pregnancy, organ differentiation is more or less complete and the foetus is described as being fully developed. Birth normally occurs around the 40^th week of pregnancy.
(Dencker & Eriksson 1998, LST 1989, Harris 1997, Rogers & Kavlock 1996).

The Programming Hypothesis

A number of findings reported over the last decade suggest that expoure to environmental factors in early life can increase the risk of disease later in life. For example, low birth weight, thinness and short body length at birth has been associated with increased rates of cardiovascular disease and non-insulin dependent diabetes in adult life. To explain such findings, the concept of physiologic programming or imprinting in early life has emerged. Interference with such genetic programming has been demonstrated in a variety of test systems and reflects the action of a factor during a sensitive period or window of development to exert organisational effects that persist throughout life. Programming agents may include growth factors, hormones, and nutrients. These factors may produce adaptations that permanently alter adult metabolism and responses in a direction optimising survival under continued conditions of malnutrition, stress, or other deprivation, but such responses might be detrimental during later life.(Barker 2000, Seckl 1998, Johansson 1996).

Placental development and function

The placenta is the interface between the mother and conceptus. The unborn child receives all its nutrition via the placenta and also xenobiotics may enter the circulation of the conceptus through placental transfer after maternal exposure. Placental development begins immediately after implantation of the blastocyst and by the 4^th week a circulation is established on both the maternal and the embryonic side of the placenta. The maternal physiology as well as the properties of the xenobiotics influence the placental transfer. The rate of transfer is affected by e.g. placental structure, placental blood flow, pH differences between the maternal and foetal blood circulation as well as the molecular size, the lipid solubility, the ionising state, and the protein binding property of the compound per se. Rodent studies have shown that during pregnancy, the pH of maternal plasma remains fairly constant, but the pH of the embryo/foetal compartment changes from slightly alkaline (relative to the maternal plasma) during early organogenesis to a more acidic environment during late organogenesis and foetal development. Therefore, placental transfer and potential accumulation of weakly acidic substances is favoured during the embryogenesis, while weakly alkaline substances are more likely to be transferred during late gestation.
The placenta is extremely permeable to chemical substances and it is now believed that almost all xenobiotics enter the foetal circulation. Chemical substances, which pass maternal membranes, are likely also to pass the placental barrier. Therefore, in general the foetus is not protected against xenobiotics that circulate in the maternal blood.
(Clarke 1997, LST 1989, Hakkola et al. 1998).

Postnatal period

This period appears to be vulnerable with respect to the physiological development of the nervous, immune, and endocrine/reproductive system as these systems continue to develop until adolescence. This heightens concern that toxicity during the postnatal developmental periods may have consequences throughout adult life. Particular attention has been paid to delayed functional postnatal toxicity. This effect has been observed for several neurotoxic pesticides in adult animals as a result of exposure to subtoxic doses during a developmental period of high susceptibility, but there is also concern for delayed effects on the reproductive and immune systems.

nervous system

Especially the CNS should be considered a major target organ as its development is very complex and the developmental period is longer than for other organs (see Figure 2.1 - in Annex 1). Exposure to toxic agents (e.g. lead, DDT, organophosphate pesticides, PCBs) during the peri/postnatal developmental period may induce persistent functional/ behavioural effects that become manifest shortly after birth or later in life. However, experimental and clinical data have revealed that the consequences of age-related exposure to xenobiotics are difficult to predict. Thus, for DDT, it has been reported that new-born and pre-weaning rats are less susceptible than adults with respect to acute toxic effect. Concerning chronic effects (neurotoxicity), damage can be induced in the foetus at levels not causing effects in the mother. Exposure to toxic agents during the perinatal/neonatal period can also potentiate and/or modulate the reaction to adult exposure to xenobiotics. Studies in mice indicate that differences in adult susceptibility to neurotoxic substances are not necessarily an inherited condition, but may be acquired by exposure to environmental chemical substances during perinatal life when the maturational processes of the developing brain and central nervous system are at a stage of critical vulnerability.

Stages in the development of the nervous system include proliferation, differentiation, migration, synaptogenesis and axonal growth, and myelination. The major organ structures are formed as a result of cell proliferation during early organogenesis followed by cell migration in which the neurones travel to their final destination. However, cell migration is not completed until several months after birth and the cellular differentiation, which is characterised by formation of connections and myelination, is partly postnatal and lasts to the third or fourth year of life. The locations and numbers of cell receptors are very different in the immature and the adult individual.

Brain growth in children occurs rapidly during the first two years of life and at the age of two, about three-fourth of the total number of cells in the brain is present. However, in humans the full number of neurones is already obtained at the perinatal stage and the brain growth after birth is due to myelination of white matter, maturation of axonal and dendritic outgrowth, and multiplication of glial cells. The subsequent growth after the age of two years continues more slowly.

The brain size in infants and children is proportionally larger compared with adults. In a new-born child, the brain weighs about one-third of the adult brain. Compared to this, the new-born body weight only constitutes 4% of the adult weight. The cerebral blood flow per mass unit of brain weight is about 25% higher in a 10-year old child compared to a 65-year old adult. Thus, children have a higher relatively brain mass as well as a higher cerebral blood flow than adults.
The blood-brain barrier is gradually developed during gestation and is not complete until around 6 months after birth, and therefore the developing CNS is much more sensitive to toxic injury than the adult CNS. The higher relative cerebral blood flow and immaturity of the blood-brain barrier, combined with increased unbound free fraction of xenobiotics in the infant blood (see toxicokinetics), may result in an increased exposure of the infant CNS to potential toxic agents. Further, the high lipid content in the CNS and its relatively greater mass in children may influence the distribution and storage of xenobiotics in infants. In contrast to humans, where the brain growth spurt begins during the third trimester of pregnancy and continues throughout the first two years of life, the period in rats and mice is neonatal, spanning the first three to four weeks of life. This knowledge is relevant in relation to testing of chemical substances.

immune system

There are structural and functional differences between the immune system of children and adults. The rapid maturation of the immune system that occurs during the peri- and postnatal periods is, in part, driven by unintended (food, infections, and other environmental agents) and intended (vaccination) exposure to antigens during development. Only little is known about how the developing system might be affected by xenobiotics. However, the rapid changes that occur during perinatal development indicates that exposure to chemical substances potentially can perturb the immune system in a variety of ways and at various points in the maturation process. It has been shown that impairment of the differentiation of thymocytes into immunocompetent T-cells can be induced by chemical damage to the thymic epithelial cells (e.g. 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD)). The effect seems most profound and persistent when the exposure takes place in the pre- and/or neonatal period.

