APPENDIX II-AP: G. Wolterink, et al, Risk Assessment of Chemicals: What About the Children?
This appendix is copied from:
RIVM report 613340005/2002
Risk Assessment of Chemicals: What About the Children?
G. Wolterink, A.H. Piersma, J.G.M. van Engelen.
This investigation has been performed by order and for the account of the Ministry of
Health, Welfare and Sports within the framework of project 613340, .Advisering
With regard to risk assessment of chemicals, children are not little adults. Their pattern of
exposure (quantitatively and qualitatively), as well as both the toxicokinetics and the
toxicodynamics of a chemical will be different, and therefore it should be carefully examined
whether children are adequately protected against adverse effects of chemicals.
In this report a concise overview of the relevant data on the differences between adults and
children with respect to exposure, kinetics and dynamics of chemicals is presented, and the
adequacy of currently used toxicological tests for regulatory purposes is discussed. In
addition, in view of the potentially increased vulnerability of children a number of
recommendations for further development of risk assessment of chemicals is presented.
1 Introduction 8
2 Exposure 10
2.1 Dietary exposure 10
2.2 Other routes of exposure 10
2.3 Aggregate and cumulative exposure 11
3 Physiology 12
4 Toxicokinetics 13
4.1 Absorption 13
4.1.1 Oral absorption 13
4.1.2 Inhalatory absorption 13
4.1.3 Dermal absorption 13
4.2 Distribution 14
4.3 Elimination 14
4.3.1 Metabolism 14
4.3.2 Excretion 15
5 Toxicodyhamics 16
5.1 Development 16
5.1.1 Development of the respiratory tract 17
5.1.2 Developmental immunotoxicity 17
5.1.3 Developmental neurotoxicity 17
5.2 Endocrine disruption 19
5.3 Carcinogenicity 19
6 General conclusions 20
6.1 Exposure 20
6.2 Toxicokinetics and toxicodynamics 20
6.3 Adequacy of toxicological tests 20
6.4 Vulnerability of children: Is an additional assessment factor necessary? 21
6.5. Gaps in risk assessment and directions for further research 22
Appendix 1 Mailin list
In regulatory toxicology there is increased awareness and concern that children and adults
may differ in their susceptibility to xenobiotics. In this report a concise overview of the
relevant data on the differences between adults and children with respect to the kinetics,
dynamics and exposure to chemicals is presented and adequacy of currently used
toxicological tests for regulatory purposes is discussed. In view of the potentially increased
vulnerability of children a number of recommendations for further development of risk
assessment of chemicals are made.
There are three major areas in which children and adults differ: exposure to and
toxicokinetics and toxicodynamics of xenobiotics. Especially the situation in which children
are higher exposed than adults this needs full attention.
Children consume more food and drink more fluids per kg body weight than adults, and their
dietary pattern is different and less varied. Moreover, children have a relatively high
inhalatory rate (which may lead to a higher inhalatory exposure) and a high body surfacebody
weight ratio (which may result in a higher dermal exposure). Children may also be more
exposed to toxic substances than adults since children spend more time in the same room or
area, are in closer contact with a contaminated surface (e.g. by crawling) and display less
hygienic behaviour (mouthing of hands, objects, surfaces; pica behaviour). The route of
exposure may be of importance for the potentially toxic effects of a chemical. In most
toxicological studies for regulatory purposes the oral route of administration is used.
However, the expected route of exposure of a child should be taken into consideration in the
design of toxicological studies since the systemic exposure to a chemical may differ due to
different levels of absorption and the absence of a first pass effect following dermal and
inhalatory absorption. A further point of concern, for adults as well as children, is the
aggregate exposure to a specific chemical from different sources and the cumulative exposure
to different substances with the same mechanism of action (e.g. organophosphates and
The physiological differences between children and adults may affect the kinetics of a
substance in the body, which may render the child less or more susceptible to toxic effects of
a chemical. For instance, oral absorption of a substance may be affected by the different
gastric pH, gastric emptying rate, concentration of digestive enzymes and gut flora. The high
respiratory activity and higher body surface-body weight ratio may increase the relative
inhalatory and dermal absorption of substances. The high body water content, the low plasma
protein binding capacity and the permeability of the blood brain barrier may affect the
distribution of a chemical. The immaturity of the metabolic enzymes in the liver and the low
renal blood flow and glomerular filtration rate may affect the elimination of a xenobiotic.
With respect to toxicodynamics, i.e. the interaction between a chemical and the body (organs,
tissues) a major concern is the influence that a chemical may exert on the developing organs
and systems in young children. Disruption of proliferation, differentiation, migration and
maturation of cells may have severe and irreversible consequenses. In humans, the
development of certain organs or systems, e.g. the respiratory tract, the immune and
endocrine systems and the brain, continues long after birth. The presently used reproduction
toxicity tests and the newly introduced neurodevelopmental toxicity test mainly focus on
reproductive and neurotoxic effects and are not designed to detect, for instance, immunotoxic
effects, effects on lung development or general effects on histopathology or haematology. It
is recommended that it is ascertained that, in case of exposure through the milk of the dams,
significant quantities of test substance are excreted in the milk. Moreover, since the critical
windows in the development of laboratory animals and children are not necessarily the same,
the exposure period should be carefully examined.
Since there is a multitude of processes that may differ between children and adults, and the
net result of these differences is not clear, at present there is not sufficient information to give
a general quantitative statement with respect to differences in vulnerability. For instance, an
increased absorption of a substance in a child does not necessarily lead to an increased risk if
there is no formation of a toxic metabolite or if there is an increased elimination of the
substance. It should be noted that in risk assessment, the use of an intraspecies factor of 10
implies that the .most sensitive child. is about 10x more sensitive than the .average. human,
and thus that there is a 100-fold variation in susceptibility in the entire human population. In
addition, the use of the default assessment factor of 10 for interspecies extrapolation implies
that the average human is 10 times more sensitive than the most sensitive animal tested. In
general, if a full set of toxicological data is available, the presently used assessment factors
(10 x 10) are considered adequate in safeguarding the human population. However, the use of
an additional assessment factor in order to protect the sensitive groups in the human
population, among others children, should always be considered, on a case-by-case basis.
