Children and the unborn child
1. Introduction
Patterns of illness in children have changed considerably in this century with increased incidences of e.g. asthma, birth defects, childhood cancers, and learning disabilities being reported. The aetiologies of many diseases of childhood are due to a combination of factors, including genetic susceptibility, socio-economic factors and environmental exposures during vulnerable periods of development. (US-EPA 1998, EHP 1998a, Routt Reigart 1998, Gee 1999, Suk 1999).
Children are at risk of exposure to a lot of high-production-volume synthetic chemical substances which have been introduced into the market within the past 50 years; these chemical substances are used widely in consumer products and are dispersed in the environment.
Children as well as the unborn child have in some cases appeared to be uniquely vulnerable to chemical substances because of their biological growth and development. Furthermore, children may be more heavily exposed than adults to certain chemicals and pollutants in the environment as children, on a body weight basis, breathe more air, drink more water, and eat more food than adults; additionally, their behaviour patterns, such as play close to the ground and hand-to-mouth activities, can increase their exposure.
Recently concern about the probable vulnerability of infants and children to environmental chemicals has been an important issue for discussion. Initially, the USA identified this as an area of concern and more recently the EU has been active in this area. Also international organisations as e.g., OECD and Non Governmental Organisations (NGOs) have considered this area of importance.
US-EPA / ILSI conference
In 1990, the U.S. Environmental Protection Agency (US-EPA) and the International Life Sciences Institute (ILSI) sponsored a conference on Similarities and differences between children and adults: implications for risk assessment; the conference papers are published in ILSI (1992). The conference came out with a number of conclusions:
 | Children are not simply small adults but rather are a unique population for health risk assessment. |
| Differences in sensitivity between children and adults are chemical specific and must be studied and evaluated on a case-by-case basis. |
| Because of their physical vulnerability and diminutive stature, infants and children are often assumed to be more susceptible to the potential toxic effects of the chemicals found in the environment. |
| An analysis based on available data, however, suggests that susceptibility clearly depends on the substance and the exposure situation. In some cases, there may be no difference at all in the responses of children and adults. In other cases, different physiological and metabolic factors, pharmacokinetics, and diet and behaviour patterns, among other influences, demonstrably can render children more or less susceptible than adults. |
National Research Council
In 1993, the National Research Council (NRC) in USA published a report Pesticides in the diets of infants and children (NRC 1993). NRC pointed out that
| Age-related variability in the susceptibility to chemical substances may occur and children can be either more or less susceptible than adults depending on the chemical in question. |
| New-borns are considered to differ most in comparison to adults. |
| Quantitative differences in toxicity between children and adults are generally less than a factor of 10. |
| Children’s intake of pesticide residues from foodstuffs are different when compare to adults. |
| Differences in exposure are generally the more important source contributing to a higher risk than the age-related differences in susceptibility to toxicants. |
Symposia in USA
Recently, two important symposia have been held in the USA: The Conference on Children’s Environmental Health: Research, Practice, Prevention, and Policy, 21-23 February 1997 in Washington, DC and The U.S. EPA Conference on Preventable Causes of Cancer in Children, 15-16 September 1997 in Arlington, VA. The papers from these symposia are published in EHP (1998a).
Both of these symposia identified as cause for concern the rise in the prevalence of many disease processes involving children, such as the rise in incidence of certain childhood cancers including brain cancers, acute lymphoblastic leukaemia, Wilm’s tumour, and testicular cancer. Neither of these symposia alleged that environmental agents are directly responsible for these rises in incidence, but both provided indications as to the interaction of environmental exposure with other factors to produce greater risks of cancer in children.
US-EPA initiatives
In September 1996, the US-EPA published a National Agenda which outlined an approach to the protection of children from environmental risk and suggested a research strategy to develop the scientific information necessary to improve protection of children (US-EPA 1996). In the same year the Food Quality Protection Act (FQPA 1996) was approved which requires the US-EPA to upgrade risk assessment procedures for setting residue tolerances in foods; this act gave special emphasis to the protection of infants and children from pesticides. In April 1997, President Bill Clinton issued an Executive Order that demanded increased emphasis on the protection of children from environmental health risks and safety risks (Clinton 1997). In May 1997 the Administrator of the US-EPA established the Office of children’s Health Protection to support the Agency as it implements the President’s Executive Order as well as the National Agenda. The mission of the Office is to make the protection of children’s health a fundamental goal of public health and environmental protection in the United States. The US-EPA activities are published in the Children’s Environmental Health Yearbook (US-EPA 1998).
