This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, the World Health Organization, or the Commission
    of the European Communities and persons acting on its behalf.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization, and on behalf of
    the Commission of the European Communities

    World Health Orgnization
    Geneva, 1986

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

        ISBN 92 4 154259 4  

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    1.1. Objective
    1.2. Definitions
         1.2.1. Infant and young child
         1.2.2. Chemical
    1.3. Physiological basis for concern
         1.3.1. Small size and large surface area in relation to 
         1.3.2. The higher metabolic rate and hence higher 
                consumption of oxygen and intake of air per unit 
                body weight in the infant compared with the adult 
         1.3.3. Rapid growth
         1.3.4. Different body composition from adult
         1.3.5. Functional immaturity of the organs and systems of 
                the body 
         1.3.6. Breast milk, infant formulae, and water as sources 
                of chemicals 
    1.4. Applicability of data on experimental animals to 
         human infants and young children
         1.4.1. Some similarities in growth and development
                between man and experimental animals
         1.4.2. Some differences in growth and development
                between man and experimental animals
    1.5. Conclusions


    2.1. Introduction
    2.2. The alimentary tract
         2.2.1. Milk
        Human milk
        Other types of milk
        Infant feeds
    2.3. The respiratory tract
    2.4. The skin
    2.5. Conclusions


    3.1. Introduction
    3.2. Absorption
         3.2.1. Absorption from the gastrointestinal tract
         3.2.2. Absorption from the lungs

    3.3. Tissue distribution
         3.3.1. Binding of chemicals to proteins
         3.3.2. Distribution within the body
    3.4. Biotransformation of organic chemicals
    3.5. Elimination from the body
         3.5.1. Elimination by the kidneys
         3.5.2. Elimination by the liver
         3.5.3. Elimination by other routes
    3.6. Conclusions


    4.1. Introduction
    4.2. Effects of chemicals on general growth and development
    4.3. Effects of chemicals on some organs and systems
         4.3.1. Nervous system
         4.3.2. Kidneys
         4.3.3. Liver
         4.3.4. Lungs
         4.3.5. Haematopoietic system
         4.3.6. Immune system
         4.3.7. Endocrine system
         4.3.8. Skin
         4.3.9. Bones and teeth
    4.4. Carcinogenesis
    4.5. Conclusions


    5.1. Nutrition
    5.2. State of health
    5.3. Social and cultural way of life
    5.4. Conclusion





1. Introduction
2. Assessment of the importance of chemicals in breast milk
    2.1. Source of chemicals
    2.2. Chemicals within the mother's body and their secretion in 
    2.3. Development and limits of methods for measuring chemicals 
         in milk 
    2.4. Risks to the infant
    2.5. Assessment of contamination of breast milk following 
         maternal exposure 
         2.5.1. Method of collection of breast milk
3. Conclusions



    Every effort has been made to present information in the 
criteria documents as accurately as possible without unduly 
delaying their publication.  In the interest of all users of the 
environmental health criteria documents, readers are kindly 
requested to communicate any errors that may have occurred to the 
Manager of the International Programme on Chemical Safety, World 
Health Organization, Geneva, Switzerland, in order that they may be 
included in corrigenda, which will appear in subsequent volumes. 


c,d    Dr L. Amin-Zaki, Abu Dhabi, United Arab Emirates
          (formerly Professor of Paediatrics, University of
          Baghdad, Iraq)

c      Dr V.N. Anisimov, Laboratory of Experimental Tumours,
          N.N. Petrov Research Institute of Oncology,
          Leningrad, USSR

b,c    Professor E.A. Bababunmi, Laboratory of Biomembrane
          Research, Department of Biochemistry, University of
          Ibadan, College of Medicine, Ibadan, Nigeria

a,b,c  Professor D. Barltrop, Westminster Children's
          Hospital,London, United Kingdom  (Rapporteur)

a      Dr G. Becking, Health and Welfare, Ottawa, Canada (on
          temporary assignment to WHO Regional Office for
          Europe, Copenhagen, Denmark)

a      Dr A. Bernard, Unit of Industrial and Medical
          Toxicology, Faculty of Medicine, Catholic University
          of Louvain, Brussels, Belgium

a      Professor B. Clayton, Department of Biochemistry,
          University of Southampton, Southampton, United

d      Dr R.L. Dixon, Laboratory of Reproductive and
          Developmental Toxicology, National Institute of
          Environmental Health Sciences, Research Triangle
          Park, North Carolina, USA

a      Dr O.P. Ghai, Department of Paediatrics, All India
          Institute of Medical Sciences, New Delhi, India

b      Dr A.A. Jensen, National Institute of Occupational
          Health, Hellerup, Denmark

a,c    Dr J.H.P. Jonxis, Groningen University, Groningen, The

a      Dr S.K. Kashyap, National Institute of Occupational
          Health, Gujarat, India

a,b    Professor F.H. Kemper, Institute of Pharmacology and
          Toxicology, University of Münster, Münster, Federal
          Republic of Germany

b,c    Dr R.D. Kimbrough, Toxicology Branch, Clinical
          Chemistry Division, Centre for Disease Control,
          Atlanta, Georgia, USA

b,c    Professor W. Klinger, Institute of Pharmacology and
          Toxicology, Jena, German Democratic Republic

 Participants (contd.)

a      Dr B.A. Kolygin, Department of Oncopaediatrics, Petrov
          Research Institute of Oncology, Leningrad, USSR

b,c    Professor W. Koransky, Institute of Toxicology, Philipps
          University, Marburg, Federal Republic of Germany

a,b,c  Professor K. Kostial, Institute of Medical Research
          and Occupational Health, Zagreb, Yugoslavia  (Vice-

c      Dr N. Lery, Centre de Toxicovigilance, Hospital E.
          Herriot, Lyons, France

a,c    Dr L. Macho, Institute of Experimental Endocrinology,
          Slovak Academy of Sciences, Bratislava, Czechoslovakia

a,c    Dr R.A. McCance, University of Cambridge, Cambridge,
          United Kingdom

b      Professor D. Neubert, Institute of Toxicology and
          Embryo-Pharmacology of the University of Berlin,
          Berlin (West)

a,b    Dr S. Ostrowski, European Association for Studies on
          Nutrition and Child Development, Paris, France

c      Dr R. Parini, Department of Paediatrics, University
          of Milan Medical School, Milan, Italy

b      Dr P.K. Ray, Industrial Toxicology Research Centre,
          Lucknow, India

a      Dr H.H. Sandstead, US Department of Agriculture,
          Agricultural Research Service, North Central Region,
          Human Nutrition Research Centre, Grand Forks, North
          Dakota, USA

b      Dr L. Sann, Debrosse Hospital, Lyons, France

a      Professor F. Sereni, Department of Paediatrics,
          University of Milan Medical School, Milan, Italy

b,c    Dr R.J. Smialowicz, Health Effects Research Laboratory,
          US Environmental Protection Agency, Research
          Triangle Park, North Carolina, USA

a      Dr E.M. Smith, Albright & Wilson Ltd., London, United

c      Dr H. Sourgens, Institute of Pharmacology and
          Toxicology, University of Münster, Münster, Federal
          Republic of Germany

 Participants (contd.)

a      Dr A.G. Spinola, Department of Preventive Medicine
          UFBa, Bahia, Brazil

b      Dr A. Ueki, Pharmaceuticals and Chemicals Safety
          Division, Pharmaceutical Affairs Bureau, Ministry of
          Health and Welfare, Tokyo, Japan

a      Dr D. Wassermann, Department of Occupational Health,
          Hebrew University, Hadassah Medical School,
          Jerusalem, Israel

a,b,c  Dr E. Widdowson, Department of Medicine, Addenbrooke's 
          Hospital, Cambridge, United Kingdom   (Chairman)

b,c    Dr S. Wood, Department of Labour, Dublin, Ireland

a,c    Professor T. Yoshimura, University of Occupational and
          Environmental Health, Department of Clinical 
          Epidemiology, Kitakyushu, Japan

 Representatives of other Organizations

c      Dr V. Morgenroth, Chemicals Division, Environment
          Directorate, Organisation for Economic Cooperation
          and Development, Paris, France

 Joint Secretariat

b      Dr M. Belsey, Maternal and Child Health, World
          Health Organization, Geneva, Switzerland

a,b,c  Dr A. Berlin, Health and Safety Directorate, 
          Commission of the European Communities, Luxembourg 

b,c    Dr J. Facer, Department of Health and Social Security,
          London, United Kingdom

a      Dr B. MacGibbon, Department of Health and Social
          Security, London, United Kingdom

b      Dr M. Mercier, International Programme on Chemical
          Safety, World Health Organization, Geneva,

a,b,c  Dr J. Parizek, International Programme on Chemical
          Safety, World Health Organization, Geneva,
          Switzerland  (Co-Secretary)

a      Dr P.M. Shah, Maternal and Child Health, World Health
          Organization, Geneva, Switzerland

 Joint Secretariat (contd.)

b,c    Dr S. Tarkowski, Regional Officer for Toxicology, WHO
          Regional Office for Europe, Copenhagen, Denmark

a   Attended the IPCS Working Group/CEC Workshop in Cambridge,
    20-24 June 1983.
b   Attended the IPCS/CEC Follow-up Consultation in
    Luxembourg, 13-17 December 1984.
c   Attended the IPCS/CEC Task Group Meeting in Cambridge,
    19-23 March 1985.
d   Prepared a background paper for the IPCS Working Group/CEC
    Workshop in Cambridge, 20-24 June 1983, but was unable to


    The preparation of this document was initiated and organized 
jointly by the UNEP/ILO/WHO International Programme on Chemical 
Safety (IPCS) and the Commission of the European Communities (CEC) 
with the active support of the Department of Health and Social 
Security (DHSS) as part of the United Kingdom's contribution to the 

    The IPCS and CEC, concerned with the need to identify 
approaches and to develop methodologies for the protection of 
sensitive segments of the population from the health risks due to 
exposure to chemicals, agreed to convene an IPCS Working Group/CEC 
Workshop to discuss the principles for evaluating health risks from 
chemicals during infancy and early childhood.  DR E. WIDDOWSON, 
FRS, Cambridge made the local arrangements for the first IPCS/CEC 
meeting in Cambridge at Sidney Sussex College, 20-24 June 1983.  
Twelve background papers were prepared by the participants for the 

    At this meeting, the aims were to assess the importance of the 
problem; develop interim conclusions; draw up an outline for a 
publication; and establish a workplan for its preparation.  The 
meeting was opened by Dr J. Parizek on behalf of the IPCS and by 
Dr A. Berlin on behalf of the CEC. Dr B. MacGibbon welcomed the 
participants on behalf of the DHSS.  Dr E. Widdowson was elected 
Chairman and Professor K. Kostial Vice-Chairman.  The Chairman 
designated Professor D. Barltrop as the Rapporteur for the final 
publication to be prepared after the meeting, and Dr H. Sandstead 
as the Rapporteur for the interim conclusions.  DR E. WIDDOWSON, 
FRS, agreed to provide scientific guidance throughout the project. 

    The individual sections of the document prepared by the 
participants on the basis of the discussions at the above meeting 
were reviewed and completed at an IPCS/CEC follow-up Consultation 
held at the invitation of the Health and Safety Directorate of the 
Commission of the European Communities (CEC), in Luxembourg, 13-17 
December 1984. 

    The complete text prepared by the Chairman, DR E. WIDDOWSON, 
FRS, and the Rapporteur, PROFESSOR D. BARLTROP, was then considered 
and finalized at the IPCS/CEC Task Group meeting held in Cambridge 
at Sidney Sussex College, 19-23 March 1985. This meeting was again 
hosted and financially supported by the Department of Health and 
Social Security (DHSS) as part of the United Kingdom's contribution 
to the IPCS. 

    The work of all the participants, in particular that of DR E. 
WIDDOWSON, FRS, and PROFESSOR D. BARLTROP, is highly appreciated, 
and the financial support of the Department of Health and Social 
Security is gratefully aknowledged. 