For future developments in risk assessment of chemicals with respect to children a number of
recommendations are made. For adults as well as children more insight into the specific
exposure scenarios is needed. It is proposed to design a decision tree which indicates whether
a toxicological data set and the knowledge on the specific exposure are adequate for risk
assessment for children. The suitability of young animal toxicity tests should be investigated.
A comparison of the dose-response data and the NOAELs of tests in adults and juveniles may
provide insight in the range of intraspecies variation with respect to age. Since for
pharmaceuticals human data are available it will be worthwhile to follow the developments in
the field of kinetics and dynamics of paediatric pharmaceuticals. By using distributions of the
physiological and kinetic parameters and PBPK modeling it can be assessed which group of
children is most at risk for a certain chemical.
In regulatory toxicology, recently attention has been focussed on the possible differences
between children and adults with respect to their susceptibility to xenobiotics. In order to
assess the adverse health effects of xenobiotics a variety of toxicological tests in animals has
been developed, among others reproduction toxicity tests. Whereas these tests are generally
accepted for hazard identification of prenatal effects, concern has been risen that the
toxicological tests presently used may not be adequate to detect some specific effects of
perinatal exposure to xenobiotics . It has been shown that there are differences in
toxicokinetics and toxicodynamics between the developing animal and the developing child.
In addition, the exposure pattern and exposure levels to xenobiotics may also differ between
children and adults. The question has arisen whether the present procedures for risk
assessment do adequately protect children against adverse effects of chemicals.
In literature the term .child. may have a dual meaning. On the one hand it may refer to a
human being that has not yet reached adolescence. On other occasions the term .child. is used
to identify a specific period in the development of a human being from birth to adulthood.
According to the classification by Crom  a neonate is less than 1 month of age, an infant is
1 to 23 months of age, a child is 2 to 12 years of age and an adolescent is 13 to 18 years old.
In the present report the terms .child. and .children. refer to the entire period from birth up to
and including adolescence, while the terms neonate and infant refer specifically to the periods
in life as described by Crom.
Children may be exposed to toxic substances for longer periods or to higher external doses
than adults, because children may spend more time in a room or area in which a toxic
chemical is present (e.g. bedroom), are in closer contact with a contaminated surface (e.g. by
crawling), display more hand-to-mouth behaviour, and display less hygienic behaviour (e.g.
mouthing of objects/surfaces, pica behaviour). In addition, children have a higher body
surface to body weight ratio  and relatively higher food [1, 4], water  and oxygen
intakes , which may increase their exposure on a body weight basis.
It has become clear from inadvertent exposures that, for certain chemicals, children may be
more vulnerable to the toxic effects than adults. This increased vulnerability of children may
be the result of differences in toxicokinetics and toxicodynamics. As compared to adults,
especially in the early postnatal stages of life marked differences in kinetics and dynamics of
substances may exist.
Most data on toxicity of chemicals come from animal studies. Based on the daily dose that
causes no adverse effects in the animals, i.e. the No-Observed-Adverse-Effect-Level
(NOAEL) an Acceptable Daily Intake (ADI), expressed as mg/kg bw/day, is calculated for
humans. To extrapolate the data from the animal studies to the human situation assessment
factors are applied. A factor of 10 is used to allow for species differences (4 for
toxicokinetics, 2.5 for toxicodynamics) and another factor of 10 is applied to safeguard the
variability in the human population (3.2 for toxicokinetics, 3.2 for toxicodynamics).
The concern that children may potentially be at higher risk, due to specific sensitivities and
incomplete data with respect to toxicity and exposure led to new legislation in the United
States. The Food Quality Protection Act of 1996  requires that .« …an additional tenfold margin of safety for the pesticide chemical residue and other sources of exposure shall be applied for infants and children to take into account potential pre- and postnatal toxicity and completeness of data with respect to exposure and toxicity to infants and children…”.
In the present report a concise overview of the relevant data from public literature on
differences in exposure, and in susceptibility, due to toxicokinetic and -dynamic differences
between children and adults is presented. The adequacy of the presently used toxicological
tests is discussed and directions for further research are indicated.
Whether children should be considered as a special sub-population in risk assessment of
chemicals should in first instance be based on the exposure profile of children and not on the
hazard profile of a chemical (only). Since children have a different dietary pattern, a different
activity pattern and behave differently from adults, the exposure pattern and exposure levels
of children may substantially differ from that of adults.
2.1 Dietary exposure
Infants may be exposed to xenobiotics through breastfeeding and by consumption of other
liquid and solid food products. Children have a higher need for nutrients and a higher caloric
demand and hence consume more food and drink more fluids per kg bodyweight than adults.
Accordingly their relative exposure to xenobiotics in food is increased. It should be noted
that, although children consume the same food products as adults, their dietary pattern is
different and less varied . For instance children consume relatively large quantities of dairy
products and fruit.
2.2 Other routes of exposure
Apart from exposure to chemicals that are present in food, individuals may be exposed to
chemicals through inhalation, dermal exposure or non-dietary oral exposure. As a
consequence of their higher inhalatory rate, children have a higher intake of gaseous or
airborne chemicals. Also dermal exposure in children may lead to higher systemic levels due
to a higher body surface:body weight ratio.