The absolute size of the lymphatic organs decreases during the adolescent period. In spite of this decrease, the immune functions increase in capacity to respond as body growth progresses.

Data have shown that development of allergy from oral sensitisation apparently occurs mainly during the first years of life. The special sensitivity of infants may be related to increased intestinal uptake of allergens, and the immaturity of local and systemic immunological response. Sensitisation to food proteins may occur prenatally or postnatally. However, intrauterine sensitisation is believed to be a rare event.

Contact allergy to chemical substances may occur both in children and adults. There is probably no difference in the ability of children being sensitised compared to adults. It is generally acknowledged that sensitivity to contact allergens increases with age and environmental exposure.

reproductive system

As sex hormones cause numerous effects on a variety of tissues of males and females, including the gonads, bones, skin, hair follicles, and skeletal muscles, substances that interfere with hormonal systems may influence the development of an organism.
In the age of 10-11 years, the human female enter the pubertal period. In the puberty, the breasts enlarge and develop, primarily in response to the increase in oestradiol and progesterone levels, but the process are also influenced by glucocorticosteroids and thyroid and growth hormones. The menarche usually occurs about age 13. During puberty, a large increase in total body fat is seen.
In the male, the onset of puberty is about age of 12-13 years and the first outward physical signs are penile growth and an increase in testicular size due to increase in the diameter of the seminiferous tubules as spermatogenesis is initiated. These changes are primarily caused by an increased testosterone level. Other events related to the increased hormone production are e.g. stimulation of cell division in the epiphyseal cartilage of the long bones (leading to growth spurt), facial hair growth, deepening of the voice and increase in muscle mass.

It has been shown that a number of the chemical substances present in the environment may exert oestrogenic, anti-androgenic, or related activities on reproduction in laboratory animals (e.g. alkylphenols, DDEs, PCBs, dioxins). Similar effects on humans cannot be excluded, although there is as yet no evidence to prove a causal link between environmental endocrine modulators and humans reproductive health.
Normal masculine differentiation occurs under the influence of the SRY-gene and several other autosomal genes and androgens are required for this process. Disorders of gonadal development are frequently associated with testicular germ cell neoplasia. Oestrogens act through a specific nuclear receptor. Normal masculine differentiation occurs even in the absence of a functioning oestrogen receptor, but the individual with this receptor defect will develop poor semen quality. Oestrogen receptor deficient male mice were subfertile and few were able to sire a litter. Oestrogens are involved in the feedback regulation of gonadotropin secretion and suppression of FSH secretion during the proliferation period may result in small testes and low sperm production capacity in adult life.
During the perinatal period, the rodent Sertoli cells of the testis have been shown sensitive to thyroid hormones. Low plasma levels of thyroid hormones extend Sertoli cell proliferation and delay the differentiation, which results in an increased number of these cells in the adult testis. Several xenobiotics (e.g. PCBs) have the ability to cause disturbances in the thyroid hormone homeostasis.

references, postnatal period

(Barbera 1997, Barker 2000, Bruckner & Weil 1999, Dencker & Eriksson 1998, LST 1989, Graeter & Mortensen 1996, ILSI 1996, WHO 1989, Johansson et al. 1996, Johnson et al. 1997, MST 1995, National Research Council 1993, Olin 1998, Renwick 1998, Roul et al. 1999, Schilter & Huggett 1998, Seckl 1998, Snodgrass 1992, Østergaard & Knudsen 1998).

Lactation period

In the sucking period, the human xenobiotic metabolising systems are still immature, but the new-born is no longer protected by the maternal metabolic system. Thus, the infant may be highly susceptible to xenobiotics in this period. However, to some extent the new-born is still protected as the breast milk has been subjected to the maternal metabolic system.
Most water-soluble substances are excreted into the milk by simple diffusion. Lipid soluble compounds are transported along with lipid molecules from plasma into the mammary gland. Several factors play a role in determining the quantity of a xenobiotic that may be transferred to breast milk. Compounds such as dioxins, DDT, PCBs, lead, mercury, and organochlorine pesticides are known to occur in breast milk. The amount of a certain substances transferred to the milk is dependent on:

	Physico-chemical factors of the substance: Degree of ionisation, molecular weight, lipophilicity, and protein binding capacity.
	Maternal factors: Dosage, frequency, and route of exposure to the compound.
	Infant conditions: Amount and frequency of feeding.

The blood plasma has a pH value about 7.5, whereas the value in milk is about 6.5. As the cellular membranes are primarily permeable for non-ionised molecules, the concentration in the milk will be higher than in the blood if the compound is slightly alkaline and lower if the compound is slightly acidic. A high protein binding capacity will lower the secretion into the milk as this results in smaller amount of free substance available for diffusion through mammary alveolar membranes.
Of concern for neonatal exposure are lipid soluble toxicants that had previously accumulated in maternal fat stores before and during pregnancy. As the body fat content returns to non-pregnant levels, the concentration of lipophilic toxicants in the rest of the body increases and this may cause enhanced potential for lactational transfer of harmful substances.
(Bennett 1997, Clarke 1997, Danmarks Apotekerforening 1976, Kacew 1992).