1.  The infant and young child have different structural and 
functional characteristics from those of the older child and adult.  
These represent stages in normal growth and development and may 
affect their vulnerability when exposed to chemicals.  They 

    -   larger body surface area in relation to weight;

    -   higher metabolic rate and oxygen consumption and
        hence greater intake of air per unit body weight;

    -   different body composition;

    -   greater energy and fluid requirements per unit body

    -   special dietary needs, including the dependence of
        the infant on milk.

2.  Chemicals may enter the body of the infant and young child 
through the alimentary tract, the respiratory tract, or the skin.  
Those that traverse the mammary gland are potentially important 
contaminants of human and artificial milks.  Water used in the 
preparation of infant formulae is also a possible source of 
chemicals for the young infant.  Special behaviour characteristics 
of young children are important in determining exposure to 

3.  Generally speaking, chemicals, both organic and inorganic, are 
absorbed more readily by the infant than by the adult. The organic 
compounds undergo biotransformation less readily in the infant, and 
the kidneys are immature and less able than those of the adult to 
excrete chemicals, whether inorganic or the polar products of 
biotransformation.  Thus, a greater proportion of a similar dose of 
a chemical per unit body weight is likely to accumulate in the body 
of the infant compared with that in the older child or adult. 

4.  Exposure to chemicals during early postnatal development can be 
associated with dose-effect and dose-response relationships, which 
differ from those resulting from exposure in later years. 

    The exposure of the infant to chemicals can give rise, not only 
to immediate effects, but also to manifestations due to the 
disturbed maturation of organ systems and their altered response to 
other environmental influences. 

5.  Variations that exist in the health and nutritional status
of children reared in different social and cultural environments 
may influence exposure and modify response to chemicals in the 
environment.  Recognition of this will assist in the identification 
of children at risk and enable appropriate preventive and remedial 
measures to be adopted. 


1.  When health risks from chemicals are evaluated, the special 
characteristics of infants and young children must be recognized.  
Health care workers should be made aware of these characteristics. 

2.  The development of a strategy relating to chemicals detected in 
breast milk requires a thorough appraisal of the merits and 
disadvantages of the available options.  The risks of continued 
exposure to a chemical through breast feeding have to be balanced 
against the risks of infection or nutritional deprivation, where 
breast feeding is curtailed or discontinued. 

3.  Clinical and epidemiological data should be collected following 
the inadvertent exposure of infants and young children to 

4.  Developmental toxicology should be promoted and the methodology 


1.1  Objective

    The main objective of the Group concerned in the preparation of 
this report was to investigate the need for specific approaches in 
evaluating the health risks associated with exposure to chemicals 
(both organic and inorganic) during infancy and childhood, on the 
basis of a review of postnatal physiology, metabolism, and special 
characteristics of exposure. 

1.2  Definitions

1.2.1  Infant and young child

    It was agreed to follow the recognized definitions for infant 
and young child.  The neonatal period extends from birth to 4 
weeks, infancy up to one year, and young childhood from 1 to 5 
years.  It was recognized, however, that account should also be 
taken of the physiological stages of development and of the mode 
of nutrition, exclusive liquid feeding (breast or bottle) or mixed 
feeding.  The age of transition from one type of feeding to the 
other depends significantly on social customs. 

1.2.2  Chemical

    In the context of this report, a chemical is taken to mean any 
substance, whether organic or inorganic, irrespective of toxicity, 
other than well recognized nutrients or drugs, that may enter the 
infant's or child's body. 

1.3  Physiological Basis for Concern

    There are many ways in which infants and young children differ 
from older children and adults, and these differences may affect 
their vulnerability, when exposed to chemicals. 

1.3.1  Small size and large surface area in relation to weight

    A new-born infant weighing 3.5 kg is one-twentieth of the 
weight of a 70-kg man, but the surface area of the infant is one-
eighth as great.  Thus, the area of skin that could be exposed to a 
chemical is 2.5 times as great per unit body weight in a naked 
child as in a naked adult. 

1.3.2  The higher metabolic rate and hence higher consumption of 
oxygen and intake of air per unit body weight in the infant 
compared with the adult 

    Because infants and young children have a larger cooling 
surface per unit body weight than adults, and because they are 
growing rapidly, they have a higher resting metabolic rate and rate 
of oxygen consumption per unit body weight.  The oxygen consumption 
of an infant aged between one week and one year, at rest, in a 
thermoneutral environment, is about 7 ml/kg body weight per min 

(Hill, 1964); that of an adult, under the same conditions, is 3.5 
ml/kg per min.  Thus, the volume of air passing through the lungs 
of the resting infant is twice that of the resting adult per unit 
body weight and therefore twice as much of any chemical in the 
atmosphere would reach the lungs of the resting infant compared 
with that reaching the lungs of the adult per unit body weight, in 
the same period of time. 

    The ability of an infant to increase its metabolic rate and 
consumption of oxygen and air is limited to 2 - 3 times the basal 
level (Hill, 1964).  The metabolic rate in an adult increases much 
more during heavy exercise, but this degree of activity is not 
usually continued for long periods of time. An adult weighing 70 kg 
and expending energy equivalent to 3000 kcal in 24 h consumes 
oxygen at the rate of 6.2 ml/kg body weight per min, which is 1.8 
times the adult's basal rate, but less than the infant's basal 
level.  An environ-mental temperature below the thermoneutral one 
increases the metabolic rate and the requirement for oxygen.  Since 
the thermoneutral temperature is higher for infants than for 
adults, the same moderately low environmental temperature will 
cause an increase in the oxygen consumption of the infant before 
that of the adult, and, in fact, cold and crying are the main 
causes of an increase in oxygen consumption above the basal level 
in young infants.  As the infants become older and more active, 
muscular activity plays a more important part. 

1.3.3  Rapid growth

    The infant gains weight more rapidly during the first 4 - 6 
months after birth than during the rest of its life.  This is 
illustrated in Fig. 1 and 2, where the body weights published by 
Tanner et al. (1966) have been used for constructing the curves.  
Fig. 1 shows the increment in weight per month between birth and 18 
years, and illustrates the fact that a male infant gains more 
weight per month during the first 4 - 6 months than a boy does at 
the height of the puberty growth spurt.  The increment in weight of 
the female infant is essentially similar, but the gain per month 
during adolescence is less for a girl than for a boy.  This greater 
increment in weight per month in infancy is being added to a much 
smaller body than the lesser increment in the adolescent and when 
the gains in weight per month are expressed as g/kg weight at the 
beginning of the month (Fig. 2), the very high rate of growth of 
the infant is even more striking.  The organs as well as the major 
tissues of the body participate in this rapid growth (Table 1).  
Chemicals reaching the body by any route, and capable of 
accumulating in the body during infancy, may, in some instances, be 
incorporated into the body tissue in greater amounts than later on 
in childhood, when growth is slower.  This is particularly true if 
the chemical is taken in by an infant on a long-term basis.  It may 
be argued that a single dose of a chemical that is not acutely 
toxic clinically may be less harmful for the infant than the same 
dose per unit body weight would be for the older child or adult, 
because the chemical would be more rapidly diluted.  Clearly, the 
ability to eliminate substances from the body is also important, 
and this is discussed in section 3.  There is also the possibility 
that the chemical within the body may itself hinder growth. 



Table 1.  Increase in weight of body and 
organs during the first 9 months after 
Body/organ         Increase                                
                   (g/kg weight at birth)                  
Body               1810                                    
Brain              1480                                    
Liver              1420                                    
Kidneys            1580                                    
Heart              1160                                    
Lungs              1500                                    
a   Based on: values given in Diem & Lentner (1970).

    The constituents of some organs and tissues have a slower rate 
of turnover than those of others.  The lipids, for example, once 
laid down, have a slow rate of turnover compared with protein, in 
all parts of the body including the brain. Fat-soluble chemicals, 
which might be incorporated into brain lipids during the rapid 
growth of the brain in infancy (Dobbing & Sands, 1973), would not 
enter the tissue in significant amounts after the growth of the 
brain has ceased.  The fatty acid composition of brain lipids of 
rats and guinea-pigs can be appreciably altered, early in life, by 
the nature of the fat in the diet of the mother during pregnancy 
and lactation (Svennerholm et al., 1972; Pavey & Widdowson, 1980). 
Information on man is lacking. 

1.3.4  Different body composition from adult

    Infants have a different body composition from adults.  As in 
adults, the contribution of fat to the body weight varies 
considerably between one individual and another in infants, but the 
average is about 15% in full-term new-born infants and in adult 
men.  However, infants have a higher percentage of water and a 
smaller percentage of solids in the lean body tissue.  The infant, 
at term, has 82% of water in its lean tissue compared with 72% in 
the adult (Widdowson & Dickerson, 1964).  The additional water in 
the infant is mainly extracellular, the volume of extracellular 
fluid per unit body weight in the young infant being about twice 
that in an adult (Widdowson & Dickerson, 1964).  Thus, any chemical 
that is confined to the extracellular compartment of the body will 
have a greater volume in which to distribute itself per unit body 
weight.  The advantage of this for the infant could be offset by 
the slower rate of excretion by the kidneys (section 3). 

    The percentage of water in the organs and tissues, and thus in 
the body as a whole, decreases with age. The levels of water in 
some organs at birth, at 6 - 12 months where figures are available, 
and in the adult (Widdowson & Dickerson, 1964) are shown in Table 
2.  The decrease in water in the liver, kidneys, heart, and lungs 
is due primarily to an increase in protein; in the brain, it is due 
to an increase in myelin. 

Table 2.  Water in organs and tissues (g/kg)a
Organ/tissue          At birth    6 - 12   Adult
Whole body (fat-free  820         780      720
Brain                 900         830      770
Liver                 780         760      710
Kidneys               840         -        810
Heart                 840         830      830
Lungs                 860         -        790

Skeletal muscle

Total                  800        780      790
Extracellular          350        290      180
Intracellular          450        490      610
a   From: Widdowson & Dickerson (1964).

    Another difference between infants and adults is that most of 
the cells of the organs and tissues of infants are smaller than 
those of adults (Widdowson et al., 1972).  Small cells, like small 
bodies, have a larger surface area in relation to mass than bigger 
cells and bodies, and this in itself may have important 
implications for chemicals that may enter the cells. 

    The bones of an infant contain more water and less fat, 
protein, and mineral than adult bones.  This is illustrated in 
Table 3 for the whole femur (Dickerson, 1962b).  Unlike soft 
tissues, the chemical maturation of the bone, as evidenced by the 
decrease in percentage of water and increase in degree of 
calcification, mainly takes place after 1 - 2 years.  From the 
values in Table 3, it can be calculated that the increment per 
month of calcium in one femur is approximately 0.2 g between birth 
and 18 months, 0.48 g between 18 months and 11 years, and 1.0 g 
between 11 and 18 years.  The femur may not be completely typical 
of all parts of the skeleton, but it does seem likely that the rate 
of deposition of chemicals taken up by the bone along with calcium, 
and indeed with magnesium, sodium, and other metals present in 
bone, is likely to be greater in later childhood than in infancy.  
However, the bones of infants are smaller, and the rate of 
deposition of calcium per kg of bone per month is greater in 
infancy, being 7.8 g/kg bone between birth and 3 months, 6.8 g/kg 
between 3 and 18 months, and 1.9 g/kg bone between 18 months and 18 
years.  Thus, whether the bones of infants are considered likely to 
take up more or less of a chemical than those of older children 
depends partly on the method of expression of the rate of 

Table 3. Composition of the whole femur of the infant, child, and adulta
                    At birth  3 months   1 - 2     11 - 12     Adult
                    (full-    (milk      years     years (pre-
                    term)     feeding)   (weaned)  adolescent)
Weight femur g      16.6      26.4       63.7      326         646

Fat g/kg fresh bone 1.4       6.5        75        26          31

 Composition g/kg
 fresh fat-free bone

  Water             639       641        554       364         227
  Collagen          93        107        141       163         173
  Ca                61        54         70        138         194
  P                 28        27         33        63          83
a  From: Dickerson (1962b).