In addition, children may be more exposed to toxic substances than adults because children
may spend more time in the same room or area, are in closer contact with a contaminated
surface (e.g. by crawling), display more hand-to-mouth behaviour, and display less hygienic
behaviour (e.g. mouthing of objects/surfaces, pica behaviour). At the RIVM a consumer
exposure model (ConsExpo 3.0)  has been developed to estimate exposure levels through
inhalatory, dermal and non-dietary oral routes in adults as well as children. Exposure during
application (primary exposure) as well as after application (secondary exposure) of a
chemical is taken into account.
Specific scenarios for children, especially during the post-application phase, are implemented
in ConsExpo. These scenarios use default parameters for e.g. crawling (duration of dermal
contact with a surface etc) and hand-to-mouth behaviour that are based on literature data and
With respect to testing for regulatory purposes the intended use of the test substance should
be taken into account in deciding on the exposure route in the toxicological test. For instance,
in case a substance is intended to be vaporised, the developmental effects following
inhalatory exposure should be evaluated, since the inhalatory uptake may differ from oral
uptake and since there is no first pass elimination in the liver, this might lead to different
systemic levels. The same holds true for dermal exposure. Furthermore inhalatory exposure
may uncover local developmental effects on the lung.
2.3 Aggregate and cumulative exposure
At present, risk assessment is generally performed for individual substances coming from one
source. However, the same substance may be present in a variety of sources, which all
contribute to the exposure of an individual, the so-called aggregate exposure. Aggregate
exposure is usually referred to as the total exposure of a defined population to a certain
chemical from all relevant sources and through all exposure routes .
Apart from aggregate exposure to a specific chemical from different sources, it should be
noted that often toxic chemicals are part of a certain class of structurally closely related
substances which all exert their effect through the same mechanism of action (cumulative
exposure). Typical examples of this are classes of pesticides such as organophosphates,
pyrethroids and carbamates. Even substances belonging to different classes may affect the
same functional target. For instance, both organophosphates and carbamates inhibit
cholinesterase activity. The effects of cumulative exposure of adults and children to
functionally related substances are largely unknown and, consequently, are not considered in
the present risk assessments for regulatory purposes. Although aggregate and cumulative
exposure to chemicals is a matter of concern for the entire human population, in view of the
differences in exposure characteristics of children compared to adults, this subject needs
special attention with respect to children. Especially for substances for which the risk is
considered only on a product base for a given application (for instance pesticides), exposure
to a given active substance might be much higher due to simultaneous exposure from other
sources (e.g. veterinary medicine, biocide, pesticide) that contain the same active substance.
In the present regulatory processes these uses are not considered at the same time.
There is a number of differences in physiology between children and adults. These
differences may affect the level of exposure to a chemical, and the kinetics and dynamics of a
chemical. Kinetics refers to the processes of absorption, distribution, metabolism of a
chemical in the body and excretion from the body. Dynamics describes the interaction
between a toxic chemical and the body (tissues, organs, receptors). The most relevant
differences with respect to vulnerability and exposure of children to substances are described
in table 1.
Table 1. Differences in physiology between children and adults.
Parameter Difference ref.
About 2.5 times higher in neonates than in adults 3
body water content About 75 % in neonates, 40-60 % in adults. 10
water intake About 2-5 times higher in infants * 11
caloric demand Energy requirement and relative food consumption is 3-4 times higher in infants than
in adults *
ventilation rate Volume of inhaled air/kg bw/min is about 3 times higher in neonates than in adults 3
gastric pH About neutral at birth, shortly thereafter falling to pH 2 (adult value) 12, 13
gastric emptying rate Irregular at birth, approaching adult values by 6-8 months 14, 15
digestive enzyms Concentration of digestive enzymes is lower at birth and gradually increases during
the first year of life
gut flora Bacterial flora in the intestines is established soon after birth but changes in
composition over time
brain Relatively large in children and in development, showing a high rate of tissue
proliferation and differentiation. Blood brain barrier is underdeveloped. Brain blood
flow increased. Relative high water and low myelin content.
liver Metabolic enzyme system underdeveloped at birth, especially oxidation and
glucuronidation processes. Substantial increase within 2-6 months. Adult levels
reached within 1-3 years
kidney Renal blood flow and glomerular filtration rate low at birth, reaching adult levels in
about 3-5 and 7-12 months respectively.
Plasma protein concentration and binding capacity are lower during the first year of
immune system High level of tissue proliferation and differentiation 22
* when compared on a body weight basis
An extensive review on the differences in physiology between adults and children, with
respect to factors that influence absorption, distribution, metabolism and excretion of
xenobiotics, is provided by De Zwart et al. .
It is known that there are differences between children and adults with respect to the fate of a
toxic substance in the body. Especially in the early postnatal stages of life marked differences
in the kinetics exist. Recently the age-related differences in kinetics of xenobiotics have been
reviewed at RIVM . In the present chapter an overview of the differences between
children and adults, based on that RIVM report, is presented. The significance with respect to
risk assessment of toxic chemicals is discussed.
Substances may be absorbed through ingestion, inhalation or dermal penetration. For most
substances oral ingestion is the predominant route of exposure, however volatile substances
may be absorbed mainly by inhalation. For compounds with a logPow between .1 and 4 and a
molecular weight below 500, the transdermal route of absorption may be of significance.
4.1.1 Oral absorption
Child-specific factors that may influence the absorption of substances are gastric pH, gastric
emptying rate, activity of digestive enzymes and the existence and composition of the
bacterial gut flora, composition of bile and bile flow. At birth the pH of the stomach in the
neonate is about neutral (pH 6-8) but shortly after birth falls to pH 2, which is comparable to
adult pH [12, 13]. The neutral pH in neonates will result in a different level of ionisation of
toxins as compared to adults, which in turn affects absorption from the gut. The gastric
emptying rate is variable and irregular until 6-8 months after birth [14, 15]. The concentration
of digestive enzymes is lower at birth and gradually increases during the first year of life
. The intestinal wall of neonates is more permeable to macromolecules . The bacterial
flora in the intestines is established soon after birth, however, its composition gradually
changes over time . All these factors may increase or decrease the absorption of a toxin
from the gut.