2.1.2 The reproductive cycle: Comparisons between human and common experimental animals

Most of the substances to which humans are being exposed are assessed on the basis of data from animal experiments. Therefore, it is important to focus on the differences which exist between humans and the experimental animals used. Factors, which affect the extrapolation from animals to humans include:

	differences in the placental barrier
	differences in the rate of growth of the embryo/foetus
	physiological and biochemical differences affecting the intake, metabolism, and elimination of the substance administered
	differences in sensitivity to chemical disturbances in cells, tissues, organs and organ systems
	differences in the factors underlying reproductive damage.

At birth, there are large similarities between the placenta of certain experimental animals and the human placenta. However, during pregnancy the placenta changes greatly. Therefore, in order to assess the degree of embryo-foetal damage, it is necessary to know the state of the placenta at that point in organogenesis when the damage occurs.The transport of nutrients and other compounds to the embryo or foetus will depend on the state of the placenta at any given time. During the early stages, the histotrophic supply via trophoblasts (embryonic cells which later develop into placenta) is the main form and supply consists of maternal macromolecules, which are biodegraded in the trophoblasts, secretions from the uterus, and exudate from the maternal blood. The subsequent haemotrophic supply consists mainly of the transfer across the placenta from the maternal blood to that of the embryo or foetus. This type of supply cannot take place until after the stage of organogenesis where vessels are formed and the heart begins to circulate blood. The haemotrophic nutrition becomes the principal way around day 30 in humans and around day 9-10 in mice and rats.
Experimental animals (mice and rats) have a yolk sac placenta, which plays a very significant role during organogenesis. This is not the case for humans and monkeys in whose the yolk sac placenta is of insignificant importance. Foreign compounds may lead to malformations in rats and mice due to accumulation in the yolk sac (e.g. Trypan blue). This is not possible in humans and monkeys.

Knowledge of the different stages in the organogenesis in the various experimental animals and humans is important for the assessment of animal experiments in relation to consequences for humans. Differences in early organ development in three species are outlined in Table 2.2.

Table 2.2
Differences in development in four species (in days).

# Functional/behavioural development continues for several years
¤ trim.: trimester
* a.b.: after birth

The large variations among the various animal species with respect to duration of histogenesis (the maturation phase, including cell proliferation, where the organ is finally structured) have to be taken into account when extrapolating from animals to humans. With respect to certain fields, the human child is more developed at birth than e.g. the rat. The CNS is the organ, which shows the greatest difference between animals and man. A major part of the development is prenatal in humans, but postnatal in the rat. Thus, with respect to CNS development, the new-born rat is comparable to the human foetus at the start of the third semester and the 6-10 days old rat is comparable to the neonatal infant. Consequently, the rat being experimentally exposed in utero and during the nursing period in toxicity studies is developmentally similar to the human development in utero.

(Dencker & Eriksson 1998, LST 1989, Ojeda & Urbanski 1994, Olin 1998, Rogers & Kavlock 1996).

2.1.3 Overall, susceptible periods

Embryo-foetal period

Chemical substances that pass maternal membranes are likely also to pass the placental barrier. As the placenta is extremely permeable to chemical substances, almost all xenobiotics enter the foetal circulation. Therefore, the foetus is generally not protected against xenobiotics that circulate in the maternal blood.
During the preimplantation period the conceptus is in general considered refractory to exogenous insults in terms of induction of classical malformations, but induction of embryonic death and/or latent developmental defects may occur. The chemically induced classical malformations and/or syndromes are mainly induced in early pregnancy during the period of organogenesis.
Exposure through the following foetal period (after 8 weeks of pregnancy) is not considered to result in major malformations, but susceptibility to substances affecting specific receptors and molecular targets still under development may lead to pronounced effects on a number of developmental processes. Informations concerning induction of such changes in humans in the foetal period are relatively scarce, but based on studies in experimental animals, it appears that this period may be even more sensitive than the embryonic stage to some growth and functional disturbances. However, in humans it may be difficult to interpret whether such damages are pre- or postnatal events.
A number of findings reported over the last decade suggest that exposure to environmental factors in early life can increase the risk of disease later in life. To explain such findings, the concept of physiologic programming or imprinting in early life has emerged. Interference with such genetic programming has been demonstrated in a variety of test systems and reflects the action of a factor during a sensitive period or window of development to exert organisational effects that persist throughout life.

Peri- and postnatal periods

The peri- and postnatal periods appear to be vulnerable periods, especially with respect to the physiological development of the central nervous system. There is human evidence that exposure to toxic agents (e.g. methyl mercury, TCDD) during the perinatal period of development may induce persistent functional/behavioural effects that become manifest shortly after birth or later in life although not morphologically apparent. After birth, the physiological development of the nervous, immune, and endocrine/reproductive systems continue to develop until adolescence. Therefore, the postnatal period should also be considered vulnerable. During the breastfeeding, the infant is exposed to chemical substances through human milk. As the functionalities of many organs are still immature, the new-born may be particular susceptible to xenobiotics.

2.2 Toxicokinetics and toxicodynamics in human development

Except for a few specific substances (primarily drugs), not very much is known about whether and why the response to a compound may differ between children and adults. Especially with respect to older children and adolescents there is a paucity of information. Differences in organ susceptibility are a function of toxicokinetic and toxicodynamic parameters, including genetic, physiological and metabolic factors, mechanism of action of the chemical, and dose-effect and dose-response relationships.

The toxicokinetic aspect covers absorption, distribution, metabolic biotransformation, and excretion of the substance in question.
The toxicodynamic aspect deals with parameters such as organ sensitivity and cytoprotective mechanisms, which determines the extent of any effect or response due to the presence of the substance at the site of toxicity.
The body’s handling of substances may vary with age, but in general it appears that effects of xenobiotics on organs or end-points may be similar in children and adults. Data from drug studies in humans have shown that toxic effects in children and adults are similar qualitatively, but may differ quantitatively.