Initiatives in Europe food additives
In 1997, ILSI Europe organised a workshop on the "Applicability of the ADI to infants and children"; the workshop papers are published in Clayton et al. (1998). In answering the question how big are the differences between infants or children and adults from a susceptibility point of view?, the workshop concluded that the issue of age-related differences in susceptibility to food additives and other compounds should be addressed on a case-by-case basis. To another question addressed Are differences in food intake (between infants or children and adults) a point of concern?, the answer was that the fact that infants and children have a higher intake of some food items than adults is not part of the ADI (acceptable daily intake) but should clearly be taken into careful consideration when the ADI is used to establish the use levels of food additives in such foods. To a third question Are special safety factors or regulatory principles required for infants and children?, the workshop strongly recommended that special safety factors for infants and children should not be used, and consequently special ADIs should not be established. In case that studies indicate that infants and children are most sensitive to a particular chemical, these studies should drive the derivation of the ADI. (Larsen & Pascal 1998).
pesticides
The applicability of the ADI for permitted pesticides to infants and young children has been discussed in a report (Schnipper & Larsen 1997) prepared for an ad hoc SCF (Scientific Committee for Food) meeting on pesticides in baby food. Similarly to food additives, it was not recommendable that special safety factors should be used for infants and children and no special ADIs should be established for this age group. The ADI should, however, not be considered applicable to infants below 12 weeks of age, since the usual toxicity test regimen does not cover this situation. This means that special considerations will have to be applied to pesticide residues in infant formulas and drinking water consumed by infants below the age of 12 to 16 weeks. Furthermore, the higher intake, on a per kg of body weight basis, of some food items and beverages for infants and children should be taken into careful consideration when the ADI is used in the establishment of the MRLs (Maximum Residue Level) for pesticides in such foods and beverages.
endocrine disrupters
In the recent years there has been growing concern regarding possible harmful
consequences of exposure to chemical substances which may modulate/ disrupt the endocrine
system.
Endocrine disrupters are believed to interfere with the complex function of hormones and
signalling molecules. The activity may be by mimicking the action of naturally-produced
hormone such as oestrogen or testosterone, by blocking receptors in cells receiving the
hormones or by affecting the synthesis, transport, metabolism and excretion of hormones.
During developing the activity of the endocrine system is high and the unborn child may
therefore be specifically vulnerable to exposure of endocrine disrupting chemicals
Recently, a working group under the Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) finished a report in which the evidence for effects in humans and in environment were discussed together with the urgent demand for proper test systems for identifying chemicals causing endocrine disrupting effects. With regard to evidence the CSTEE came to the opinion that "although there are associations between endocrine disrupting chemicals, so far investigated, and human health disturbances, a causative role of these chemicals in diseases and abnormalities possibly related to an endocrine disturbance has not been verified". (CSTEE 1999).
The European Commission has elaborated an EU-strategy on hormone disrupters which has been adopted in the Council in March 2000. The Commission stresses the need for an EU-strategy on this field as very serious adverse effects on human health and the environment may be the follow of exposure to endocrine disrupting chemicals (EU-Commission 1999). The aim of the strategy is to co-ordinate and strengthen the efforts in relation to a) identification of specific substances of concern (based on existing knowledge), b) development of new test methods for the detection of endocrine effects, c) research to uncover the mechanisms, the dose-response and the consequences on environment and human health from exposure to these substances, d) regulation as the endocrine disrupting effects are to be incorporated in the regulative framework, and e) information to the public.
toys
Toys may be a significant pathway of exposure for unintended chemical exposure to especially small children. According to the EU Council Directive 88/378/EEC, toys may generally not contain dangerous chemical substances in amounts giving rise to development of adverse effects in children and specific migration limits have been set for eight metals. However, a general concern on harmful substances in toys has been expressed. Based on the EU Council Directive 88/378/EEC and an opinion of the CSTE (CSTE 1988), the European Commission gave a mandate to CEN (the European Committee on Standardisation) to develop a harmonised standard for organic chemical compounds in toys. Regulations are required for the following groups of substances: solvents, preservatives, wood preservatives, plasticisers, flame retardants, monomers, and colorants.
Following notification by Denmark, a targeted risk assessment (opinion paper) has been conducted by the CSTEE on phthalates in children’s toys and child care articles (CSTEE 1998). Subsequent to this, risk reduction steps have been developed. Recently, EU has adopted measures prohibiting the placing on the market of toys and childcare articles intended to be placed in the mouth by children under three years of age made of soft PVC containing one or more of 6 specific phthalates (DINP, DEHP, DBP, DIDP, DNOP, BBP) (EU 1999).