4.1.2 Inhalatory absorption
Children have a relatively higher caloric demand than adults , and consequently a
relatively increased respiratory activity . As a consequence, the intake over a certain
period of time of an airborne toxin, for instance in the form of a gas, aerosol or dust particle
will be increased in children on a body weight basis. In addition, pulmonary function declines
with age. Further research is required to establish how the physiological differences in the
respiratory system between children and adults affect the absorption of substances.
4.1.3 Dermal absorption
The skin in neonates is immature in comparison to that of adults. For instance, neonates have
a higher skin surface pH and skin roughness, a lower hydration of the stratum corneum and
RIVM report 613340005 page 14 of 29
desquamation of the epidermis . However, there are no indications that the dermal
absorption of substances in children is substantially different from adults .
From a recent publication in which the pharmacokinetic parameters of 45 drugs were
compared, it can be concluded that there is a tendency towards larger volumes of distribution
of these drugs in children (from neonates up to adults).
The body composition of newborn children differs from that of adults. For instance, the body
of neonates contains a higher percentage of water (75 % in neonates vs 40-60% in adults).
The body water content is about 63 % in 2 year old infants, and approaches adult values in 12
year old children . The body fat content increases from about 18 % in neonates to 30 % in
1 year old infants, followed by a decrease to 17 % in 15 year old boys. In girls body fat
content remains higher. Adult fat content is about 30% in males and 35% in females .
Moreover, neonates have a relatively underdeveloped muscular system and the head
contributes a large proportion to the body weight. There are some other differences that may
be of significance. Firstly, the plasma protein levels and binding capacity are lower in
neonates and infants, reaching adult values at about 1 year after birth . This may be of
particular importance for exposure to substances that, in the adult, are largely bound to
plasma proteins. Generally speaking chemicals that are neutral or hydrophilic or have a low
molecular weight are least likely to bind to plasma protein. Since the unbound fraction in the
blood determines the degree of distribution to other tissues, a reduction in plasma protein
binding may dramatically increase the toxic potential of a substance. On the other hand,
lower plasma protein binding may enhance the elimination of a substance.
Secondly, in the neonate the blood brain barrier is immature, which may lead to higher
exposure of the brain to hydrophilic xenobiotics, for instance cadmium. The relative size of
the brain is larger in children. Moreover the composition of the brain of neonates and children
is different from adults. There is less myelin and an increased blood flow in the brain. All
these factors may lead to a higher exposure of the brain to toxic substances. This is of
particular concern since the brains of neonates and children are still developing and therefore
more vulnerable to the toxic effects of substances acting on the nervous system.
A substance may be eliminated from the body through two different processes, metabolic
conversion and excretion. Often, excretion of a substance that is rather lipophilic, only occurs
after it has been enzymatically converted to more hydrophilic metabolites.
Metabolism of substances serves two purposes. Firstly, by metabolising a substance it often
loses its toxic potential, although in certain instances the metabolites are more toxic than the
parent compound. Secondly, metabolic processes such as oxidation, glucuronidation,
hydroxylation and sulphate conjugation increase the hydrophilicity of the molecule and
therefore render it more susceptible to renal excretion. At birth, the liver has an
underdeveloped system of metabolic enzymes. Especially oxidation and glucuronic acid
conjugation processes are immature in neonates [18, 19, 25]. This means that the rate of
detoxification (or activation) and elimination processes in the liver may be less efficient. The
various enzyme systems in the liver mature at different time points. In general, the levels
increase substantially within 2-6 months after birth. By 1 to 3 years of age the metabolic
potency of the liver approaches adult levels. Although the liver is the major organ for
metabolism of xenobiotics, other organs such as the lung, the small intestine and the kidney
may also significantly contribute to the metabolic conversion of substances . The
metabolic activity of the lung is particularly relevant for substances to which an individual is
exposed through the inhalatory route. Human and animal studies have shown that important
enzym systems in the lung that are still developing after birth are the cytochrome P450
monooxygenase system, glutathione S-transferases, epoxide hydrolases, superoxide
dismutase, catalase and glutathione peroxidase .
Substances can be excreted through renal excretion, biliary excretion, expiration or
perspiration, often after being metabolised. The renal function in the neonate, in particular the
renal blood flow and glomerular filtration rate, is low as compared to adults [20, 21], which
may lead to a prolonged half-life of the toxin or its metabolites in the blood plasma. In full
term neonates renal blood flow and glomerular filtration rate reach adult levels in about 3-5
months and in 7-12 months respectively. Due to the high caloric demand in children their
relative respiratory activity is increased. On the one hand, this indicates that in children the
relative intake of volatile toxins or toxins in aerosols through inhalation is enhanced, on the
other hand the potential to eliminate toxins or their metabolites through expiration will be
increased. Little is known about the particularities of biliary excretion of xenobiotics in
Experimental research into the pharmacokinetics of drugs has demonstrated that in the early
days after birth there may be a decreased elimination of drugs, resulting in a prolonged half
life. However, after the neonatal period has passed the elimination of drugs is often enhanced
[18, 27]. The same probably is true for non-drug chemicals.
The main difference between adults and children with respect to toxicodynamics is the
influence that toxic chemicals may exert on the developing organs in young children. The
organs in the foetus, but also in the newborn child, undergo cell proliferation (growth), cell
differentiation, cell migration, cell maturation, and development of enzyme or receptor
systems. Disruption of these processes by toxins may have severe and irreversible
consequences. For instance, postnatal exposure to lead induces increased anti-social
behaviour and decrements in cognitive function and intelligence, later in life [28, 29].