Children do not generally seem to represent a special group from a toxicokinetic viewpoint, i.e the variability between children has a similar magnitude as the variability between adults (Renwick 1998).

In the context of this document, it is most convenient to present the two items together. The chapter is meant as a general introduction to the subject toxicokinetics/-dynamics. Therefore, case stories concerning chemical substances causing toxic effect are not given in details here, but where relevant, names of substances are briefly mentioned (in brackets). Further details can be found in section 5.

With respect to prenatal toxicology, the following toxicokinetic factors have to be taken into consideration when attempting to determine whether a chemical may reach and harm the conceptus:

	The kinetics in the mother (absorption, distribution, metabolism/ elimination, and excretion).
	Transfer from the mother to the embryo/foetus via the placenta.
	The kinetics in the embryo/foetus.

Toxicokinetic conditions in the mother may have a decisive effect on the concentration of a chemical substance that reaches the embryo or foetus. During pregnancy, many physiological changes occur in the maternal organ system as a consequence of, and in order to support, the rapid growth of the foetus and reproductive tissues. These changes may in different ways influence the intake, absorption, distribution, metabolism, and elimination of xenobiotics, and may involve the gastrointestinal tract, cardiovascular system, excretory system, and respiratory system.
The gastric emptying time increases and the intestinal motility decreases, which may result in longer retention of ingested xenobiotics in the upper intestinal tract and increased possibility for enhanced absorption of xenobiotics.
The albumin concentration in plasma decreases to about two thirds of the normal level. This may lead to a higher amount of free unbound xenobiotics in the blood, hence increase the possibility for transfer via the placenta. Besides, changes in the blood concentrations of e.g. lipids, free fatty acids, and hormones during pregnancy may influence the distribution of xenobiotics in the body. By the end of human pregnancy, the total body water content has increased by up to 30% and often fat deposits have been build up. These conditions may influence the distribution of xenobiotics between the mother and the conceptus.
The cardiac output and the peripheral blood flow increases by approximately 30% during the first trimester of gestation.
The net gas respiratory minute volume is raised by about 50% due to increased tidal volume, while the pulmonary ventilation rate is not changed. Thus, volatile and airborne chemicals tend to be absorbed more readily. But this may, on the other hand, also result in faster elimination of volatile compounds from the body.
Also the renal blood flow and glomerular filtration rate are increased, which may result in enhanced renal clearance of certain xenobiotics. In experimental animals, the liver's ability to metabolise foreign substances is altered during pregnancy. In the rat, a decrease in hepatic monooxygenase and glucuronidation activities have been observed and there seems to be an overall decrease in hepatic xenobiotic biotransformation during pregnancy. This decrease in activity is almost balanced by a 40% increase in liver weight during pregnancy. A similar change in liver size is not seen in humans.
Finally, there are signs of metabolic changes and increasing activity in certain endocrine organs.

After birth, age-dependent developmental changes in physiological parameters takes place, particularly with respect to hepatic and renal function, which are described in details below. The main differences between neonates and adults are summarised in Table 2.3.
In most tissues, the cell proliferation rate is higher during development and growth compared to the fully developed organism. During infancy and adolescence, children are growing and adding new tissue rapidly, but the various organs and tissues are maturing at different rates. For example, the CNS cell population (but not the myelination) is relatively complete at two years of age and the brain achieves 50% of its adult weight by 6 months of age. In contrast, with respect to the liver, kidneys and heart, 50% of the adult weight is not achieved until the age of about 9 years. For the skeletal system, this value is reached at about 11 years of age.
The different growth rates and biochemical pathways in the various tissues causes changes in the physiological conditions which will alter the disposition of xenobiotics over time. This may imply increased organ sensitivity in foetal, neonatal, and infant organs. On the other hand, it has been speculated that the higher proliferation rate during growth may enhance the rate of tissue repair and thus leading to a decrease in sensitivity. Anyhow, the quantitative and qualitative implications of the difference in cell proliferation rate on organ sensitivity are unclear.
Experiences gained from toxicological studies in laboratory animals support the suggestion that it is not possible to make any general statements about age-related differences in organ sensitivity. For some chemical substances, immature animals are more sensitive than adults while in other cases, they are less sensitive, depending on the compound and its effects (see perinatal, neonatal, and postnatal period).

Differences in cell proliferation rate between children and adults are not the only parameter that may lead to differences in susceptibility. Receptors and other molecular targets for various xenobiotics are continuously developing during the embryonic, foetal, and infant periods. This may cause age-dependent differences in the outcome of receptor-xenobiotic interactions and even result in opposite effects of chemical substances in infants and adults.

In relation to organ sensitivity, the literature is primarily directed towards cancer and effects on the immune, reproductive, and nervous systems (see perinatal, neonatal, and postnatal period).

From animal experiments it has been shown that transplacental exposure to chemical substances can cause tumour development in the offspring. With respect to humans, it has been shown that girls born from mothers exposed to diethylstilboestrol during pregnancy were at increased risk for developing vaginal cancer. Classical animal experiments have indicated an enhanced perinatal sensitivity for genotoxic, but not non-genotoxic carcinogens. For some genotoxic chemicals, dramatically increased sensitivity can be observed if the compound is administered to animals during a critical period within few days after birth (e.g. dimethylbenz[a]anthracene (DMBA)). It has been suggested that this critical period may be when the liver is actively expressing H-ras and there is rapid growth and cell proliferation.

(Clarke 1997, LST 1989, Graeter & Mortensen 1996, Larsen & Pascal 1998, National Research Council 1993, Renwick 1998, Østergaard & Knudsen 1998).