1.3.5  Functional immaturity of the organs and systems of the body

    Most organs and systems of the body have not reached structural 
or functional maturity at birth.  Development of the nervous system 
continues in postnatal life, much of the myelination of the brain 
takes place after birth and continues until adolescence (Hoar & 
Monie, 1981).  The structural development of the lung also 
continues postnatally with an increase in alveolar surface area 
(Langston, 1983).  Several components of the immune system are not 
fully developed at birth, for example, the lymphocytes responsible 
for producing antibodies, and it has been suggested that this is 
responsible for the greater susceptibility of the new-born infant 
to certain bacterial infections (Andersson et al., 1981).  The 
gastrointestinal, endocrine, and reproductive systems, and also 
renal function, are all immature at birth.  The kidneys are less 
able than those of older children and adults to eliminate excessive 
amounts of substances normally present in milk, for example, sodium 
and phosphate (Dean & McCance, 1947a, 1948; Barltrop & Oppé, 1970), 
and this may also apply to extraneous chemicals present in, and 
absorbed from, milk. Moreover, the activities of many liver enzyme 
systems that metabolize endogenous and exogenous substances may be 
low in the new-born infant.  These topics are covered in more 
detail in section 3. 

1.3.6  Breast milk, infant formulae, and water as sources of 

    The young infant lives on a single food, milk, either from the 
breast or the bottle.  Thus, the presence of a chemical in breast 
milk, or in the powder or water used to make up an infant formula, 
is likely to have greater implications for the infant than for the 
older child having mixed feeding, where milk forms only part of the 
daily food.  Furthermore, infants take in a much larger amount of 
fluid per unit body weight than older children and adults.  An 
infant living on milk takes about one-seventh of its own weight of 

water each day, which would correspond to 10 litres for a 70-kg 
man.  This large intake is necessary for the infant, because it 
loses more water per kg body weight through the lungs, owing to the 
greater passage of air through them, the skin, because of the 
larger surface area, and the kidneys, because of the inability to 
concentrate the urine to the same extent as the older child or 
adult.  Any chemical present in the water used to make up infant 
formulae will, therefore, be taken in by an infant in larger 
quantities per unit body weight than by an older child or adult 
using the same water supply.  This is discussed in more detail in 
section 2. 

    Nowadays, it is common practice among manufacturers to add 
vitamins and trace elements to their preparations.  Occasionally, 
these have been added in such large amounts that they have been 
reported to be toxic, even though in smaller, physiological amounts 
they are essential.  Examples are vitamin D (British Paediatric 
Association, 1956) and manganese (Collipp et al., 1983). 

1.4  Applicability of Data on Experimental Animals to Human Infants 
and Young Children

    Data on the toxic effects of chemicals in man are frequently 
incomplete or even absent, and this is particularly true for 
infants and young children.  Some insight can be gained from 
observations on young animals, but any assessment of human risk on 
the basis of such studies should take into account the differences 
that exist between the species in their reactions to chemicals.  
Moreover, the conditions under which the animal data were obtained 
may not reflect the human circumstances under consideration.  
Animal data must be considered, therefore, in the context of the 
similarities and differences that are known to exist between man 
and experimental animals, and conclusions need to incorporate a 
margin of safety to accommodate known, and possibly unknown, 
species differences. 

1.4.1  Some similarities in growth and development between
man and experimental animals

    In many ways, the differences between the young infant and 
adult are the same in animals as they are in man.  Thus, the infant 
animal is always smaller than the adult and, thus, it has a larger 
surface area in relation to its body weight.  All animals that are 
homoeothermic from the time of birth have a higher consumption of 
air per unit body weight than the adult of the same species, at the 
same environmental temperature. The young of all animals species 
grow rapidly, often far more rapidly than the human infant, and 
their body composition differs from that of the adult in the same 
way that that of the human infant differs from that of the human 
adult.  The functions of the organs and systems are immature in 
early life, and most mammalian species depend on mother's milk for 
a period after birth. 

    The anatomical, physiological, and chemical differences between 
the infant and adult of an animal species are therefore in the same 
direction as they are in the human species, and, in general, the 

effects of chemicals on the young of experimental animals can be 
expected to differ from those on the adult of the species just as 
they do in man. However, the differences between species make it 
unwise to assume that the results obtained on a young animal will 
necessarily apply to the human infant. 

1.4.2  Some differences in growth and development between man and 
experimental animals 

    Different animals are born at different stages of their 
anatomical, physiological, and chemical development and, although 
the qualitative differences between the infant and adult are 
similar in man and experimental animals, the quantitative 
differences are by no means the same.  The rat is a widely used 
experimental animal in studies on the effects of chemicals on the 
infant body.  Some stages of development that take place after 
birth in the rat have already occurred in the human fetus before 
birth.  Examples are the anatomical and functional maturation of 
the hypothalamus (Dörner & Staudt, 1972) and the deposition of body 
fat.  Some aspects of development, however, only occur after birth 
in all species, for example, respiration of air and the full 
functioning of the gastrointestinal tract. 

    The new-born rat is smaller than the new-born human infant in 
comparison with the weight of the adult, and, during infancy, it 
grows at a much more rapid rate.  Thus, the discussion in section 
1.3.3 about the human infant applies with even greater force to the 
infant rat.  The rat at birth has a less mature chemical 
composition than the human infant, as evidenced by the higher 
percentage of water in its lean body tissue (Widdowson & Dickerson, 
1964).  The greater degree of immaturity of the body composition of 
the rat at birth is well illustrated by reference to the bones.  
Characteristically, rat bones have very little fatty marrow, but, 
apart from this, the composition of the adult femur is not very 
different in the 2 species.  At birth, however, the rat femur has 
less than half the concentration of calcium that there is in the 
human femur, more water, and considerably less collagen, which 
makes up the matrix on which the bone mineral is deposited 
(Dickerson, 1962a,b).  In the rat, as in man, the major changes in 
the composition of bone do not take place until the period of 
infancy is over.  The composition of bone, and of the body as a 
whole, though less mature at the time of birth in the rat than in 
man, changes much more rapidly.  All this must be taken into 
account in considering the effects of a chemical on the bones or 
bodies of young rats compared with the effects on those of human 

    The new-born rat is less mature physiologically than the human 
infant, and it matures more rapidly.  This may limit the 
application of results obtained on the young rat to the human 
infant.  This is true of the renal function (McCance, 1948), so 
that the new-born rat is less able than the adult to excrete 
chemicals administered to it (section 3.5.1). 

    The activity of the hepatic enzymes is low in both new-born 
experimental animals and new-born human infants, but the whole 
subject of enzyme activity in this context is complex and is 
considered in more detail in section 3. 

    One difference between the young of man and some animal species 
is the ability to absorb macromolecules from the intestine.  In the 
human infant, the passage of macromolecules across the intestinal 
mucosa is very limited, but in the young of such species as the 
pig, cow, sheep, and horse, macromolecules are transferred from 
the milk into the circulation in quite large amounts for a limited 
period of hours or days. In the rat, the transfer goes on all 
through the suckling period (Walker, 1979).  This may have a 
bearing on the interpretation of the results of studies on the 
intestinal absorption of certain chemicals by the new-born 
experimental animal in relation to the human infant. 

1.5  Conclusions

    The infant and young child have different structural and 
functional characteristics from those of the older child and adult, 
which represent stages in normal growth and development.  These 
include a larger surface area in relation to weight, different body 
composition, a higher metabolic rate and oxygen consumption and, 
hence greater intake of air per unit body weight, rapid growth and 
development of the body as a whole and of the organs and tissues, 
particularly during the first 6 months after birth.  Many organs 
and tissues are functionally immature at the time of birth, and 
they mature at different rates.  Moreover, infants have greater 
energy and fluid requirements per unit body weight than older 
children and adults.  All these characteristics must be taken into 
account in considering principles for evaluating health risks from 
chemicals during infancy and childhood. 

    The structural and functional differences between the infant 
and adult animal tend to follow the same direction as in the human 
species, but there are important quantitative differences in, for 
example, the stage of development at birth, the rate of growth, and 
the intestinal absorption of macromolecules.  The age of the infant 
rat or other animal corresponding to an age in the human infant 
will differ according to the aspect of development under 


2.1  Introduction

    As with adults, the potential for exposure to chemicals for 
infants and young children is through ingestion, inhalation, and 
percutaneous absorption.  Both voluntary and inadvertent exposures 
may occur, but their nature and extent are modified by the 
physiological, behavioural, and other characteristics peculiar to 
this age group.  Thus, the methods of nurture, the social, 
cultural, and occupational proclivities of the family, the quality 
of care and supervision, and the inherent behavioural patterns of 
the child, may all be significant factors for determining or 
modifying exposure. 

    The new-born infant may already have encountered toxic chemical 
agents  in utero by the placental route; for example, the sequelae 
of maternal exposure to methylmercury (Clarkson et al., 1976), 
ethanol (Jones & Smith, 1975), tobacco (US DHEW, 1979), and 
narcotics (Barr et al., 1984) are well recognized.  Moreover, the 
young infant is an obligate milk feeder, and chemicals that 
traverse the mammary gland in lactation are potentially important 
contaminants of both human and artificial milk. 

    The use of appropriate cleaning and antiseptic chemicals for 
the routine care of the skin, umbilicus, and clothing of the new-
born infant have all been associated with toxicity (Armstrong et 
al., 1969).  Similarly, effects from atmospheric contaminants have 
been encountered in neonatal units from agents used on the clothing 
or for the disinfection of apparatus and operational areas. 

    Development from infancy to childhood is marked by increasing 
mobility and exploration of the immediate surroundings.  Oral 
exploration is commonplace towards the end of the first year of 
life in which the mouth is used to sample the taste and texture of 
the objects and materials that are encountered.  Oral exploration 
may be accompanied by the ingestion of a wide variety of substances 
not normally regarded as food (pica) including soils, dusts, and 
surface coatings in the vicinity of the home.  Although mouthing 
and pica diminish with continuing development after the first year 
of life, hand to mouth activity tends to persist (Barltrop, 1966). 

    As a consequence of increasing mobility and diminishing 
supervision, poisoning due to the ingestion of toxic substances is 
very common in early childhood.  For example, in England and Wales, 
one-fifth of all hospital admissions for suspected poisoning 
involved children under the age of 5 years, amounting to 
approximately 20 000 admissions per annum. Household, 
horticultural, agricultural, and industrial chemicals were all 
implicated, though medicaments and therapeutic compounds were the 
principal agents (Vale & Meredith, 1981).  It is unlikely that all 
acute ingestions are reported, and their prevalence is not known 
with certainty.  The quality of available supervision is an 
important determinant of accidental poisoning and will itself be 
modified by social, cultural, and economic factors. 

    Infants and children will also be subject to chemical exposure 
resulting from contamination of the natural and domestic 
environments that they share with adults.  However, the provision 
of foodstuffs, beverages, clothing, furniture, toys, and 
medicaments, specifically manufactured or adapted for the young, 
may modify the route of exposure for certain chemicals; efforts are 
usually made to minimize the contamination of such materials with 
chemicals that might be harmful. 