However, generally speaking little is known at present about the influence of the majority of
chemicals on the development of organ systems. In the following sections, the potential
effects of chemicals on organ systems in laboratory animals and humans, and the adequacy of
the presently used toxicological tests in detecting potential deleterious effects, will be
discussed in more detail.
Exposure to chemicals during the phase that organs develop may have serious effects. Once
the organs have developed and enter a phase of growth they are, in general, much less
susceptible and effects induced by exogenous substances are often reversible.
With respect to risk assessment, the important question is whether the currently used
toxicological tests using laboratory animals are sufficiently sensitive to predict damaging
effects of a number of specific toxins on the developing human. The toxicological testing of
chemicals in laboratory animals is based on the assumption that the damaging effects of
chemicals in the laboratory animal can be extrapolated to humans, and vice versa. From this
assumption it follows that most of the development-disrupting effects of chemicals are
adequately detected by reproductive and teratogenic tests in laboratory animals, and that
these laboratory tests predict the potentially damaging effects of chemicals on children.
Although in long-term studies in rats and mice treatment usually already starts when the
animals are 6 weeks of age, this is still after the critical period for the development of most
organs and organ systems. At present the toxicity of substances in neonates and young
animals is tested in reproduction toxicity (OECD guidelines 415 and 416) studies. These
studies include postnatal exposure up to the weaning age (OECD415 and the F2 in
OECD416) or until adulthood (F1 in OECD416). Before weaning, exposure occurs largely
via lactation, although feed consumption increases in the third week before weaning and
dietary exposure of pups may occur. These tests allow the study of effects postnatal exposure,
especially the F1 generation in OECD416, although at present testing is generally limited to
clinical signs, food consumption, weight development and sometimes behavioural testing.
Moreover, if there are differences in toxicokinetics, sensitivity of target organs, or period of
the development of organs in the mammalian species used for toxicology tests and humans,
toxic effects of chemicals that are specific for humans may be overlooked. The brain may be
exemplary for this. At birth the development of the brain has further progressed in humans
than in rodents. However, in contrast to rodents, where brain development is largely
completed at weaning, in the human this organ continues to develop long after birth [30, 31,
32]. Although in studies on reproductive toxicity animals are exposed during the prenatal and
postnatal period, the pattern (and level) of exposure in humans may differ, especially in the
critical period with respect to brain development
Below, the particularities of the development of certain organ systems in humans, as
compared to other mammalians, and the consequences for risk assessment are discussed.
5.1.1 Development of the respiratory tract
The development of the respiratory tract occurs in several phases. In humans, the
development of the lungs, in particular of the alveoli, continues well after birth. The
development of alveoli even extends into adolescence. In this respect humans differ from rats
and mice, in which formation of alveoli occurs during the first 4 weeks after birth. It has been
observed that a number of toxins retard lung maturation, decrease the alveolar number and
surface area, and impair the function of the lung surfactant system. Little research into the
long-term consequences of exposure to these toxins has been performed, although there are
indications that the observed functional disturbances may be permanent [26, 33]. More longterm
studies are needed, however, to clarify this matter.
5.1.2 Developmental immunotoxicity
Developmental immunotoxicology is still in its infancy. The developing immune system goes
through phases of cell production, cell migration through haematopoietic organs, cell-cell
interactions, cell differentiation and cell maturation. An overview of the toxic effects of
chemicals on the developing immune system has been compiled at RIVM . Disruption of
immunodevelopmental processes may have serious consequences, such as long-term or
permanent immunosuppression. On the other hand, immune hyper-responsiveness (i.e.
allergies) or autoimmune reactions could result from disrupted development of the immune
system. Accordingly, the lack of immunological challenge due to increased hygienic
standards, and exposure to environmental factors during the development of the immune
system have been implicated in autoimmune diseases  and atopia and asthma [22, 36].
From animal studies there is evidence that the developing immune system may be not more
sensitive to the effects of toxins than the mature immune system, but that the changes in
immune function induced by the toxins may be more persistent . However, it has also
been reported that perinatal exposure to TCDD reduces vaccination responses and increases
the risk of otitis media in Dutch school children . At present, the toxicological tests used
for risk assessment are not designed to detect immunodevelopmental disturbances or
immunotoxic effects, since immunological parameters are usually not included. It is
recommended, however, to amend the current OECD guidelines for developmental and
reproductive toxicity testing so that the developing immune system is considered as a
potential target of toxicity during developmental stages .
In view of the lack in knowledge, further clinical and epidemiological studies are necessary
to give more insight in this matter.
5.1.3 Developmental neurotoxicity
The brain, in particular the human brain, is an immensely complex organ, of which the
functioning is still poorly understood. It is known that relatively subtle changes in the human
brain may alter the mental capabilities or the personality of an individual. A number of
psychiatric illnesses, e.g. mental retardation, autism, cerebral palsy, ADHD and
schizophrenia, probably have their origin in a disturbed pre-or perinatal brain development.
For some of these disturbances the involvement of chemicals has been suggested .
In humans, the development of the brain is a process that starts during early pregnancy and
continues long after the child is born. Initially the anatomical differentiation of the brain is
the most striking feature, but even when all the anatomical structures of the brain are present,
functional development still proceeds. Disruption of the anatomical as well as the functional
developmental processes may have major consequences.
The brain passes through several stages during development. First there is neurogenesis, i.e.
the stage when neurons are formed. This is followed by processes of neuronal migration,
outgrowth of dendrites and axons, formation of synaptic connections, development of
neurotransmitter systems and receptors, and myelinization.
Although in humans the anatomical development of the brain predominantly occurs before
birth, processes such as axon-, dendrite- and synapse formation continue long after birth;
some of these processes are not finished before adolescence [31, 32]. The fine-tuning of the
interactions between the various brain systems also continues for a long period after birth.