2.2.1 Absorption

Gastro-intestinal system

The gastro-intestinal tract is a major entry of xenobiotics to the body. A number of physiological changes occur in the gastrointestinal tract after birth, which could influence the absorption of xenobiotics (see Table 2.3). Thus, the relatively high gastric pH in new-born infants is one factor that may influence the absorption of xenobiotics. It has also been shown that intestinal absorption of various compounds is higher in neonate and young mammals compared with adults (e.g. lead). Decrease to the low-level uptake seen in adults occur about the time of weaning and has been associated with structural and functional maturation (reduction in pinocytotic activity) of the intestinal epithelial cells. Further, it has been suggested that development of a more selective intestinal absorption takes place with age and alterations of the diet.

Table 2.3
Examples of changes in physiological parameters.

The complexity of factors makes it difficult to predict the net effect of maturation on absorption of chemical substances. The maturation of the gastrointestinal tract occurs within about 6 months and by late infancy, most of the processes are comparable to that of the adult. Another important parameter for intestinal absorption is the biliary excretion, which depend on e.g. the enterohepatic circulation. Bile flow depends on the adequate synthesis, conjugation, secretion, and recirculation of bile acids. The two major bile acids have been found elevated in blood from one to four days old neonates. The levels then gradually declined over the next four to six months to adult values. The possible consequence of deficient bile excretion is inefficient intestinal fat digestion and inhibition of biliary excretion. Impaired fat digestion could be of toxicological importance when lipophilic chemicals are ingested.
(LST 1989, National Research Council 1993, Plunkett et al. 1992, Renwick 1998, Roberts 1992, Østergaard & Knudsen 1998).

Skin

The larger surface area to body weight ratio compared with adults may have considerable implications for the exposure to xenobiotics by skin absorption in children. The new-born has approximately a 2.5-fold greater ratio than adults and still in 13-year old children, the ratio is greater. This may have considerable implications for children whose skin is exposed to environmental chemical substances as xenobiotics often are lipid soluble and therefore easily absorbed via the skin.
The most important barrier to dermal absorption is the stratum corneum (the horny outer layer of the skin). Studies have shown that the structure of the stratum corneum is not different in infants and adults and the overall thickness remains relatively constant throughout postnatal development. However, until 3-5 days following birth, the epidermis is unkeratinised. This means a reduced barrier function in this period, which may be an important factor in relation to new-born´s dermal contact with xenobiotics (e.g. iodine, hexachlorophene, and aniline dye). After keratinisation has taken place, the percutaneous absorption appears to be comparable between infants and adults. Premature infants have been shown to exhibit an increased skin permeability for a period of more than 3-5 days.
(National Research Council 1993, Plunkett et al. 1992, Renwick 1998, Snodgrass 1992, Østergaard & Knudsen 1998).

Respiratory tract

The respiratory tract is the entrance for many chemicals (e.g. pesticides) and most xenobiotics are absorbed through the alveolar surface by simple passive diffusion.
The lung is in a period of growth and maturation during infancy and the various changes with age may be of consequence in relation to pulmonary uptake of xenobiotics. During the first years of life, there is a marked increase in the alveolar surface area. The new-born infant has approximately 10 million alveoli. By the age of 8 years, the number is 300 million, which is the adult number. The gas exchange area (alveolar surface) increases from approximately 3 m² at birth to 75 m² in adulthood and thus, the gas exchange area increases more than twenty-fold from infancy to adulthood. The full complement of mature cell is not realised in the lung until adolescence, as there is a progressive increase in the amount of elastic collagenous fibres in the alveolar wall until 18 years of age. The respiration rate decreases during adolescence from 40 breaths/minute in infants to 15 in adults whereas the tidal volume, on a body weight basis, is about the same for children and adults (10 ml/kg b.w./breath). Thus, the amount of inhaled air per unit of time, on a weight basis, in resting children is nearly three times that of the resting adult and thereby, children have a higher exposure to xenobiotics than adults. The approximately 20-fold smaller lung surface area and 3-fold higher respiratory minute volume/kg b.w. imply that children have a more than 60-fold higher respiratory minute ventilation rate (expressed as ml inhaled air/kg b.w./m² of lung surface area/minute) and thereby, a greater possibility for inhalation of xenobiotics than adults. These conditions could mean, at least with respect to local effect, that the vulnerability to xenobiotics by inhalation (e.g. oxygen, ozone) may be greater in children, particularly prematures, whose lungs are significantly less mature than the infant born at term. The lungs of a child might be able to tolerate the acute effects resulting from a toxic exposure, but subsequently develop chronic changes as a result of influence of the toxic event on lung maturation. However, it should be mentioned, that animal experiments have shown that for some xenobiotics (e.g. chlorphentermide), new-borns may be less sensitive.
A few studies concerning systemic absorption in experimental animals have indicated that lipid soluble compounds (procainamide, sulfosoxazole) were absorbed at similar rates by neonates and adults indicating that the properties of the alveolar epithelium do not change with age. However, lipid insoluble compounds (p-aminohippuric acid, tetraethylammonium bromide) were absorbed about twice as readily by 3-12 days old rats compared to adults. It is not known whether this difference can be extended to man.
(National Research Council 1993, Plunkett et al. 1992, Snodgrass 1992.)

2.2.2 Distribution

Plasma protein binding capacity is of importance for the distribution of foreign substances in the body. Xenobiotics often become bound to the albumin fraction and this may reduce the extent of tissue distribution in the body. The body composition of infants differs from that of adults (see Table 2.3) and this could influence the distribution of foreign substances.

The higher water content in infants means that the volume of distribution for hydrophilic xenobiotics may be twice as large in neonates compared with adults. In a 4-month old infant, the water content is at a level comparable with an adult. The amount of body fat is often lower in children compared with adults and this may in the same manner lead to differences in the distribution volume for hydrophobic compounds. Concerning prematures, their fat content is 1% of the body mass compared with 15% in a full term child. The relative body fat content begins to increase quite rapidly about 5-7 years of age. In females, this increase continues throughout adolescence and into adulthood. In males, there is usually a decrease in fat content during the mid to late adolescent years. Postpubertal females have approximately twice as much body fat as their male counterparts. There is a corresponding decrease in the female body water, expressed as percentage of body mass. The relatively high body fat in postpubertal girls may result in increased retention of lipid-soluble substances (e.g. DDT, PCBs and dioxins).