2.2  The Alimentary Tract 

2.2.1  Milk

    Milk may be regarded as one of the routes of excretion of 
foreign compounds that have entered the body of the lactating 
mammal.  The degree to which a particular chemical traverses the 
mammary gland depends on several factors, including its own 
physical and chemical properties, such as the degree of ionization 
and binding in biological fluids, the solubility characteristics, 
and the maternal plasma concentration achieved.  Passive diffusion, 
active transport, and reverse pinocytosis across the apical 
membrane of the mammary alveolar cell may all be involved, but the 
milk/plasma ratio cannot always be predicted for a given chemical 
in a particular species.  In general, transfer from plasma to milk 
is enhanced by high solubility in lipids, low relative molecular 
mass, and weak binding to plasma-proteins (Giacoia & Catz, 1979).  Human milk

    Nearly all chemicals to which the mother is exposed may, to 
some extent, be excreted in human milk (Jensen, 1983, 1985).  
Contamination of human milk may result from the maternal diet, 
environment, occupation, addiction, and medical treatment.  Marked 
variation in the concentrations of chemicals in milk, both between 
and within individuals, is characteristic and may reflect the stage 
of lactation, the time and method of sample collection, and the 
age, weight, and parity of the mother.  Chemical residues most 
frequently reported in human milk are the organochlorine pesticides 
(DDT) and industrial chemicals (PCBs and metabolites, HCH isomers, 
and cyclodienes such as dieldrin).  Lactation is a route of 
excretion for some of these chemicals, and adverse health effects 
have been noted in breast-fed infants when the concen-tration of 
chemicals was extremely high, as in accidental poisoning outbreaks, 
and in some cases of occupational exposure. During the Iraqi 
outbreak of methylmercury poisoning of 1971-72 (Amin-Zaki et al., 
1974), mothers who consumed bread made from seed grains treated 
with a methylmercury fungicide were found to have milk containing 
8.6% of the concentration of mercury in maternal blood collected at 
the same time (Amin-Zaki et al., 1976).  Infants who were born 
before their mothers ate the contaminated bread and who received 
methylmercury only through suckling, were found to have blood-
mercury values of up to 1.0 g/litre.  Follow-up assessment over 5 
years showed that some of the children suffered impaired 
neurological and mental development (Amin-Zaki et al., 1981). 

    In Turkey, bread prepared from seed grains treated with 
hexachlorobenzene between 1955-59 also affected infants (Peters, 
1976).  In some villages, almost all children under the age of 2 
years, who had been breast-fed by mothers who had eaten the 
contaminated wheat, died of the condition known as "pembe yara" 
(Turkish for pink sore), which included symptoms of weakness, 
convulsions, and localized cutaneous annular erythema. 

    Reports of such episodes have been rare.  However, if 
confronted with such poisoning outbreaks, exposure of infants 
through human milk should be considered.  Other types of milk

    Cow's milk, and the milk of other species used for infant 
feeding, are subject to contamination by many of the chemicals 
found in human milk, together with others that reflect local 
techniques of animal husbandry and veterinary practice. Infants fed 
milk derived from a particular animal or herd may be at greater or 
lesser risk of exposure to a given contaminant than those fed 
artificial or manufactured milk derived from the pooled secretions 
of multiple herds.  Conversely, the pooling of milk during the 
manufacture of infant feeds will tend to increase the number of 
potential contaminants in the end-product, but may diminish their 

    The food sources of lactating animals may be contaminated by 
local industrial wastes, by the application of pesticides, by 
naturally-occurring substances, such as mycotoxins, or by storage 
in containers or buildings previously contaminated with pesticides, 
disinfectants, preservatives, and other chemicals.  The 
organochlorine pesticides are well recognized fodder contaminants.  
Numerous examples are known of milk containing chemicals derived 
from animal feeds including DDT, hexachlorocyclohexane (HCH) 
(Miyabe et al., 1971), heptachlorepoxide (Smith, 1982), and 
hexachlorobenzene (Goursaud et al., 1972).  Chemicals in milk 
derived from containers of contaminated animal feed include PCBs 
(Villett & Hess, 1975), pentachlorophenol (PCP) (Haering & 
Schefer, 1980), and dieldrin (Epps et al., 1974).  The inadvertent 
substitution of a polybrominated biphenyl (PBB) product for 
magnesium oxide in prepared cattle feeds resulted in contamination 
of the milk (Isleib & Whitehead, 1975). 

    Several examples of milk contamination occurring after 
collection have been reported.  Thus, iodophors and other 
disinfectants (Kroger, 1972), dieldrin (Tadjer & Dore, 1971) and 
chlordane (Landsberg et al., 1977) have all been identified in milk 
stored in vessels that had been inadvertently rinsed or cleaned 
with, or fabricated from, previously contaminated materials.  The 
inadvertent addition of toxic chemicals to infant milk during 
manufacture is rare, though arsenic poisoning resulting from the 
use of a contaminated sodium phosphate stabilizer has been reported 
(Kitamura et al., 1953). 

    Pesticides and drugs for the control of parasitic infection and 
other diseases in lactating animals are liable to be absorbed and 
excreted in the milk, even after topical application.  Milk 
contamination with antibiotics and hormones, given for economic 
rather than therapeutic or preventative indications, may also 
occur.  Infant feeds

    Foods and beverages, other than milk, which have been 
specifically prepared or manufactured for infants and young 
children, may be diverse in composition and comprise only a 
proportion of the total dietary intake.  However, they are subject 
to the same sources of chemical contamination as foods intended for 
adults, during producion, manufacture, and packaging.  The 
potential significance of contaminants is enhanced when the dietary 
range is restricted. 

    Numerous examples of contamination at source have been 
described in common with those for human and other milk. Thus, 
residues of pesticides, antibiotics, fungicides, and heavy metals 
have all been encountered as a result of agricultural techniques, 
veterinary practice, and the use of contaminated land and water.  
An additional factor with regard to meat products is, for example, 
the use of anabolic agents, such as diethylstilboestrol, in animal 
husbandry (Umberger, 1975).  Thus, in one study, one-third of 450 
samples of baby food containing veal were found to have detectable 
estrogen activity (Loizzo et al., 1984). 

    Many chemical or non-nutritional substances are used in food 
manufacture as preservatives, anti-oxidants, stabilizers, 
emulsifiers, and thickening agents, with the intention of ensuring 
that the food is wholesome and palatable, when consumed.  Numerous 
chemical colouring agents are potentially available, and their use 
in infant foods has attracted controversy, since marketing rather 
than nutritional considerations are involved. 

    Manufactured infant and junior foods are characteristically 
distributed in appropriately small containers which, therefore, 
have a relatively large surface area/volume ratio. The degree to 
which contaminants derived from the container material, seams, or 
internal surface coatings may affect the contents is inversely 
proportional to the container volume. The degree to which the 
container design and manufacture may influence food contamination 
is indicated by the reduction of dietary lead intake observed in 
infants in the USA during the last decade, when progressive 
replacement of lead soldered side-seamed cans by welded or seamless 
containers resulted in a 47% reduction in lead intake by infants 
aged 0 - 5 months (Mahaffey, 1983). 

    Contamination of foods during preparation in the home may 
result from the use of inappropriate vessels, culinary agents such 
as cooking oils, and cleaning materials, as well as from water.  
Thus, excessive intake of copper derived from domestic cooking 
utensils has been implicated in Indian childhood cirrhosis (Marwha 

et al., 1981), and contaminated edible oils were involved in an 
outbreak of Yusho disease (Kuratsune, 1980; Japan/US Cooperative 
Science Program, 1983). 

    The use of detergent chemicals for the cleaning of cooking and 
eating utensils is inevitably associated with ingestion of the 
chemicals by all members of the household, but, in normal usage, it 
is unlikely that toxic intakes will be encountered. However, 
intakes are likely to be enhanced when rinsing or wiping is 
omitted.  Water

    Water for domestic consumption may be contaminated by chemicals 
at source, during treatment and transport, or in the home from 
domestic plumbing, cisterns, or culinary utensils. The use of 
recycled water, particularly during drought, will tend to enhance 
the concentration of some pollutants.  The direct ingestion of 
water used in the preparation of foods and beverages will involve 
children of all ages, depending on local climatic conditions and 
cultural and dietary practices. However, the use of water to 
reconstitute powdered artificial milk is a special case, 
particularly where the milk is the sole nutrient source. 

    The potential contaminants of drinking-water are numerous and 
include a wide range of metals and other elements; nitrates, 
cyanide, thiocyanate, and ferrocyanate radicals; organic compounds 
including pesticides; organic solvents; and anionic, cationic, and 
non-ionic detergents.  Asbestos and polyaromatic hydrocarbons have 
been detected.  The chlorination of water for disinfection, 
particularly in the presence of humic material, results in the 
formation of a number of haloforms or C-chlorinated compounds 
including chloroform, bromodichloromethane, and 
dibromochloromethane (Rook, 1974). 

    The significance of lead in drinking-water has been 
increasingly appreciated, particularly in areas where lead pipes 
and plumbosolvent water supplies co-exist.  Studies in a population 
in Scotland showed that there was a curvilinear relationship 
between the concentration of lead in water and that in the blood of 
artificially fed infants; 36% had blood-lead values in excess of 
350 µg/litre (Sherlock et al., 1982).  Similarly, lead intakes of 
up to 3.4 mg/week were reported from Scotland in artificially fed 
infants, whose food was measured and analysed, with correspondingly 
marked increases in blood-lead values (United Kingdom Central 
Directorate on Environmental Pollution, 1982). 

    Nitrate in drinking-water is not itself hazardous, but may be 
converted to nitrite by nitrate-reducing bacteria in the 
gastrointestinal tract of infants under appropriate conditions.  
Nitrites promote the formation of methaemoglobin from haemoglobin, 
thus impairing the transport of oxygen and causing cyanosis.  
Methaemoglobin is especially associated with the consumption of 
well water with a high nitrate content, and infants appear to be 
more susceptible to it than older children and adults (American 
Academy of Pediatrics Committee on Nutrition, 1970). 

2.3  The Respiratory Tract

    Although infants and children may inhale chemical compounds, 
information concerning the structure and function of the 
respiratory tract in this context is limited.  It is known that the 
architecture of the respiratory tract continues to develop, at 
least until the age of 18 months.  Anatomically, 3 processes have 
been identified including: 

    (a) centripetal alveolization giving rise to an extra
        generation of respiratory bronchioli;

    (b) transformation of some distal respiratory bronchioli
        into alveolar ducts; and

    (c) further branching of 1 or 2 alveolar duct generations.

    After the age of 18 months, the respiratory structures increase 
in size with a progressive increase in elastic fibre bundles in the 
alveolar wall up to the age of 18 years.  The length/diameter 
relationship of each respiratory unit remains relatively constant 
throughout development.  The effects of these architectural changes 
is thought to be minimal in the case of inhaled aerosols, but the 
position concerning suspended particulates of various sizes has 
not been well studied in childhood (Hislop & Reid, 1981). 

    Numerous chemical substances are found in the atmosphere, and 
over 1600 have been identified.  Not all of these are man-made, and 
many may be derived from a single source (Graedel, 1978).  The bulk 
of atmospheric pollution is provided by carbon monoxide, 
particulates and oxides of sulfur, hydrocarbons, and oxides of 
nitrogen.  Not all pollutants act directly; for example, the oxides 
of nitrogen may exert their effects indirectly, by virtue of their 
role in photochemical smog formation (National Research Council, 
Subcommittee on Airborne Particles, 1979). 

    The exposure of infants and children to atmospheric pollutants 
may be enhanced compared with that of adults, if the pollutants are 
emitted close to the ground or, in the case of aerosols, are gases 
or vapours of high density. 

2.4  The Skin

    Percutaneous absorption of chemical substances is known to 
occur through normal skin in both adults and children.  There is 
little evidence that the rate of absorption varies with age, since 
the limiting factor would appear to be the thickness of the 
stratum corneum, which is relatively constant throughout postnatal 
development after a full-term birth. Different processes of 
absorption are thought to exist, but the transcutaneous flux cannot 
be predicted with certainty, since marked variations in absorption 
rates have been observed between closely related chemical 
compounds.  While absorption through normal skin does not vary with 
age, absorption is greatly enhanced when the skin barrier is 
damaged or when the substance is applied under an occlusive 

dressing.  A problem specific to infants is that napkins (diapers) 
serve as an occlusive dressing, which may promote the absorption of 
chemicals applied to the buttocks and increase the likelihood of a 
systemic effect.  Absorption may be further enhanced by skin 
reactions in the napkin area. 

    The prematurely born infant may constitute a special case, 
since studies on the development of the stratum corneum in fetal 
life suggest that the permeability barrier is incomplete until just 
before term (Singer et al., 1971).  Thus, pre-term infants bathed 
with a solution of hexachlorophene showed greater peak blood 
concentrations of the compound than full-term infants subjected to 
the same procedure (Greaves et al., 1975). 