In humans the blood brain barrier is only fully developed from the middle of the first year of
life . This means that a chemical such as cadmium, to which the adult blood-brain barrier
is impermeable, may well enter the brain in infants. In the rat, it has been reported that
exposure to certain pesticides during the development of the blood brain barrier may alter the
permeability of this barrier, even for a prolonged time after cessation of the exposure to these
It is known from animal studies that the developing brain is more susceptible to certain
chemicals than the adult brain . It should be noted that substances that are capable of
causing disturbances in the developing nervous system are not necessarily neurotoxic in
adults. Furthermore, even short periods of exposure to toxic chemicals, such as PCBs, PBDEs
and pesticides, may induce long-lasting behavioural disturbances [43, 44].
The risk assessment of neonatal exposure to toxic substances, based on studies using
laboratory animals, is hampered by the fact that in certain instances adequate animal models
are lacking. Gross abnormalities as a result of neurotoxic damage will probably be detected
by studies in animals. However, more subtle, but clinically relevant effects will be difficult to
uncover. For instance, learning and memory tasks in animals are probably only sensitive
enough to detect relatively large effects on cognitive functioning. Relatively small decreases
in cognitive abilities in human individuals, as a result of neurodevelopmental disturbances
following exposure to neurotoxins, will be difficult to detect. The possible involvement of
neurotoxins in the development of psychiatric disorders will be even harder to detect in
animal experiments since many manifestations of these disorders are typical for the human
species and are also influenced by life-style and other exogenous factors.
In rats, the major species used for toxicological testing, the brain growth spurt and the
anatomical and functional development of the central nervous system occurs for a large part
after birth. In the reproduction toxicity tests the dams are treated until weaning. In case the
test substance is excreted in substantial amounts in the milk, this test may provide a reliable
indication on the neurodevelopmental effects of a substance. However, for substances which
are poorly excreted in milk, the reproduction toxicity studies cannot be used to establish
neurodevelopmental properties of a substance.
US-EPA has implemented a guideline for developmental neurotoxicity  and the draft for
a new OECD guideline (426) for the testing of neurodevelopmental toxicity of substances
probably will be implemented soon. The developmental neurotoxicity test is aimed at
detecting anatomical, histological and functional disturbances induced by interaction of a
substance with the developing brain. In principle the guideline proposes to administer the test
compound during pregnancy and lactation in the food, however, other means of
administration may also be used. In the guideline it is, however, not required to assess the
levels of compound in the milk in order to determine whether the pups are actually exposed
after oral administration of the test compound to the mother. Further, if the substance
undergoes a high rate of biotransformation, the exposure of the infant through lactation may
differ than when directly exposed to the parent compound itself.
In case the level of exposure is too low, the test compound should be administered directly to
the pups, provided that stress does not preclude this possibility. The intended use of the test
substance may prompt for a different route of exposure. For instance, in case a substance is
intended to be vaporised, the developmental effects following inhalatory exposure should be
evaluated, since the uptake rate and amount that is absorbed may differ from oral uptake.
Since following inhalatory exposure there is no first pass elimination in the liver this may
lead to different systemic levels. Furthermore inhalatory exposure may uncover local
developmental effects on the lung. For dermal exposure the same reasoning holds true.
5.2 Endocrine disruption
Endocrine disruption is not a specific end point of toxicity but rather refers to health effects
that may be mediated by mechanisms affecting hormone homeostasis. Children may be
especially vulnerable in this respect as their homeostatic mechanisms are immature. In animal
studies, effects on morphologic development of the urogenital system may indicate endocrine
mechanisms. For example, the uterotrophic assay carried out in immature female rodents
assesses weight effects and histological effects on the uterus of substances during a
developmental phase when the juvenile uterus is responsive to estrogenic compounds,
although at the same time the endogenous production of estrogens is very low. Such a system
is more sensitive than the adult uterus, which is already stimulated by endogenous estrogen.
However, as yet it is unclear as to when a uterotrophic effect in the juvenile uterus should be
considered adverse. At present, various new test systems using young animals are being
developed for endocrine disruption, but their role in the risk assessment process has yet to be
established. The possible specific relevance of the endocrine disruption issue for children and
their development is however beyond dispute.
Little is known about the specific vulnerability of children to the genotoxic and carcinogenic
effects of chemicals. Charnley and Putzrath  summarized the results of studies on 30
chemicals in which the effects of age on chemically induced carcinogenesis in rodents were
evaluated. Overall, the percentage of studies indicating that young animals were more
susceptible than adults (37 %) was about equal to the percentage of studies indicating that
young animals were less susceptible than adults (53 %). However, as Landrigan et al. 
pointed out in a comment, the chemicals included in the studies represent less than 0.2 % of
the high production volume chemicals. Moreover, most studies used only one dose level,
making it difficult to draw conclusions on differences in sensitivities. Evidently more
research is needed in order to gain insight in the relative vulnerability of children to the
carcinogenic effects of chemicals.
6 General Conclusions
Exposure of children to toxic chemicals may differ substantially from that of adults. As a
consequence of their increased metabolic needs, their increased body surface to body weight
ratio and their behaviour (e.g. crawling, hand-to-mouth behaviour) the relative exposure (per
kg bw) of children to xenobiotics is likely to be higher than that of adults in case of similar
external exposure. So, if children are likely to be exposed, it is necessary in the risk
assessment for chemicals to perform a separate exposure assessment for children.
6.2 Toxicokinetics and toxicodynamics
It is evident that there are differences between children and adults in the kinetics and
dynamics of toxic substances, which may render the child less or more susceptible to the
toxic effects of a chemical.
Therefore, in cases where children are likely to be exposed, in addition to the assessment of
the specific exposure pattern, also the toxicological profile of a xenobiotic should be carefully
With respect to toxicokinetics, the present data indicate that there are a lot of physiological
differences between adults and children, that might result in a different internal dose in
children compared to adults. However, it is difficult to predict the overall result of the
different processes (for instance: a substance may be more extensively absorbed, but less
metabolised to a toxic metabolite, or cleared more rapidly). Therefore, more insight is needed
in the differences in toxicokinetic processes between adults and children. One way to study
these differences is by using generic PBPK models (see paragraph 6.5).