As mentioned above, the plasma protein binding capacity (primarily albumin) is of importance for distribution of xenobiotics. This is well known from the clinical pharmacology. Infants seem to have lower concentrations of mature albumin in the blood and therefore a decreased protein binding capacity. Adult values are seen about the age of 10-12 months. In addition, the content of free fatty acids in the blood is high in neonates and this may lead to a replacement of xenobiotics from albumin. The lowered capacity will increase the free fraction of xenobiotics in the blood and in this way affect the extent of distribution. A higher circular blood flow rate in children compared to adults may also influence the tissue distribution of xenobiotics. For some drugs, it has been shown that adult values are reached about one year of age.

(National Research Council 1993, Plunkett et al. 1992, Renwick 1998, Snodgrass 1992, Østergaard & Knudsen 1998).

2.2.3 Metabolism

The level of expression of xenobiotic metabolising enzymes shows a wide inter-individual variability depending on the age and tissue investigated. The most important parameter for the elimination of a wide range of xenobiotics is the activity and concentration of the key xenobiotic metabolising enzymes in the liver. 90-98 % of the xenobiotics are metabolised in this organ.

The liver undergoes various morphological and functional changes perinatally, including differentiation of hepatocytes and emergence of constitutive enzymes. The enzyme systems responsible for xenobiotic metabolism are usually grouped in phase I oxidative enzymes, consisting mainly of oxidative cytochrome P450 (CYP) enzymes, and phase II conjugating enzymes, such as uridine diphospho- (UPD)-glucuronosyltransferases, sulfotransferases, and glutathione S-transferases.
The phase I enzymes produce more polar products and may promote formation of reactive metabolites. The phase II enzymes catalyse reactions where the more polar metabolites are conjugated with water-soluble endogenous molecules which results in conjugates being more easily excreted. The toxicological consequences of exposure to chemical substances will depend on the balance between the phase I and II reactions.^
In humans, 14 CYP families have been described and the main site of expression of xenobiotic metabolising CYPs is the liver. The members of the CYP families 1 and 3 are considered to a great extent to metabolise xenobiotics, while the other families participate in the metabolism of endogenous substrates.
It should be mentioned that infants as well as adults show individual variability in xenobiotic metabolic capacity. This variability is to a large extent genetically determined, but environmental factors (e.g. exposure to chemical substances) can also play an important role in modifying the metabolic capacity of individuals

(Cresteil 1998, Hakkola et al. 1998, Renwick 1998, Østergaard & Knudsen 1998).

Embryo-foetal period

Animal models show that the metabolism of some, but not all, xenobiotics is mediated mainly by extraembryonic tissues and reflects the metabolic phenotype of the mother rather than that of the conceptus. The embryo/foetus of common experimental animals is relatively deficient in its capability to metabolise drugs and other foreign substances until near the time of birth or even in postnatal life.
In contrast, the existence of a xenobiotic metabolising system in the human foeto-placental unit has now been established. The individual enzymes responsible for the metabolism of foreign compounds in the human conceptus are, however, still poorly characterised. The liver of the human foetus possesses a relatively well developed metabolic capacity towards xenobiotics. The xenobiotic metabolising enzymes start their development in mid gestation and maybe as early as the first trimester of gestation. The isoforms CYP3A7, 3A4 and 4A1 are expressed in significant amounts in the foetal liver. Other isoforms have been detected (CYP 1A1 and 3A5), but only at very low levels. They are mostly active on endogenous substances, but especially CYP 3A4 and 3A7 metabolise many foreign compounds and may play a major role in the foetal metabolism of xenobiotics. The CYP 2E1 seems not to be active in the foetal liver.

The prenatal expression pattern is clearly different from that in the adult liver. The reactions are fewer in number and their levels are generally lower. The total amount of P450 per mg microsomal protein in the foetal liver constitute 20 to 70% of the level in the adult liver. The P450 isoforms develop independently and show different onset. Some CYP forms are expressed in higher amounts in the foetal than in the adult liver whereas other P450 isoenzymes are low at birth and increase with age. Concerning esterase activity in the foetal human liver, it has been shown that it constitutes one third of that in adults.
Among phase II enzymes, epoxide hydrolase (which converts epoxides into dihydrodiols) is active in the foetal liver and account for 50% of the adult activity. The glutathione S-transferase p is abundant in the foetal liver, but regresses after birth. The a and, especially, the µ forms of S-transferases are present at rather low levels in the foetal liver. UDP-glucuronyl-transferase activities towards exogenous molecules and bilirubin were found to be extremely low in the foetal liver.

In the human foetus, CYP protein has been found in the adrenals. The content may be higher than that of the foetal liver and thus the adrenals may be able to metabolise xenobiotics.
Further, several other embryonic and foetal tissues including lungs, kidneys and cardiac tissue exhibit low metabolic activity for xenobiotics, among which are many carcinogens and mutagens.

It has been shown that a xenobiotic metabolising system exists in the human placenta and substances that pass through the placenta may therefore be metabolised during transfer. However, the metabolic profile of the placenta is clearly more restricted compared to the maternal liver and the individual enzymes responsible for the metabolism of foreign compounds are still poorly characterised.
The total microsomal P450 content/mg protein in the human full-term placenta constitutes 10-30% of the level in the adult liver. Multiple enzyme systems have been suggested to participate in the placental biotransformation of xenobiotics and the CYPs constitute such a system. Most of the placental P450 consist of steroid metabolising CYP forms, especially CYP19 (aromatase). Xenobiotic metabolising CYPs represent only a minority of the total P450 and, apart from cigarette smoke-induced CYP1A1 activities, placental activity toward foreign compounds is low.
It has been shown that CYP1A1 metabolises and activates several compounds that are considered to be carcinogenic in humans. Besides the CYP activities, phase II conjugation capacity has been demonstrated in placenta. However, several of the enzymatic activities present in the maternal liver are absent or exist at very low levels in the placenta. It is suggested that individual genetic factors influence the enzymatic activity in placenta.