    A pertinent factor in infants is the relatively large surface 
area to body weight ratio; thus, compounds absorbed through a given 
part of the skin surface will result in greater tissue 
concentrations than in an adult (Wester & Maibach, 1982). 

2.5  Conclusions

    Infants and young children may be exposed to chemicals by the 
gastrointestinal, respiratory, and percutaneous routes. The 
relative importance of these routes will vary with age according to 
the nature of the diet, the behavioural characteristics, and the 
maturation of the system involved. 

    Since infants are obligate milk feeders, they will ingest 
chemicals that cross the mammary gland during lactation. These are 
potentially important contaminants of both human milk and infant 
formulae containing the milk of other species. Similarly, chemicals 
contaminating the water used for the reconstitution of powdered 
milks will contribute to the ingested burden.  Foods and beverages 
specially manufactured for infants and young children are also 
potentially important sources, especially when the dietary range is 
restricted. Oral exploration, hand to mouth activity, and pica 
contribute to the risk of ingestion of chemicals encountered in the 
domestic environment. 

    Limited information is available concerning the absorption of 
inhaled chemical atmospheric pollutants in relation to the 
continuing development of the respiratory tract.  However, exposure 
of infants and children to atmospheric pollutants may be enhanced 
compared with that of adults, when the source of emission is close 
to the ground, and under circumstances in which gases or vapour of 
high density are involved. 

    Chemicals can be absorbed through normal skin, but, in infants 
and children, the relatively large surface area to body weight 
ratio may result in greater tissue concentrations than in the 
adult.  Percutaneous absorption is enhanced when the skin is 
damaged or macerated, or when the substance is applied under an 
occlusive dressing such as a napkin (diaper). The prematurely born 
infant may constitute a special case, since the permeability of the 
skin is greater, because of the incomplete development of the 
stratum corneum. 


3.1  Introduction

    Because of the morphological, biochemical, and physiological 
characteristics of the infant and young child described in section 
1, the kinetics of chemicals gaining access to their bodies need 
special consideration, particularly with regard to the timing of 
the maturation processes governing absorption, distribution, 
biotransformation, and elimination from the body. 

3.2  Absorption

    A chemical may be absorbed through an external (skin) or 
internal (gastrointestinal and respiratory tract) surface. 
Absorption depends on the physical and chemical characteristics of 
the chemical, its concentration gradient, the conditions at the 
site of absorption, and the biological characteristics of the 
absorptive surface.  The conditions at the site of absorption and 
the characteristics of the absorptive surface can be expected to 
change with age; for example, postnatal changes in pH in different 
parts of the gastrointestinal tract and skin, and alterations in 
the thickness and structure of membranes of the gastrointestinal 
tract and lungs (Hoffmann, 1982) cause changes in perfusion, which 
in turn influence the concentration gradient. 

3.2.1  Absorption from the gastrointestinal tract

    Absorption from the gastrointestinal tract is an important way 
in which chemicals enter the body of the infant and young child.  
It is influenced by pH, total mucosal surface area, blood supply, 
perfusion rate, and period of contact of the chemical with the 
absorptive surface, that is the gastric emptying and intestinal 
transit time.  All these change with postnatal development. 

    The absorption of some chemicals by infant animals is greater 
than that by young adults of the same species.  This can be 
explained by several factors, including immaturity of the 
gastrointestinal tract, the characteristics of the infant's diet, 
and the greater proportion of nutrients absorbed.  This is of 
benefit for growth, but is a disadvantage as far as non-nutritive 
chemicals are concerned.  Much of the evidence for this comes from 
studies on experimental animals exposed to metals.  Thus, the adult 
rat absorbs 1% or less of lead added to its diet compared with 40 - 
50% for the infant animal (Kostial et al., 1971, 1978; Forbes & 
Reina, 1972a,b).  According to Alexander et al. (1974) and Ziegler 
et al. (1978), infants and young children absorb substantially more 
lead than adults, but Barltrop & Strehlow (1978) did not find any 
age-related differences.  The intake of lead by the infants studied 
by Alexander et al. (1974) and Ziegler et al. (1978) was greater 
than that of the children in the study of Barltrop & Strehlow 
(1978), and this may explain the different result. 

    Methylmercury is well absorbed in the gastrointestinal tract of 
infants and young children, as it is in adults (Berlin, 1983).  
Some methylmercury is evidently re-excreted into the intestine and, 
if this is demethylated by the intestinal bacteria, the mercuric 
mercury from it is excreted in the faeces.  In mice, there is an 
increase in intestinal demethylation at weaning, and the results of 
 in vitro studies have shown that the microflora in faeces from 
young infants receiving milk have negligible demethylating ability 
compared with those of weaned children and adults (Rowland et al., 
1983).  Thus, it seems likely that more of a dose of methylmercury 
will be retained within the body of young infants than of older 
children and adults. 

3.2.2  Absorption from the lungs

    Chemicals permeate the air-blood barrier by simple dif fusion, 
but the thickness of the membrane, its lipid composition, surface 
area, and porosity determine pulmonary absorption.  Lipid-soluble 
chemicals are absorbed at similar rates by the lungs of new-born 
and adult rats, but hydrophilic chemicals are absorbed at a more 
rapid rate by young animals (Hoffmann, 1982). 

3.3  Tissue Distribution

3.3.1  Binding of chemicals to proteins

    Most of chemicals bind to plasma-proteins.  The amount of 
binding depends mainly on the concentration and structure of the 
binding proteins, the affinity constant, and the presence of other 
compounds capable of modifying the chemical-protein interaction.  
In the new-born infant, several factors contribute to a lower 
plasma-protein binding than in the adult. The concentration of 
albumin in the plasma of neonates, and hence the number of binding 
sites, is low.  Moreover, these binding sites are occupied by 
endogenous substances such as fatty acids, steroids, and bilirubin.  
Thus, new-born infants have a lower capacity for binding chemicals 
to plasma-albumin, and competition at the binding site may lead to 
the release of, for example, bilirubin, resulting in kernicterus.  
Moreover, hypoxaemia and acidosis may also decrease binding 

3.3.2  Distribution within the body

    From early fetal to adult life, the fluid compartments of the 
body change continuously.  The larger extracellular space in 
infancy (section 1.3.4) provides a larger volume for the 
distribution of water-soluble chemicals that do not penetrate the 
cells, and plasma concentrations of these chemicals may be lower in 
infants than in adults, even if the total body burden per unit body 
weight is greater. 

    Alterations in the morphology, physiology, and biochemistry of 
the organs, as well as in their weight relative to the body as a 
whole, may affect the distribution of chemicals. The brain is 
proportionately larger in the infant than in the adult, and rapid 
myelination during the first year after birth may favour the uptake 

of lipophilic compounds.  Metals, too, are retained in the brain 
more readily in infancy than in adulthood.  Momcilovic & Kostial 
(1974), for example, found that a far greater percentage of the 
intake of lead was retained in the brain of the suckling rat than 
in that of the adult, and that the rate of removal was slower.  
Similarly, Kostial et al. (1978) and Wong & Klaassen (1980) found 
that a greater percentage of the intake of cadmium was retained in 
the brain of the suckling rat than in that of the adult; Jugo 
(1980) made a similar observation for mercury. There is little 
direct evidence about the human brain.  By analogy with animals, it 
seems likely that the concentration of lead in the brains of 
infants exposed to lead would rise more rapidly than the 
concentration in the brains of older children or adults exposed to 
a similar dose. 

    Methylmercury is known to accumulate in brain tissues, 
predominantly in grey matter, but whether the brains of infants and 
young children accumulate more than those of adults is not known. 

    Other tissues take up metals more readily in the early period 
of life, when the animal is growing rapidly, than when growth has 
slowed down or ceased; this particularly applies to the bones.  The 
concentration of lead in human bones doubles between infancy and 
the late teen years (Barry, 1975). 

    The liver and kidney also accumulate metals.  At birth, the 
concentrations of cadmium and mercury are low.  Henke et al. 
(1970), using neutron activation analysis, determined the cadmium 
concentrations in the liver and kidneys of 41 children and adults 
and found that they increased 200 fold during the first 3 years 
after birth.  The total increase in cadmium in the liver and kidney 
was greater than appears from the concentration, because both 
organs increased considerably in weight. 

3.4  Biotransformation of Organic Chemicals

    The kinetic behaviour of organic chemicals in living organisms 
is generally characterized by several processes modifying the 
duration of their action.  The limiting factors are either 
excretion through the kidneys, bile, or gastrointestinal tract, or 
biotransformation mechanisms in the liver or other organs.  The 
products of biotransformation are generally more polar than the 
original compound and, thus, are more readily excreted. 

    Biotransformation is brought about by enzyme activity, either 
associated with microsomal systems in the liver or with enzymes in 
the plasma or other tissues. 

    The biochemical processes involved in the biotransformation of 
organic chemicals can be divided into 2 phases: 

    Phase 1.  hydroxylation, dealkylation, dehydrogenation,
              reduction, hydrolysis, and other reactions
              producing a conjugable grouping; and

    Phase 2.  biosynthetic reactions, whereby conjugates are
              formed with endogenous polar molecules; these
              conjugates are, generally, readily excreted.

    Both Phase 1 and Phase 2 reactions are generally slower in the 
new-born infant than in the adult.  Consequently, blood-plasma 
half-lives of chemicals in which the degradation and elimination 
are dependent on one or the other or both of these types of 
reactions are generally appreciably longer in neonates than in 

    The rate of maturation of processes concerned with the 
biotransformation of organic chemicals varies from one reaction, 
and from one chemical, to another.  Highest activities are reached 
in children aged 12 - 16 years, after which there is generally a 
decline.  A detailed description, with full documentation, has been 
published by Klinger (1982). 

3.5  Elimination from the Body

3.5.1  Elimination by the kidneys

    The renal function of the full-term infant at birth is immature 
by adult standards, and this applies both to glomerular and 
tubular function (McCance & Young, 1940; Dean & McCance, 1947b).  
The rapid growth of the young infant (section 1.3.3) involves the 
retention of nitrogen and minerals, so that the equivalent of only 
part of the nitrogen and minerals absorbed from the food requires 
to be excreted by the kideys.  The breast-fed infant or the infant 
fed on a formula similar in composition to breast milk is able to 
do this satisfactorily, and so maintain the composition of the body 
fluids at their proper level (McCance & Widdowson, 1957a).  
However, excessive intakes of nutrients, such as protein 
(nitrogen), phosphorus, and sodium, are not excreted completely by 
the kidneys of the new-born infant or animal, and the 
concentrations in the plasma rise (McCance & Widdowson, 1956, 
1957b).  Retention of chemicals introduced into the body of the 
infant may be due to both renal immaturity and insufficient 

    The function of the renal tubules at full-term birth is less 
mature than that of the glomeruli, but it matures more rapidly 
(Edelmann & Spitzer, 1976).  This is important in the young infant 
for the chemicals that depend on tubular secretion for their 
elimination from the body.  Moreover, the reabsorption of chemicals 
from the tubular lumen into the tubular cells also varies with age 
and depends, in part, on the pH of the urine.  Weak organic acids 
are reabsorbed more readily by the infant, but, more important, the 
low capacity for biotransformation by the infant's liver results in 
organic chemicals reaching the kidneys in their original lipophilic 
form, and these are not excreted, but reabsorbed into the 
circulation (for reviews, see Scheler, 1980; Braunlich, 1981). 

    Some metals depend on the kidneys for their elimination from 
the body, and the results of animal studies suggest that suckling 
rats excrete less of their body burden of cadmium, mercury, and 

manganese than adults (Kostial et al., 1978). Infants appear to 
excrete a smaller proportion of absorbed lead by the renal route 
than adults (Ziegler et al., 1978). 

3.5.2  Elimination by the liver

    The excretion of chemicals in the bile is an important means of 
elimination, though some of the chemicals excreted through the bile 
may be reabsorbed in the gut and re-enter the body, thus resulting 
in their enterohepatic circulation.  They cannot penetrate the 
epithelium of the biliary duct.  Many chemicals are excreted by the 
liver as glucuronides in the bile, but the formation of 
glucuronides is limited in the new-born infants (section 3.4). 