With respect to toxicodynamics there is evidence that the differences between children and
adults may be rather large, especially during early development. The anatomical and
functional development of organ systems may render children more sensitive to toxic effects
of xenobiotics than adults, which are fully developed. In principal, these effects will be
detected in the presently used reproduction and developmental neurotoxicity studies.
It must be kept in mind, however, that the critical windows in the development of laboratory
animals and man are not necessarily the same, and therefore, the exposure period should be
carefully examined. In addition, special attention should be paid to the route and level of
exposure, with regard to extrapolation of results in animal studies to the human situation.
At present, a lot of research with regard to sensitivity of children is going on in the field of
pharmaceuticals. Since for the risk-assessment of chemicals in general only information on
toxicokinetics and toxicodynamics in laboratory animals is available, it is important to
closely follow the developments in the paediatric pharmacology area.
6.3 Adequacy of toxicological tests
It is generally assumed that most of the effects of chemicals on postnatal development are
adequately detected by studies on reproductive toxicity and developmental toxicity in
laboratory animals, and that these laboratory tests are also predictive for the toxicity of
chemicals in children. It should be noted, however, that the presently used toxicity tests focus
on developmental, reproductive and neurotoxic effects, while other parameters (e.g.
histopathology, haematology, immunology) in pups are not investigated.
The newly introduced neurodevelopmental toxicity test (OECD 426) may detect effects of
substances on the anatomy and function of the brain. However, relatively subtle
neurodevelopmental disturbances caused by the test substance may be overlooked, and the
usefulness of this test still has to be proven. Also substance-induced neurodevelopmental
disturbances underlying typically human psychopathology may not be detected by tests in
animals. It should also be noted that the treatment regimen in the test animal might not
adequately represent the exposure of the young child. For instance, postnatal exposure of the
pup through feeding of the mother will be low for substances that are poorly excreted in milk.
Infants and children receive, apart from milk, other solid and liquid foods and may thus be
exposed to chemicals via other routes than breast milk. Thus, for substances for which
excretion in milk is low the test substance should be administered directly to the pups,
providing that stress does not preclude this possibility. For substances to which children are
exposed dermally or by inhalation, toxicological tests should use the same administration
Moreover, the presently used protocols for toxicological testing are not adequate for detecting
effects of early exposure to substances on carcinogenicity and certain developmental
disturbances. For instance, substance-induced disturbances in the immune and endocrine
systems may not be uncovered by toxicological tests since no specific tests aimed at detecting
disturbances in the functioning of these systems are used. Guidelines to test for
(developmental) effects on the immune system are in preparation. The investigation of a
broader set of toxicological parameters in the multi-generation toxicity test, especially the
parameters that are affected in (sub-)chronic toxicity studies, may provide at least part of the
information that is lacking at present.
6.4 Vulnerability of children: Is an additional assessment factor necessary?
From a theoretical point of view it is evident that, due to the complex process of development
of organs and organ systems, children may be more vulnerable than adults to the toxic effects
of certain chemicals. A typical historical example is the detrimental effect of lead. However,
there are not many indications that the current risk assessment procedures do not adequately
protect the sensitive groups, such as children, in the human population. There may be several
explanations for this:
- The data from the present toxicological tests may be indeed adequate for extrapolation to
the human situation, using the present assessment factors.
- An increase in vulnerability due to one factor may be compensated by a reduction in
vulnerability due to another factor (for instance, a high absorption of a chemical may be
compensated by a high elimination).
- Adverse effects have been identified in epidemiological studies, but an adequate relation
to exposure to chemicals may be not clear or proven.
- Adverse effects caused by exposure to chemicals are not identified in epidemiological
At present there is not sufficient information, however, to give a general quantitative
statement whether the presently used default assessment factor of 10 for intraspecies variation
is adequate to protect children in risk assessment of chemicals. However, in general, the use
of an intraspecies factor of 10 implies that the .most sensitive child. is about 10x more
sensitive than the .average. human, and thus that there is a 100-fold variation in susceptibility
in the entire human population. In addition, the use of the default assessment factor of 10 for
interspecies extrapolation implies that the average human is 10 times more sensitive than the
most sensitive animal tested.
In general, if a full set of toxicological data is available, the presently used assessment factors
(10 x 10) are considered adequate in safeguarding the human population. However, the use of
an additional assessment factor in order to protect the sensitive groups in the human
population, among others children, should always be considered, on a case-by-case basis.
6.5 Gaps in risk assessment and directions for further research
With respect to exposure of children more insight in specific exposure scenarios is needed to
get a better estimation of the actual exposure level, especially when it is expected that
children might be higher exposed than adults.
- The deviant dietary pattern of children should be taken into account in the exposure
assessment. For pesticides this is already common practice, in other frameworks this
aspect needs more attention.
- In the exposure assessment, not only point estimates, but also distributions of intake
levels should be taken into account in the exposure assessment.
- For the establishment of Maximum Residue Levels the deviant dietary pattern of
children should always be taken into account.
- The contribution of the oral, dermal and inhalatory routes of exposure to the total
dietary and non-dietary exposure of children should be considered. Because of the
different behaviour and physiology of children, both the absolute and the relative
contribution of the various routes to the actual exposure will be different compared to
- What are the effects/risks of aggregate exposure to a substance, or the cumulative
exposure to substances, either structurally related or from a different chemical class,
with a common mechanism of action. Based on the scientific data models for
aggregate and cumulative risk assessment should be developed for the population
(and thus also for children).
Criteria for the adequacy of the data set: Decision tree.