Although metabolic capacity has been discovered both in the foetus and placenta, the contribution of their metabolising enzymes to the total kinetics of drugs or xenobiotics administered to the mother is probably minimal. This is due to the relatively small size and low metabolic activity of the embryo/foetus and placenta compared with the mother. The maternal liver remains the major capacity of metabolism throughout pregnancy.
However, although the total capacity of the foetal liver to convert xenobiotics to both toxic and non-toxic metabolites is low, local toxic consequences, resulting from metabolism in the foetal compartment, may occur.

(Cresteil 1998, Hakkola et al. 1998, Renwick 1998).

Infant and child

The hepatic xenobiotic metabolism is still immature in humans at birth, especially in the pre-term neonate, but matures rapidly over the first months of life. Adult levels of most enzyme systems are achieved at 3-6 months of age. However, some investigations have shown that the total P450 content was about one-third of the adult value until one year of age. The isoforms CYP2D6 and 2E1 surge within hours after birth, but are probably not seen in the human foetal liver. CYP3A4 increases and 2C develops during the first weeks after birth and CYP1A2 is expressed after one month. Differences are observed in in vitro rate of postnatal maturation of different demethylation pathways indicating involvement of different isoenzymes. It has been shown that esterase activity was at the same level in 1-24 months old infants and adults.

Only few data are available in the literature regarding the ontogeny of Phase II enzymes in human tissues. The glutathione S-transferases a and µ are, as mentioned, present at rather low levels in the foetal liver, but the amount increases within three months after birth. UDP-glucuronyl-transferase activities towards exogenous molecules and bilirubin were extremely low in the foetal liver as well as in neonates aged less than 10 days. However, the majority of UDP-glucuronyl-transferase isoforms present in adult liver microsomes had developed within three months after birth.
Based upon rat studies, it has been suggested that conjugation of simple substrates is high at birth and then declines to adult levels, whereas the activity towards the more bulky substrates is low at birth and then increases. In agreement with this is the fact that neonates are more susceptible than older individuals to the bulky substance chloramphenicol due to diminished glucuronide conjugation. Glucuronic acid conjugation of many drugs reaches the adult values around 6 months of age. The evidence of impaired sulphate conjugation is less clear.

With respect to acetylation, studies have shown that infants have a limited capacity for acetylation of certain compounds and in some cases the adult phase II pattern is not reached until the age of two years.

Similar enzymatic changes take place in neonatal laboratory animals over the first 2-3 weeks of life prior to weaning. There seems to be a general pattern in phase I enzyme activity, in which there is an increase in activity postnatally that reaches a maximum level within the first weeks of life. In rats, the in vitro hepatic phase II activities increase 16-fold between birth and day 20. There seems to be differences in the expression of the various enzymes. Conjugation of simple substrates is high at birth and decreases to adult levels after 7 days. In contrast, the activity towards bulkier substrates is low at birth and increases after 20 days.

Metallothioneins are important in the binding and detoxification of toxic metals. There are low concentrations in most tissues in adult animals but levels can be increased by exposure to e.g. metals. The concentrations of metallothioneins in the liver increase dramatically in rats in the three days prior to birth and high levels are maintained for 7 days after birth following which there is a rapid decrease towards adult concentrations. A similar profile was found in neonatal mice and human liver samples.

Children have a higher basal level of metabolism than adults as the metabolic rate is inversely related to body size. The smaller body size, the greater surface to body mass ratio and the higher metabolic rate. A decrease of 66% in the surface area to body mass ratio is seen when an individual develops from infant to adult. The discrepancy in the ratio of surface area to body weight between children and adults is 2.3 at birth, decreasing to 1.8, 1.6, 1.5, and 1.3 at 0.5, 1, 5, and 10 years, respectively. The generally higher rates of metabolism will result in more rapid elimination of the parent compound and in greater or more rapid formation of metabolites. Further, the mass of the liver in relation to the whole body is larger in infants and children compared with adults. This will also contribute to the relatively higher metabolic activity observed in infants and children.
Expressing exposure as mg/kg b.w., which is traditionally used, may represent an extra safety margin because in scaling down from an adult to a child, the equivalent dose for an infant or child, based on surface area, will be higher than that based on body weight. A dose equivalent to 10 mg per adult would be 1.37 mg per one year-old infant based on body weight, but 2.32 based on surface area. Thus, the use of body surface area gives a better adjustment for parameters such as intermediary metabolism and basal metabolic rate.

The above indicates that in the neonate and young infant, the metabolic activity is low and therefore, the individual may be very sensitive to xenobiotics in this period. On the other hand, toxicity is quite often caused by the production of toxic intermediates. Since enzymes involved in their production (most notably the different P450 forms, but also conjugation enzymes) are not fully developed during the early infant period, compounds requiring biotransformation to become toxic may sometimes be less toxic to these individuals.

About 6 months of age, the adult levels of enzyme activity are almost obtained. Due to the higher basal metabolic rate in children, the metabolic activity may be even higher in children than in adults. However, whether this results in more, equal or even less sensitivity to xenobiotics in the older infant and child depends on the nature of the compound. It is difficult to generalise about age-dependent deficiencies in the metabolism of xenobiotics because the various enzyme systems mature at different time points. The age at which metabolism is similar to the adult value, may be different for each compound.

(National Research Council 1993, Plunkett et al. 1992, Renwick 1998, Snodgrass 1992, Wells & Winn 1997, Østergaard & Knudsen 1998).

2.2.4 Excretion

Xenobiotics are predominantly eliminated from the body by renal and biliary excretion. Volatile compounds may be exhaled via the respiratory system.