3.5.3  Elimination by other routes

    Other routes of excretion include the gastrointestinal tract, 
the respiratory tract, and the skin.  They are non-regulatory and, 
while they may be important for some chemicals, information is 
limited about age-related differences in elimination. 

3.6  Conclusions

    Generally speaking, both organic and inorganic chemicals are 
absorbed more readily by the infant than by the adult, but the 
organic chemicals undergo biotransformation less readily. For some 
chemicals, alternative biochemical pathways may exist. 

    The kidneys of the neonate are immature and less able than 
those of the older child or adult to excrete chemicals, whether 
inorganic or the polar products of biotransformations. A greater 
proportion of a similar dose of a chemical per unit body weight is 
therefore likely to accumulate in the body of the infant, and the 
concentration of the chemical in the blood and tissues of the 
infant will be higher.  The possible effects of this are discussed 
in section 4. 


4.1  Introduction

    Differences in kinetics can enhance the toxicity of a chemical 
in the infant but, in some cases, may result in a qualitative 
difference of response or in a lower toxicity, depending on the 
intermediary metabolite.  In addition, the qualitative and 
quantitative response of the target tissues to the same internal 
dose of a chemical may be different at various stages of postnatal 
development because of the gradual development of characteristics 
of the target tissues.  A third aspect of developmental toxicology, 
which should be recognized, is the fact that a chemical introduced 
into the body of an infant or young child may affect the structural 
and functional development of a particular organ or system, which 
may interfere with the growth and development of the body as a 
whole.  Animal studies have shown that the toxic effects of certain 
chemicals are different at different stages of development.  
Moreover, chemicals reaching the body early in life may produce 
delayed effects in later years.  The response of the growing infant 
may therefore be different from that of the fully grown adult. 

    The problems of extrapolating quantitatively from animals to 
man and reaching conclusions on the implications of evidence from 
animal studies for human health are well known. These problems are 
greater during the new-born period, since the stage of development 
at the time of birth varies considerably between species (section 
1.4.2).  Information from clinical experience of exposure is 
limited, and systematic epidemiological data from studies on 
infants are sparse, so that the results of studies on animals may 
provide the only information available.  When information 
concerning human infants is available, it should be given 

4.2  Effects of Chemicals on General Growth and Development

    General growth and development are possible indicators of the 
effects of chemicals on infants and children, whether the exposure 
occurred prenatally or postnatally.  The principles for evaluating 
the effects of prenatal exposure have been considered in an earlier 
Environmental Health Criteria publication (WHO, 1984).  Factual 
information about the effects of postnatal exposure is scarce.  In 
a study on the infants of mothers who had consumed bread 
contaminated with a methylmercury fungicide during lactation, Amin-
Zaki et al. (1981) found abnormal neurological signs in some 
infants at the first examination and in more infants on subsequent 
occasions.  Delayed motor and other aspects of development, 
including intelligence, were not detected when the infants were 
first seen, but were observed at follow-up examinations during the 
next 5 years. 

4.3  Effects of Chemicals on Some Organs and Systems

4.3.1  Nervous system

    The brain of the infant at birth is not fully developed. The 
full number of neurones is not reached until about 2 years of age 
(Dobbing & Sands, 1973); myelination is not complete until 
adolescence (Hoar & Monie, 1981). 

    Brain development involves changes in the proportions of myelin 
and non-myelinated tissue.  Shuman et al. (1975) observed status 
spongiosus in the myelin sheaths of the reticular formation of 
premature infants, following exposure to hexachlorophene, but no 
lesions were present in the non-myelinated part of the brain.  
Brain lesions were not produced during the first 8 - 10 days after 
birth in the rat. However, between 10 and 25 days, when myelination 
takes place, the suckling rats became sensitive to hexachlorophene 
(Nieminers et al., 1973; Ulsamer et al., 1975). 

    There are changes in the sensitivity of the brain of the rat to 
hormones or drugs during development, and this has been correlated 
with the development of the cell receptors (Macho et al., 1972; 
Valcana & Timiras, 1978).  On the basis of experimental data, Czaba 
(1984) concluded that, during maturation, cell receptors in several 
organs require reinforcement by the appropriate hormone at a 
critical stage of development.  This process can be hindered or 
prevented by the presence of molecules analagous to the hormone, or 
by a drug or other chemical that binds to the receptor and so 
prevents reinforcement by the hormone and hence normal development. 

    Many confounding factors and co-variables such as nutrition, 
socio-economic status, and mental stimulation have to be taken into 
account when evaluating the effects of a chemical on the 
functioning of the human brain.  Only when good information on 
these factors is available will it be possible to make a valid 
interpretation of the observations on brain function after exposure 
to a chemical.  This has been discussed most extensively in the 
case of lead (United Kingdom Department of Health and Social 
Security, 1980; MRC, 1984) (section 3.3.2). 

4.3.2  Kidneys

    The functional immaturity of the infant's kidneys has already 
been discussed (section 3.5.1).  Specific  reports of their 
susceptibility to chemicals are not available, but results of 
animal studies suggest that some compounds are less toxic to the 
immature kidney than to the mature organ.  For example, the same 
dose of mercuric chloride per unit body weight that produced renal 
failure in adult rats did not have any effect on renal function in 
new-born rats (Kavlock & Gray, 1983).  Information is lacking on 
the effects on renal function of the accumulation of chemicals in 
the human kidney during the early years of life (section 3.3.2). 

4.3.3  Liver

    The pre-term infant may still have foci of extra-medullary 
haematopoiesis in its liver, but the histological appearance of the 
liver at term is similar to that of the adult.  The activity of 
enzymes responsible for the biotransformation of chemicals in the 
liver of the infant is not equal to that of the adult (section 
3.4).  However, it appears to be possible to induce the activity of 
microsomal enzymes in the liver of neonates to some extent.  If 
infants have been exposed to phenobarbital, either during 
intrauterine life, or immediately after birth, the synthesis of 
components of certain microsomal enzyme systems in the liver is 
accelerated.  The metabolism and urinary excretion of bilirubin is 
increased (Maurer et al., 1968; Trolle, 1968; Ramboer et al., 
1969).  Increased activities of some drug-metabolizing enzymes have 
also been found in new-born infants exposed to phenobarbital 
before, or immediately after, birth.  Such infants were able to 
metabolize drugs such as diazepam more readily than infants not 
exposed to phenobarbital, and their urinary excretion of hydroxy 
derivatives was greater (Morselli, 1976). 

4.3.4  Lungs

    Animal studies indicate that some chemicals, such as nitrofen, 
retard the development of the lung in the rat fetus (Kimbrough et 
al., 1974), but there do not appear to be any reports of effects of 
chemicals on the lung specific to infants.  It seems that the 
response of the infant's lungs to ingested or inhaled chemicals has 
not been investigated sufficiently.  A greater degree of impairment 
of respiratory function might be expected in infants compared with 
adults for a given level of exposure, particularly to particles of 
substances that result in obstructive symptoms.  An excess 
mortality rate was found in infants aged less than 12 months 
compared with older children and young adults in a population 
exposed to atmospheric pollution with sulfur dioxide (Lawther & 
Waller, 1975). 

4.3.5  Haematopoietic system

    The maturation and differentiation of haematopoietic cells in 
the bone marrow are processes that continue throughout life, and 
represent one of the most rapidly renewing cell populations.  
Although the haematopoietic system and the blood are well known to 
be the target of many chemical agents, there is little information, 
at present, on any specific vulnerability of the developing bone 
marrow.  An example of the vulnerability of the red cells in young 
children is the occurrence of methaemoglobinaemia after exposure 
to very low doses of methaemoglobin-forming compounds, e.g., 
nitrates (Kiese, 1974). 

4.3.6  Immune system

    Studies of immune ontogenesis have revealed that new-born 
mammals do not possess fully competent immune defence systems.  
While human infants have more highly developed immune systems than 
some other mammals at birth, the human infant is still 
immunologically immature. 

    The development of the immune system in mammals involves a 
sequence of steps that begins early in gestation.  Perturbation or 
abrogation of this developmental sequence of events can lead to 
immune dysfunctions that may be life-threatening. Defects in the 
development of the immune system, due to heritable changes in the 
lymphoid elements, have provided clinical and experimental examples 
of the consequences of impaired immune development (for review, see 
Heise, 1982). 

    The most profound effects of chemicals that modulate the immune 
system of animals occur when dosing of the compound begins during 
the development of the lymphoid system (Vos, 1977).  Although there 
are no data on the immunological effects resulting from perinatal 
exposure of infants to chemicals, the potential for such effects 
should not be ignored. 

    The extent of adverse effects on the immune system resulting 
from exposure of adult animals to a wide variety of environmental 
chemicals has only recently begun to be appreciated (Vos, 1977).  
Even less is known about the magnitude of the immunological effects 
resulting from fetal and neonatal exposure to environmental 
chemicals.  It would be expected that disruption of the normal 
sequence of events in the development of the immune system by 
chemicals would result in alterations in the competence of the 
system.  Such alterations may not only lessen the host's ability 
to combat infection and neoplasia but may also lead to 
hypersensitivity or to a failure in the control of homeostasis, 
which may lead to autoimmunity.  The immunological effects of 
perinatal exposure to chemicals in animals have been reviewed by 
Roberts & Chapman (1981) and Schmidt (1984).  Exposure during 
gestation and/or early in postnatal life to chemicals such as 
2,3,7,8-tetrachlorodibenzodioxin (Vos & Moore, 1974; Faith & Moore, 
1977; Luster et al., 1980), lead (Luster et al., 1978; Faith et 
al., 1979), hexachlorobenzene (Vos et al., 1979), and 
benzo( a )pyrene (Urso & Gengozian, 1980) has been shown to affect 
the developing immune system of animals.  However, no specific data 
are available for human infants. 

4.3.7  Endocrine system

    Chemicals may affect the developing endocrine system directly, 
or they may interact with some step of the regulating axis 
controlled by the pituitary, hypothalamus, or other part of the 
brain.  The interaction between a chemical and the neuroendocrine 
organs can also affect the reproductive and other systems.  Some 
pesticides have been shown to possess estrogenic activity 
(McLachlan et al., 1981).  Exposure of experimental animals in the 
early postnatal period to chemicals with androgenic or estrogenic 
activity induced disturbances of sex differentiation in the 
hypothalamus and acyclic ovarian function in females (Barraclough, 
1961, 1966; Takewaki, 1968; Flerko, 1975). 

    Chemicals that give rise to premature onsent of puberty in 
children are of particular importance.  Premature thelarche in 
large numbers of young children in Puerto Rico was attributed to 

estrogens in infant foods containing meat (Saenz de Rodriguez & 
Toro-Sola, 1982); the cause of a similar outbreak in an Italian 
school (Scaglioni et al., 1978) was not discovered.  Exposure to 
chemicals with androgenic or estrogenic activity may also affect 
growth and final stature. 

    The development of the regulatory function of the adrenal 
glands of experimental animals is altered by the administration of 
compounds such as steroids and diazepam to the new-born animal 
(Hcik 1969a, 1970; Erdosova et al., 1977), and results in changes 
in adrenal function and in the reaction of the pituitary-adrenal 
axis to stress stimuli later in life (Levine & Mullins, 1967; Hcik, 
1969b, 1970; Libertun & Lau, 1972). 

    A special risk for new-born infants is an excessive intake of 
iodine, leading to an abnormal rate of accumulation in the thyroid 
gland.  Exposure to high concentrations of iodine or goitrogenic 
compounds can alter the function of the thyroid gland, resulting in 
a deficient production of thyroid hormones at the time when 
appropriate levels of the hormones are important for the maturation 
of functions of the brain, liver, and other organs.  Premature 
infants are particularly prone to the development of hypothyroidism 
as a result of iodine overdose (Chabrolle & Rossier, 1978; Malpuech 
et al., 1978; L'Allemand et al., 1983). 