As mentioned before, the presently used reproduction and developmental neurotoxicity tests
will probably detect many of the effects of chemicals on the developing laboratory animal.
On the other hand, in the present report a number of situations have been described in which
humans differ from laboratory animals and in which toxicological tests in animals are not
adequate in detecting adverse effects of substances, such as developmental neurotoxicity or
immunotoxicity, on the human child. Thus, it may be concluded that, in view of the
potentially increased vulnerability of children, risk assessment of chemicals should be made
on a case by case base. We propose that in the near future a decision tree is designed which
can be used to assess whether the available toxicological data set is adequate for risk
assessment of children.
Suitability of young-animal toxicity tests
The suitability of young-animal toxicity models for extrapolation to the human situation
should be investigated. Furthermore, it is interesting to compare the dose-response data and
NOAELs of adult test animals to those of juvenile test animals, to gain more insight in the
range of intraspecies variation, with respect to age, in a test animal population. However,
young animal models will only be relevant in case developing systems are targets for a
compound or for its metabolites. Regarding studies in animals this would imply that the
choice of an animal model can be better substantiated, leading to a refinement of experiments
and a reduction in the number of animals required for testing.
It is obvious that the physiology and toxicokinetics in children are different from that in
adults. However, it is difficult to get insight in the overall result of the differences, especially
in a quantitative sense. A valuable tool in this respect is PBPK- modeling based on the
physiology of children. By using distributions of the physiological and kinetic parameters and
PBPK modeling it can be assessed which group of children is most at risk for a certain
chemical (e.g. lean or fat children).
The authors would like to thank ir. P.M.J. Bos, dr. H. van Loveren, dr. M.N. Pieters, dr.
M.T.M. van Raaij, and dr. A. J.A.M. Sips for their valuable comments.
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Appendix 1 Mailing list
1. Drs. J. Dornseiffen, VWS, VGB i.o.
2. Dr. ir. J. de Stoppelaar, VWS, Directie VGB i.o.
3. Mr. J.A.M. Whyte, VWS, GZB
4. Dr. H. Jeuring, KvW
5. Directie RIVM
6. Dr. ir. D. Kromhout, sectordirecteur VCV
7. Dr.ir. M.N. Pieters, CRV
8. Dr. M.T.M. van Raaij, CRV
9. Dr. A.J.A.M. Sips, LBV
10. Dr. A.J. Baars, CRV
11. Dr. F.X.L. van Leeuwen, CRV
12. Dr. P.H. van Hoeven-Arentzen, CRV
13. Drs. T.G. Vermeire, CSR
14. Dr. G.J.A. Speijers, CRV
15. Drs. A.G.A.C. Knaap, CRV
16. Dr. C. Rompelberg, LBV
17. Drs. J. van Eijkeren, LBV
18. Dr. L.L. de Zwart, LBV
19. Dr. ir. M. J. Zeilmaker, LBV
20. Dr. ir. P. Bos, CRV
21. Dr. W.H. Könemann, CSR
22. Dr. H. van Loveren, LPI
23. Dr. H.E.M.G. Haenen, LGM
24. Dr. J.W. Van der Laan, LGM
25. Dr. ir. H. Derks, LGO
26. Dr. J. Bessems, TNO-Voeding, Zeist
27. Dr. C. Groen, Kinesis, Breda
28. Dr. M.C. Lans, CTB
29. Dr. L.P.A. Steenbekkers, Universiteit Wageningen
30. Dr. H.F.G. van Dijk, Gezondheidsraad
31. Dr. D. Kloet, RIKILT, Wageningen
32. Dr. S. Olin, ILSI Risk Science Institute, Washington, USA
33. Dr. G. Charnley, Health Risk Strategies, Washington, USA
34. Dr. N. Freeman Rutgers University, New Jersey, USA
35. Dr. G. Heinemeyer,Federal Institute for Health Protection of Consumers and
Veterinary Medicine, Berlin, Germany
36. Dr. W. Snodgrass, University of Texas, Galveston, USA
37. Dr. J. Hughes, University of Leicester, Leicester
38. Dr. I. Kraul, Danish EPA, Copenhage
39. Dr. M. Maroni, Università di Milano, Milan.
40. Dr. K. Thoran, National Chemicals Inspectorate, Solna, Sweden
41. Dr. J. Herrman, WHO, Geneva, Switzerland
42. Dr. A. Moretto, University of Padova, Italy
43. Dr. A. Boobis, Imperial College School of Medicine, London, UK
44. Dr. L.P. Davies, Therapeutic Goods Administration, Barton, Australia
45. Dr. V.L. Dellarco, Office of Pesticide Programs, US-EPA, Washington DC, USA
46. Dr. J. Borzelleca,
47. Dr. H. Häkansson, Karolinska Institute,
48. Dr. S. Page, WHO,
49. Dr. M. Tasheva,
50. Dr. R. Solecki, Federal Institute for Health Protection of Consumers and Veterinary
51. Dr. I. Dewhurst, Pesticide Safety
52. Dr. S. Logan, Therapeutic Goods
53. Dr. F.R. Puga, Instituto Biologico,
54. Dr. W. Phang, Office of Pesticide
55. Dr. K.L. Hamernik, Office of Pesticide
56. Dr. J.J. Larsen,
57. Dr. T. Marrs, Food Standard Agency,
58. Dr. C. Vleminckx, Scientific
59. Dr. D.B. McGregor, Toxicology Evaluation
60. Dr. E. Mendez, Office of Pesticide
61. Dr. A.W. Tejada, FAO,
62. Dr. D.J. Hamilton, Dept. of Primary
63. Dr. L.T. Haber, Toxicology Excellence for
64. Depot Nederlandse Publikaties en Nederlandse Bibliografie
65. Bureau Rapporten Registratie
66. Bibliotheek RIVM
68-77 Bureau Rapportenbeheer