Renal excretion

Renal excretion is the principal pathway for elimination of substances and is dependent on glomerular filtration, tubular reabsorption, and tubular secretion. The renal functions are immature in humans at birth and for a variety of xenobiotics, the renal clearance is low in new-borns (e.g. certain antibiotics), especially in the pre-term neonate. However, rapid maturation takes place over the first three to six months of life, followed by a gradual increase in function up to 6 years of age. The ability to concentrate urine is low at birth, but reaches the adult level at about 16 months of age.

All glomeruli are developed at birth, but immature and not fully functional. Histological examination of the kidneys has shown that in the neonatal period, the glomerular basal membrane is rather thick and becomes thinner in the weeks after birth. The glomerular filtration in new-borns is approximately one-third of the adult value, but seems to mature within the first months after birth. The glomerular filtration rate increases about 4-fold during the first 72 hours after birth in full term infants and adult values are in general reached by 3-6 months of age.
The tubular reabsorption is probably developed already at birth, whereas the maturation of tubular secretion seems to take five to eight months. Creatinine clearance is reduced particularly in pre-term infants. The renal clearance of a radiolabelled marker revealed a rapid increase in renal function during the first 12 weeks after birth followed by a gradual increase up to 6 years of age. Renal blood flow (expressed per gram of kidney) increases within the first 5 months. The value is found to be constant between one and 16 years of age.
Besides the influence of the maturation processes, the amount of compound cleared by the kidney is influenced by the degree of protein binding and the renal blood flow.

Postnatal changes similar to humans take place in the neonatal rat during the first weeks of life, prior to weaning. Glomerular filtration rate in 10 days old rats is about one-half that of adults. Effective renal blood flow (per gram of kidney) and glomerular filtration rates are low in 4-week old rats, but approach adult values by 7 weeks of age.

The immature renal function seen in neonates leads to decreased elimination and prolonged serum half-lives for any compound that relies on renal excretion. About the age of 6 months, most of the renal functions have reached adult levels. At this time, the elimination of xenobiotics (at least drugs) may show a very varying pattern. The renal clearance may be higher as well as lower in infants compared with adults, depending on the compound.

Biliary excretion

During the first months of life, the new-born infant has a decreased ability to conjugate and eliminate substances in the bile. This may lead to accumulation of xenobiotics in the body and consequently toxic reaction (e.g. hexachlorophene).
Animal studies have in a similar way shown that new-born and young rats have a lower capacity to excrete certain compounds into the bile. Further, studies with non-metabolised as well as metabolised agents (e.g. via glucuronidation) have shown that both the parent compound and the metabolite is excreted more slowly in neonatal rats compared to adults.

Respiratory excretion

The respiratory minute ventilation, on a body weight basis, is about three times higher in children than adults. This may cause differences in the excretion rate of volatile substances between infants and adults.

(National Research Council 1993, Plunkett et al. 1992, Renwick 1998, Snodgrass 1992, Østergaard & Knudsen 1998).

2.2.5 Overall, toxicokinetics and toxicodynamics

Age-related differences in toxicokinetics/-dynamics occur in both experimental animals and humans, particularly in relation to hepatic xenobiotics metabolism and renal function. Except for a few specific substances, not very much is known about whether and why the response to a compound may differ between age-groups. In general, it appears that effects of xenobiotics on organs or end-points may be similar in children and adults e.g., liver necrosis observed in adults will also be observed in children.

As regards toxicodynamics, age-dependent differences are primarily related to the specific and unique effects that chemical substances may have on the development of the embryo, foetus and child in that the physiological development of the nervous, immune, and endocrine/ reproductive systems continue to develop until adolescence. Furthermore, receptors and other molecular targets for various xenobiotics are continuously developing during the embryonic, foetal and infant periods. This may cause age-dependent differences in the outcome of receptor-xenobiotic interactions and even result in opposite effects of xenobiotics in infants and adults.

During pregnancy, many physiological changes occur in the maternal organism as a consequence of, and in order to support, the rapid growth of the foetus and reproductive tissues. These changes may in different ways influence the intake, absorption, distribution, metabolism, and elimination of xenobiotics.

Metabolic capacity has been discovered both in the human foetus and placenta, but the contribution of their metabolising enzymes to the total pharmacokinetics of drugs or xenobiotics administered to the mother is probably minimal. The human foetus and the placenta possess metabolic capacity, but the contribution of these metabolising entities to the total kinetics is probably minimal.
In the early infancy, the organs are still rather immature and various maturation processes are taking place. The complexity of all these factors makes it difficult to predict the net effect on absorption, distribution, and elimination of chemical substances. However, the maturation of the gastrointestinal system, liver, and kidneys has generally taken place within 6-12 months after birth. By late infancy, most processes related to metabolic activity and excretion are probably comparable to that of the adults for most compounds. Because of the immature function of the organs, the neonates and young infants may have lower biotransformation and elimination capacities. This may render these individuals less able to detoxify and excrete xenobiotics and thereby more vulnerable to toxicants. On the other hand, if toxicity is caused by toxic intermediates produced via biotransformation, young infants may be less sensitive.
In the subsequent late infancy and childhood, metabolism and excretion of xenobiotics may be equal to or even higher than in adults due to the higher basal metabolic rate and relative liver size. It is difficult to generalise about age-dependent deficiencies in the metabolism of xenobiotics because the various enzyme systems mature at different time points. The age at which metabolism is similar to the adult value may be different for each compound.
Concerning the lungs, prematures may be more vulnerable to xenobiotics (at least with respect to local toxic effect) as their lungs are significantly less mature compared with the infant born at term.
With respect to dermal absorption, it should be stressed that although children do not show increased percutaneous absorption, the surface to body weight ratio is higher compared with adults until the age of > 10 years. This may lead to enhanced susceptibility.

2.3 References

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