4.3.8  Skin

    The skin is a complex structure, the functional development of 
which is incomplete until after puberty.  Clinically, the cutaneous 
manifestations of disease vary with age, and some disorders are 
confined to infants and children.  Thus, it would be expected that 
age-related differences in the response of the skin to chemicals 
would be encountered.  Chloracne was found to occur principally in 
young children rather than adults in a population exposed to dioxin 
(TCDD, 2,3,7,8-tetrachlorodibenzo-para-dioxin), suggesting the 
greater susceptibility of the child (Fara et al., 1982). 

    Chemicals applied to the skin may be absorbed and induce 
systemic effects.  New-born infants whose skin was treated with an 
antibacterial preparation containing 3% hexachlorophene developed 
blood levels of the compound similar to those known to cause brain 
damage in animals.  Similarly, some 40 deaths in French infants in 
1972 were attributed to the use of baby powder accidentally 
contaminated with 6.6% hexachlorophene (Marzulli & Maibach, 1975).  
Some environmental pollutants or contaminants are known to be 
readily absorbed through the skin, and this subject has been of 
particular interest in paediatric therapeutics.  Thus, both fatal 
and non-fatal exposures occurred when pentachlorophenol was used in 
a laundry room resulting in contamination of napkins used in the 
hospital nursery (Armstrong et al., 1969). 

4.3.9  Bones and teeth

    The bones undergo considerable change during postnatal 
development with regard to growth, change in shape, and 
composition.  Immature bones contain more water and less collagen 

in the matrix than mature bones, and the degree of mineralization 
is much lower (section 1.3.4) (Table 3). Minerals, including 
strontium, caesium, and lead, tend to be deposited in the bones, 
together with calcium, during the process of mineralization.  Lead 
may affect the conversion of 25-hydroxy vitamin D to the 1.25-
hydroxy metabolite in the kidney (for review, see Mahaffey, 1981). 

    Interference with skeletal development may result from the 
action of lead in altering the balance of osteoblastic and 
osteoclastic activity, and from the direct action of chemicals such 
as fluoride. 

    The discoloration of developing teeth after administration of 
tetracycline is an example of the particular propensity for 
accumulation or fixation of chemicals in hard tissues.  The results 
of studies on primates suggested that excessive exposure to 
selenium during the development of the teeth might increase 
susceptibility to caries (Bowen, 1972). 

4.4  Carcinogenesis

    Maternal exposure to carcinogens may lead to exposure of the 
fetus through the placenta and to exposure of the infant through 
breast milk.  The transfer of chemicals to the fetus depends on the 
relative molecular mass and solubility of the chemical, non-ionized 
and lipid chemicals entering the fetus most readily.  Lipophilic 
chemicals may be retained in the tissues of the fetus and have been 
found in tissues of still-born infants (Curley et al., 1969).  
Transplacental transfer of carcinogens has recently been reviewed 
(WHO, 1984). 

    So far, no epidemiological observations on human infants have 
been reported in which the occurrence of cancer was associated 
solely with exposure to carcinogens in the early postnatal period.  
The few existing data come from animal studies and, in most of 
these, the route of exposure was parenteral and not through the 
mother's milk.  For example, the injection of aflatoxin resulted in 
liver cancer in mice, but only when administered to new-born 
animals (Vesselinovitch et al., 1972). 

    Within the past decade, it has been increasingly recognized 
that not all carcinogens act by the same mechanism.  Many of the 
environmental chemicals, particularly the halocarbons, are though 
to be promoters of carcinogenesis rather than initiators.  Many of 
these types of chemicals are persistent in the organism and are 
secreted in breast milk (section (Appendix I).  The 
mechanism of action of promoters is not well understood at present, 
and effects on health at the low doses received by infants and 
young children are not clear. 

    An intrinsic problem in studying prenatal and postnatal 
exposure to carcinogens is the capacity for metabolic activation in 
the tissues of the fetal or new-born organism, compared with that 
of the adult (section 3.4).  In this respect, pronounced species 
variations have been shown between rodents and primates, including 
man.  The perinatal development of different organ systems varies 

considerably among species.  All these variables make extrapolation 
from animals to man extremely difficult. 

    The significance for human health of early postnatal exposure 
to tumour growth promoters or co-carcinogens is not known. 

4.5  Conclusions

    The structural and functional characteristics of infants and 
young children described in sections 1, 2, and 3 might make them 
more or less vulnerable than older children and adults, when they 
are exposed to chemicals at a similar dose per unit body weight.  
However, it should be emphasized that reports of specific effects 
are rare.  This may be because such specific effects do not exist 
or because they have passed largely unnoticed.  The examples quoted 
here show that exposure to certain chemicals during early postnatal 
development can be associated with dose-effect and dose-response 
relationships that differ from those resulting from exposure in 
later years. 

    Exposure to chemicals during early postnatal development can 
give rise, not only to immediate effects on health, but also to 
manifestations resulting from the disturbed maturation of organ 
systems and their altered response to other environmental 
influences.  Depending on the chemical concerned, the vulnerability 
of the developing organ systems can be higher or lower than that of 
the more mature systems. 

    It is recommended that, if laboratory tests suggest that the 
body burden of a chemical is a cause for concern, follow-up studies 
should be made.  Children who have been accidentally exposed to 
chemicals that might affect the reproductive organs should be 
followed prospectively to determine possible effects on puberty and 
reproductive capacity.  Similarly, if other organ systems are 
likely to have been affected, prospective studies should, if 
possible, be made to assess functional development, morbidity, and 


    Considerable variations exist in the health and nutritional 
status of children reared in different social and cultural 
environments.  The response of children exposed to chemicals may 
therefore be modified in certain sections of a population to a 
degree that cannot readily be predicted. Although analogous data 
for the severity of response to infections, such as measles, are 
well documented, information concerning chemical exposure and its 
sequelae is limited. 

5.1  Nutrition

    The intake of chemicals contaminating foods and beverages will 
vary with the amount of food consumed, the range and variety of 
dietary items selected or available, and the methods of 
preparation.  Children with high intakes of marine fish will, for 
example, have a greater intake of methylmercury from polluted 
sources than those in which fish constitutes only a small 
proportion of the diet (Turner et al., 1980). Conversely, some 
pesticide residues in milk are decreased by heating, drying, 
evaporation, or pasteurization, so that less of these substances 
will occur in children consuming manufactured or processed milk, as 
opposed to the raw product.  The duration of milk feeding in 
infancy, the method of weaning, and the interval before a normal 
adult diet is introduced are important factors that vary greatly 
between social, cultural, and ethnic groups. 

    Specific dietary components may interact with ingested 
chemicals, thus modifying their availability for absorption. The 
relative solubility of the chemical in the lipid or aqueous 
fractions of the diet, and the potential for physical interaction 
or adsorption to non-adsorptive mechanisms at the enteral surface 
of the gut mucosa, may all have a role in determining the 
bioavailability of the ingested chemical. Thus, the absorption of 
lead, consumed simultaneously with the diet, is markedly lower 
compared with its absorption from aqueous solutions, partly due to 
interaction with other dietary components.  In animals, and 
possibly in man, lead absorption is reduced by diets rich in 
calcium and phosphorus, but is increased when the intake of these 
nutrients is restricted (Barltrop & Khoo, 1975). 

    The consequences of nutritional deficiency for the absorption 
of chemicals cannot be predicted with certainty. In kwashiorkor, 
both the digestive and absorptive functions of the gut may be 
impaired and the activation of chemicals during conjugation 
reactions reduced, particularly acetylation with amino acids 
(Thabrew et al., 1982).  On the other hand, specific mineral 
deficiencies, for example, a lack of calcium, may stimulate 
absorptive mechanisms shared by other, potentially toxic, divalent 
cations (Barltrop, 1979).  Iron deficiency in children has been 
related to enhanced absorption and retention of lead, but the 
mechanism involved is uncertain.  Interactions between essential 
and toxic metals after they have been absorbed into the body have 
been described.  Zinc, for example, competes with lead for 

receptors on the enzyme aminolaevulinic acid dehydratase (Nordberg, 
1979), but the significance of this in infants and children is 

5.2  State of Health

    Several diseases in addition to nutritional disorders may 
modify the exposure and response of infants and children to 
chemicals.  Ill health associated with diminished activity or 
mobility of the child will, for example, alter the balance between 
exposures related to the indoor as opposed to the external 
environment.  Conditions requiring the long-term administration of 
oral therapeutic agents or modified diets will inevitably alter the 
intestinal milieu and hence the absorption of ingested chemicals. 

    The absorptive ability of the gut is modified in a wide range 
of diseases, including the enteropathies and chronic diarrhoeal 
states encountered in childhood arising, for example, from acquired 
or inherited food intolerance.  The steatorrhoea associated with 
childhood malabsorptive disorders such as coeliac disease is known 
to impair the absorption of lipid-soluble substances such as 
cholecalciferol and alpha-tocopherol (Harrison, 1980), and would 
therefore be expected to have a similar effect on the absorption of 
other lipid-soluble chemical compounds. 

    Children with chronic renal or hepatic dysfunction will have an 
impaired ability to excrete, metabolize, and, in some cases, store 
chemicals that have been absorbed, which may therefore accumulate 
in the body.  Compromised integrity of the dermal or respiratory 
epithelium by disease will enhance the potential for the absorption 
of chemicals by these routes. 

    Some children have genetically determined variations in their 
ability to metabolize or respond to certain chemicals. Thus, 
deficiency of the enzyme glucose-6-phosphate dehydrogenase (EC, which is encountered in some sub-populations, is 
characterized by a haemolytic reaction in response to various 
triggering agents.  Such reactions in childhood have been reported 
after exposure to chemicals including naphthalene, aniline dyes, 
and nitrofurantoin (Willoughby, 1984). 

5.3  Social and Cultural Way of Life

    There are many complex interactions between environmental 
chemicals and the social and cultural ways of life.  The effects of 
place of residence, mobility, state of health, nutritional status, 
and family income cannot always be distinguished without resort to 
sophisticated epidemiological methods.  Cultural and social 
attitudes to child care and supervision differ between 
subpopulations and are clearly important in relation to acute or 
short-term exposures.  The mechanisms whereby class and cultural 
differences modify exposure are not always apparent.  For example, 
the different blood-lead values found in Negro versus Hispanic 
children in New York and in Asian versus Northern European children 
in the United Kingdom have yet to be adequately explained 
(Barltrop, 1982).  Family practices with regard to personal 

hygiene, and especially handwashing before meals, may be important 
determinants of exposure resulting from hand to mouth activity in 

5.4  Conclusion

    Recognition of social and cultural factors that influence 
exposure and modify response will assist in the identification of 
children at risk and enable appropriate preventive and remedial 
measures to be adopted. 


1.  Infants and young children differ from older children and 
adults in some of their morphological, physiological, biochemical, 
metabolic, and behavioural characteristics, and in their 
nutritional requirements. 

2.  The response of infants and young children to chemicals may 
differ from that of adults by virtue of their biological 
characteristics.  Moreover, a feature of these responses is that 
the processes of development may themselves be modified by exposure 
to chemicals. 

3.  The effects of chemical exposure and their relationship to dose 
may vary with age.  The expression of the effects of chemicals may 
be greater or lesser than in the adult, depending on the chemical 
species concerned; the kinetics of its absorption, 
biotransformation, and elimination; and the degree of maturation of 
target organs and tissues. 

4.  The characteristics of infants and children are such that they 
determine the pattern of exposure to chemicals.  The pathways 
involved are related to development and vary with the environment 
of the child.  Thus, skin contact, the consumption of breast milk 
or its substitutes, the ingestion of substances other than food, 
may each be predominant routes at different stages of development. 

5.  The exposure, uptake, and effects of chemicals may be modified 
by factors that are characteristically encountered in early life, 
including the mode of nutrition, social, economic, and cultural 
conditions, and disease. 

6.  The expression of chemical effects may not be immediate, but 
may be delayed until a later age.  The health of adults may thus be 
compromised by chemical exposures in early life. 