Amsterdam Conference
In 1998, the "First International Conference on Children’s Health & Environment" took place in Amsterdam 12-13 August. At this conference, the susceptibility of children including the unborn child to exposure to chemical substances was discussed. No proceedings are at present available from the conference.
London Conference
In 1999, the "Third Ministerial Conference Environment and Health" was held in London, 16-18 June.
One of the reports presented at this conference Children in their environment:
vulnerable, valuable and at risk (Gee 1999) provides a summary of what we know, and
don’t know, about children’s vulnerability to a selection of key environmental
hazards. The report points out that "Children are not "little adults" but
are particularly vulnerable to pollutants because of their immature biological
development, behaviour, metabolism, greater exposure to pollutants relative to body
weight, and longer life at risk than adults".
The conference concluded that "Children are more susceptible than adults to the
effects of environmental health threats and therefore require special protection" and
proposed specific actions to address the public health problems of injuries, environmental
tobacco smoke, asthma and emerging threats.
Initiatives in Denmark
In Denmark, the US-EPA National Agenda gave rise to a number of questions to the Minister of Health regarding the responsibility for protection of children and pregnant women against exposure to environmental contaminants and later the Prime Minister was asked to investigate the needs for a national agenda. In June 1998, the Prime Minister requested a common review by the Ministry of Environment and Energy, the Ministry of Food, Agriculture and Fisheries, and the Ministry of Health. In order to put more focus on and discuss these concerns and to form the basis for the common review, a conference on "Protection of children and pregnant women against dangerous substances" was held on 28 October 1998 and planned jointly by the Ministry of Health, the Ministry of Environment and Energy, the Ministry of Food, Agriculture and Fisheries, The Ministry of Labour, the Ministry of Housing and Urban Affairs, the Ministry of Social Affairs and the Ministry of Education. The ministerial report (in Danish) was published in September1999 (Danish Ministerial Report 1999).
Another initiative taken in Denmark was a "Seminar on Environment and Child Health" in Copenhagen 19 March 1998 organised by the European Environment Agency, Child Watch International, Danish Children’s Council, Danish Ecological Council, and WHO.
Test guidelines for reproduction and developmental toxicity
OECD
A number of chemicals are known to produce developmental neurotoxic effects in humans
and other species. These effects may arise in the offspring from exposure of the mother
during pregnancy and lactation and can occur at lower dose levels than in adults. In
Copenhagen in June 1995, an OECD Working Group on Reproduction and Developmental Toxicity
discussed the need to update existing OECD Test Guidelines for Reproduction and
Developmental Toxicity, and the development of new Guidelines for end points not yet
covered.
The working group recommended that a guideline for developmental neurotoxicity should be
written, based on a US guideline. In June 1996, a consultation Meeting was held in
Copenhagen to provide the OECD Secretariat with guidance on the outline of a new guideline
on developmental neurotoxicity. In October 1999, a proposal for a new OECD Guideline 426
Developmental Neurotoxicity Study was developed based on comments from the scientific
community.
Concurrently with the revision of the existing guideline on 2-generation reproductive
toxicity (TG 416), the work on testing and assessment of endocrine disrupters began in
December 1996 and in February 1998, a Working Group on Endocrine Disrupter Testing and
Assessment (EDTA) was established. A revised TG 416 was circulated for comments in October
1998 and it was asked whether there is a chance to build in endocrine disruption endpoints
into the current revision of the TG 416.
EU
For the evaluation of new industrial chemicals (i.e. introduced after 18 September 1981), Annex V of Council Directive 67/548/EEC (1967) includes a series of test methods. These include among others a teratogenicity test in rodents and non-rodents (B.31) and one-generation (B.34) and two-generation (B.35) reproduction toxicity tests. The test methods in Annex V are based on OECD guidelines and are normally updated concurrently with updating of the OECD guidelines.
US-EPA
A guideline for developmental neurotoxicity study was issued by US-EPA in 1991 (US-EPA
1991) and a revised US guideline was proposed in 1995.
The guideline provides an evaluation of the potential functional and morphological effects
on the developing nervous system that may arise in offspring following exposure of the
maternal animal during gestation and lactation. The guideline was designed to test a wide
variety of classes of chemicals, e.g., pesticides and industrial chemicals; however, it
was never intended that every chemical should be required to undergo such testing. Testing
is required on a case-by-case basis taking into consideration what other toxicity
information is available on each chemical or class of chemicals. (Francis 1992).
Aim of the project
The present project has been initiated by the Danish Environmental Protection Agency with the purpose of elaborating a detailed review and update the knowledge on the exposure and vulnerability of humans to chemical substances during the embryonic, foetal, and postnatal periods. The report is intended to form the scientific basis for future regulatory work of the Danish EPA in the protection of children and the unborn child to environmental chemical substances. Consequently, the report primarily focuses on chemical substances and regulatory aspects for which the Danish EPA has the responsibility. However, other chemical substances, such as drugs, have been included when they provide illustrative examples within the context of this report.
References
Clayton B, Kroes R, Larsen JC and Pascal G (1998). Applicability of the ADI to infants and children. Food Addit Contam 15.
Clinton (1997). Protection of children from environmental health risks and safety risks. Executive Order # 13045, Washington, DC: The White House.
CSTEE (1999). CSTEE opinion on human and wildlife health effects of endocrine disrupting chemicals, with emphasis on wildlife and on ecotoxicology test methods. Report of the Working Group on Endocrine Disrupters of the Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) of DG XXIV, Consumer Policy and Consumer Health Protection. March 1999.
CSTEE (1998). CSTEE opinion on phthalate migration from soft PVC toys and childcare articles. The Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) of DG XXIV, Consumer Policy and Consumer Health Protection. November 1998.
CSTE (1988). Scientific Advisory Committee to Examine the Toxicity and Ecotoxicity of Chemical Compounds: Organic Chemical Compound and Safety of Toys. CSTE/88/V/E.
Danish Ministerial Report (1999). Redegørelse om beskyttelse af børn og gravide mod farlige stoffer. Miljø og Energiministeriet, Sundhedsministeriet, Ministeriet for Fødevarer, Landbrug og Fiskeri september 1999.
EHP (1998a). Children’s environmental health. Cancer in children. Environ Health Perspect 106 (Suppl 3).
EU (1999). Commission decision of 7 December 1999 adopting measures prohibiting the placing on the market of toys and childcare articles intended to be placed in the mouth by children under three years of age made of soft PVC containing one or more of the substances di-iso-nonyl phthalate (DINP), di(2-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), di-iso-decyl phthalate (DIDP), di-n-octyl phthalate (DNOP), and butylbenzyl phthalate (BBP). 1999/815/EC.
EU-Commission (1999). Community Strategy for Endocrine Disrupters, a range of substances suspected of interfering with the hormone systems of humans and wildlife. Communication from the Commission to The Council and The European Parliament. Brussels, 17.12.1999 . COM(199) 706 final.
FQPA (1996). Food Quality Protection Act. Amend FIFRA and FFDC. Public 104-170, 3 August 1996.
Francis EZ (1992). Regulatory developmental neurotoxicity and human risk assessment. Neurotoxicol 13, 77-84.
Gee D (1999). Children in their environment: vulnerable, valuable, and at risk. Background briefing children and environmental health WHO Ministerial Conference Environment & Health, London, 16-18 June 1999, WHO Regional Office for Europe, European Environment Agency.
ILSI (1992). Similarities and differences between children and adults: Implications for risk assessment. Eds. Guzelian PS, Henry CJ and Olin SS. ILSI Press Washington D.C.
Larsen JC and Pascal G (1998). Workshop on the applicability of the ADI to infants and children: consensus summary. In: Clayton B, Kroes R, Larsen JC and Pascal G eds. Applicability of the ADI to infants and children. Food Addit Contam 15, 1-9.
NRC (1993). Pesticides in the diet of infants and children. US National Research Council).
Routt Reigart J (1998). Our children and the environment. Environ Health Perspect 106, A263-A264.
Schnipper A and Larsen JC (1997). The applicability of the ADI (Acceptable Daily Intake) for permitted pesticides to infants and young children. Report prepared for the EU Scientific Committee for Food.
Suk WA (1999). Physiological, anatomical, biochemical and genetic differences between children and adults. Abstract. Exposure Assessment in Children: A Consumer Exposure Workshop 9-10 September 1999, Solna, Sweden.
US-EPA (1998). The EPA children’s environmental health yearbook. United States Environmental Protection Agency.
US-EPA (1996). Environmental health threats to children. Washington, DC: U.S. Environmental Protection Agency.
US-EPA (1991). Guideline 83-6 Developmental neurotoxicity. Washington DC:US Environmental Protection Agency.