7.  The development of a strategy relating to chemicals detected in 
breast milk requires a thorough appraisal of the merits and 
disadvantages of the available options.  Any risk of continued 
exposure to a chemical through breast-feeding has to be balanced 
against the risk of infection or nutritional deprivation, should 
breast-feeding be curtailed or discontinued. 


1.  When health risks from chemicals are evaluated, the special 
characteristics of infants and young children must be recognized.  
An appropriate methodology based on the knowledge of these 
differences should be used. 

2.  Preventive measures should take account of the special 
conditions of exposure to chemicals characteristic for infants and 
young children, including exposure through breast milk. 

3.  Health care workers should be made aware of the special risks 
related to chemical exposure during infancy and childhood. 

4.  Any increased incidence of a disease possibly related to 
chemical exposure should be reported and investigated. Awareness of 
this among health care workers should be improved.  The 
establishment of an appropriate surveillance system should be 

5.  Clinical and epidemiological data should be collected following 
the inadvertent exposure of infants and young children to 

6.  Developmental toxicology should be promoted and its methodology 
improved in order to increase the predictive power of experimental 
animal and other laboratory studies. 

7.  Studies are urgently needed to evaluate the risk associated 
with exposure during infancy and early childhood to the initiators 
and promoters of carcinogenesis. 


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WOLFF, M.S.  (1983)  Occupationally derived chemicals in
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1.  Introduction

    The breast-fed infant requires special consideration in 
circumstances in which chemical contamination of the mother's milk 
is suspected, or has been confirmed.  Young infants are 
characteristically dependent on milk, and the structural and 
functional development of their organs and tissues is adapted to 
the milk of their own species.  The potential risks of exposure to 
chemicals in breast milk must therefore be assessed, taking into 
account the benefits of breast-feeding together with the 
disadvantages of feeding an alternative milk, in terms of 
developmental toxicology. 

    The benefits of breast-feeding, particularly in the developing 
countries, are now universally acknowledged.  In these societies, 
nearly all women of all classes breast-feed for 12 months or more.  
The decline in breast-feeding in many developed countries has 
recently been reversed; interestingly, both the decline in, and 
return to, breast-feeding began among the most socially advantaged 
women (WHO, 1981).  National and international authorities have 
been concerned that, in view of the health risks involved in the 
preparation and provision of breast milk substitutes in developing 
societies, mothers in these countries should not go through the 
changes in infant feeding practice that have occurred in the 
developed world. Thus, the Member States of the World Health 
Organization have committed themselves to the protection and 
promotion of breast-feeding as the first, and one of the most 
critical, steps in sound infant nutrition policies (WHO/UNICEF, 

    This Appendix is concerned with principles for evaluating the 
possible consequences to health of chemical contaminants in breast 
milk.  The evaluation of risks potentially associated with these 
chemicals in the quantities that may be consumed must be carefully 
weighed against the assessment of the risks of alternative methods 
of infant feeding. 

    The breast milk of a well-nourished mother has an optimal 
composition to meet the nutritional needs of the full-term infant 
in early life, and there are associated immunological, 
psychological, and economic advantages.  In view of the importance 
of breast milk for the nutrition and health of the infant, evidence 
of any harmful effects of a foreign chemical that it may contain 
must be carefully considered before recommendations are made that 
breast-feeding should be curtailed or discontinued. 

2.  Assessment of the Importance of Chemicals in Breast Milk

2.1  Source of chemicals

    Women may be exposed to chemical substances from many different 
sources, including air, food, water, drugs, cosmetics, and the 
occupational environment. 

2.2  Chemicals within the mother's body and their secretion in milk

    Chemicals that are easily metabolized and are eliminated from 
the mother's body in the faeces and urine are only secreted in 
significant quantities in breast milk following recent high-level 
chemical exposure (Wolff, 1983; Jensen, 1985). 

    Other chemicals, such as heavy metals and persistent 
halocarbons, are less readily removed from the body.  Some metals 
accumulate mainly in the liver, kidney, and bone, whereas 
persistent halocarbons accumulate in the lipids of the body.  Long-
term exposure, even to low concentrations of such chemicals, may 
build up considerable body stores.  On the other hand, a short-term 
change of diet is not likely to alter the concentration of 
halocarbon in the mother's fatty tissues. 

    A dynamic equilibrium for persistent lipophilic chemicals 
exists between different tissue compartments.  The concentrations 
of these chemicals in adipose tissue, blood, and milk is in 
proportion to the fat content; thus, the concentration in blood is 
far lower than that in whole milk, and the concentration in milk is 
far lower than that in adipose tissue.  There is a relatively good 
correlation between concentrations of organic halocarbons in the 
lipids of blood, adipose tissue, and milk.  This is illustrated for 
DDT in the lipids of milk and adipose tissue in Fig. I.1. 


2.3  Development and limits of methods for measuring chemicals in 

    During the 1960s and 1970s, techniques such as gas 
chromatography were developed, which increased the scope and 
accuracy of analytical methods for the determination of chemicals 
in breast milk.  Studies were made in various countries, and many 
different halocarbons were detected.  The sensitivity of the 
methods was greatly increased with the introduction of glass 
capillary columns in gas chromatography, high resolution liquid 
chromatography, and mass spectrometry, and it is now possible to 
detect some environmental chemicals in human milk fat at the ng/kg 
level (Jensen, 1985). Similarly, the sensitivity of methods for 
measuring heavy metals has also greatly increased in recent years 
with the introduction of electrothermal atomic absorption 
spectrophotometry, mass spectrometry, and neutron activation 

    These newly developed methods require specialized laboratory 
staff and facilities, as well as quality assessment programmes, to 
ensure the accuracy and precision of results. The analyses are 
often time-consuming and costly to perform. This limits the number 
that can be made, and this must be taken into account when 
developing strategies and requirements for the determination of 
chemicals in breast milk. 

2.4  Risks to the infant

    The presence of chemicals in breast milk must be seen in 
perspective.  Because a chemical has been detected and measured, it 
does not mean that it is necessarily harmful to the infant in the 
quantities consumed. 

    The magnitude of chemical burdens derived from breast milk 
cannot be assessed in isolation but must be related to those 
obtained from other routes of exposure.  Additional contributions 
to the uptake of chemicals by the infant may occur through the 
percutaneous and respiratory pathways and, in some cases, there is 
a pre-existing burden sustained  in utero from placental transfer. 

    The evaluation of the risks associated with a given chemical in 
breast milk requires knowledge of: 

    (a) intake of the chemical by the infant;

    (b) availability for absorption from the infant
        intestinal tract;

    (c) kinetics of uptake, transport, distribution, 
        metabolism, excretion, and net retention by the 
        infant body;

    (d) effects on developing organs, tissues, and systems of
        the young infant; and

    (e) long-term sequelae in later childhood and adult life.

These considerations are discussed in sections 3 and 4 of this 
publication.  Information about most of them is incomplete. 

    In breast-fed infants, the concentrations of halocarbons in the 
blood, for example, polychlorobiphenyls (PCBs), were found to 
increase after birth and reached the maternal levels after 3 
months; the increase continued until breast feeding was stopped; 
thereafter, the concentrations of halocarbons decreased (Kodama & 
Ota, 1980).  An association between breast-feeding and high 
concentrations of persistent halocarbons in the body fat of infants 
has also been observed (Niessen et al., 1984), and it has been 
calculated that, within a few months of birth, the concentration of 
halocarbons in the fat of the infant may be equal to that in the 
maternal fat (Wickizer et al., 1981; Mes et al., 1984).  Although 
the period of breast-feeding is short in relation to the life span, 
the chemicals accumulated in the body during these months may be 
retained for many years (Jensen, 1985). 

    At present, there appears to be only one preliminary report of 
a prospective study in which 850 breast-fed infants were 
periodically examined, and the milk was analysed for halocarbons 
(Rogan & Gladen, 1982).  The main result at the time the report was 
written was that the mothers with the greatest concentration of 
2,2 bis(4-chlorophenol)-1,1-dichloroethylene (DDE) in their milk 
did not breast-feed for as long as those with the least, and they 
gave their infants formula at an earlier age. 

2.5  Assessment of contamination of breast milk following
maternal exposure

    The purpose of investigating the chemical contamination of 
breast milk in the context of this publication is to assess the 
possible harm to infants if they continue to take milk from exposed 
mothers.  The daily intake of a contaminant depends on the volume 
of breast milk taken and on the concentration of the chemical in 
the milk.  At all ages, the intake of milk by a full-term breast-
fed infant varies considerably between individuals.  This depends 
partly on body weight; 150 ml/kg body weight per day can be taken 
as a representative intake, after the first week.  This gradually 
falls after 2 months to about 120 ml/kg per day at 4 - 6 months. 

    The concentration of lipophilic chemicals in milk is clearly 
related to its fat content, and this varies with the stage of 
lactation, the maternal diet, the time of day, and during the 
course of a single feed.  There is also a variation in 
concentration of protein-bound and water-soluble chemicals at 
different stages of lactation.  Thus, the infant's intake of 
chemicals is not constant from day to day, or within one day, or 
even within a particular feed.  How then should samples of breast 
milk be collected for analysis to obtain a reasonable figure 
representing the infant's intake of the chemical in question?  If 
the chemical is lipid-soluble, much of the difficulty is removed if 

the percentage of fat is also determined and the concentration of 
the chemical expressed per unit weight fat.  Then, the following 
equation can be applied: 

                  TD = C x F x M


TD =    daily intake of contaminant (units per kg body weight
        per day)

C =     average concentration of contaminant in milk fat
        (units per g fat)

F =     average concentration of fat in milk (g/g milk)

M =     average consumption of milk (g/kg per day).

2.5.1   Method of collection of breast milk

    Methods for collecting breast milk have already been described 
in the report of a WHO Collaborative Study on Breast-Feeding (WHO, 

3.  Conclusions

    Because of the importance of breast-feeding to the health and 
development of the infant, a strategy related to chemicals detected 
in breast milk requires a thorough appraisal of the advantages and 
disadvantages of the available options.  In evaluating the risk of 
continued exposure to a chemical through breast-feeding, the risk 
of nutritional deprivation or infection, if breast-feeding is 
curtailed, must be assessed simultaneously before a decision is 

    For this reason, studies are required to establish a 
relationship between levels of environmental exposure of mothers 
(and hence subsequent milk contamination) and effects on the health 
of breast-fed infants.  Surveys of concentrations of chemicals in 
breast milk should be undertaken as part of the strategy for infant 
nutrition.  The finding of chemicals in breast milk should lead to 
an evaluation of the implications for the health of the infant. 


JENSEN, A.A.  (1985)   Toxic substances in mother's milk,
Luxembourg, Commission of the European Communities.

KODAMA, H. & OTA, H.  (1980)  Transfer of polychlorinated
biphenyls to infants from their mothers.  Arch. environ.
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(1984)  Polychlorinated biphenyls and organochlorine
pesticides in milk and blood of Canadian women during
lactation.  Arch. environ. Contam. Toxicol., 13: 217-223.

HOFMANN, U.  (1984)  Chlorinated hydrocarbons in adipose
tissue of infants and toddlers: inventory and studies on their
association with intake of mother's milk.  Eur. J. Pediatr.,
142: 238-243.

ROGAN, W.H. & GLADEN, B.C.  (1982)  Duration of breast-feeding
and environmental contaminants in milk.  Am. J. Epidemiol.,
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ROGAN, W.J. & GLADEN, B.C.  (1985)  Study of human lactation
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WHO  (1981)   Contemporary patterns of breast-feeding: report
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WHO  (1985)   The quantity and quality of breast milk. Report
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World Health Organization.

WHO/UNICEF  (1981)   Infant and young child feeding: current
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(1981)  Polychlorinated biphenyl contamination of nursing
mothers' milk in Michigan.  Am. J. public Health, 71: 132-137.

WOLFF, M.S.  (1983)  Occupationally derived chemicals in
breast milk.  Am. J. ind. Med., 4: 259-281.

    See Also:
       Toxicological Abbreviations