Review
Children's exposure to environmental pollutants and biomarkers of genetic damage: I. Overview and critical issues

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Abstract

In the last decade, molecular epidemiological studies have provided new perspectives on studying environmental risks in pediatric populations, based on the growing understanding that children may be more susceptible to toxicants than adults. Protecting children's health is a social priority, and specific research programs have been initiated with this purpose in the United States and Europe. These programs address the development of (i) less invasive methods for biological specimens collection, (ii) specific tools for interpretation and validation of biomarkers, (iii) methods for translating biomarker results into intervention strategies and for integrating them with environmental monitoring and health data, (iv) optimal ways to obtain consent and provide information to children and/or their parents participating in the studies and (v) techniques for the effective communication with policy makers and the public. Critical issues in children's environmental research discussed in this paper include specific needs of study design, exposure assessment, sample collection and ethics. Special consideration is given to the autonomy of the child in giving consent, the details and nature of the information provided, and the need to warrant controlled access to sensitive information. The use of incentives such as gifts and payment to ensure the participation of school-aged children is specifically discussed. Examples of field studies that are focused on the effects of pesticides, air pollution and formaldehyde are used to illustrate advantages and limitations of biomarker studies in children.

Introduction

Protecting children's health is a social priority. Specific programs have been initiated in the United States and Europe in recognition of this fact [1], [2], [3].

In the year 2000, the United States Congress passed the Children's Health Act [4]. The National Institute of Environmental Health Sciences (NIEHS) and the United States Environmental Protection Agency (US EPA) funded eight Centers for Excellence in Children's Environmental Health Research in 1998, and funded four more in 2001. The Centers are required to conduct community-based research on the causes and mechanisms of children's disorders with environmental etiologies. Currently, a major National Children's Study is being planned by NIEHS, EPA and the center for disease control (CDC) to follow the growth and development of approximately 100,000 children and evaluate environmental impacts on their health [5], [6].

In 2003, the European Commission launched the SCALE program, that stands for Scientific evidence, focused on Children, to raise Awareness, improve the situation by use of Legal instruments and ensure a continual Evaluation of the progress made [3]. SCALE is aimed at assessing and minimizing the adverse health effects of environmental pollution on children. The main goals of the SCALE program are development of a common European information system and adequate political measures to improve children's environmental safety. SCALE focuses on environmental health indicators, priority diseases (i.e., respiratory diseases, neurodevelopment and childhood cancer), integrated monitoring and children's research needs.

A partial overview of the European research in children's health has identified approximately 100 studies with over 400,000 children participating in existing biomonitoring and or research activities conducted in the member States and acceding Countries [3]. Forty-four studies dealt with exposure to heavy metals, 15 with dioxins/PCB and 5 with exposure to endocrine disruptors. Twenty-seven studies included the identification of biomarkers of asthma and allergy, but only a limited number of them investigated cytogenetic biomarkers in relation to environmental pollution. The methodological differences detected between the studies warranted the need for harmonization programs aimed at (i) generating a broader data set regarding exposure and its relationship to health outcomes, (ii) improving the chance of detecting spatial and temporal trends, (iii) allowing comparisons between geographical areas, (iv) quantifying the contribution of different environmental compartments (e.g., air, water, food, etc.) and (v) identifying emission sources to provide policy makers with better information for the planning of sound environmental actions and the implementation of control measures.

The leading priorities to be addressed in such an action program include the development of non-invasive methods for biological specimen collection, the way of providing information to and obtaining consent from study children (or their parents/guardians), the development of specific tools allowing for the interpretation and validation of measurements with biomarkers, the translation of biomarker results into intervention strategies and integration with environmental monitoring and health data, and the effective communication with policy makers and the general public [4].

In 2001, the European Network on children's susceptibility and exposure to environmental genotoxicants (CHILDRENGENONETWORK) [7] was planned as a concerted effort focusing on the effects of environmental exposure to genotoxic agents during various stages of childhood. Recommendations concerning the need for new research projects as well as ethical, legal and social aspects of biomonitoring in children will be delivered by the end of 2005 to the European Commission and are expected to positively influence European research in the field.

The purpose of this article is to review main issues in studies of genetic damage in children. Several examples of biomarker studies in children from Europe and the United States are used to illustrate the challenges faced by investigators conducting such studies, and the lessons learned.

Section snippets

Exposure assessment in children

The recent interest in studying children's exposure to environmental toxicants stems from the new understanding that pediatric populations may be more susceptible to these agents, including carcinogens [8], [9], [10]. Because of vast differences in behavior and physiology, children's exposure patterns are quite different from those of adults. Children have higher daily intakes (per kilogram of body weight) of food, water and air than adults, and therefore, may have a disproportionately higher

Susceptibility to DNA damaging agents

The presence of a causal association between exposure to genotoxic agents during developmental stages of life and increased risk of cancer is suggested by findings from experimental and epidemiological studies [26], [27]. Recent trends in childhood cancers in the USA and Europe seem to confirm children's increased exposures to genotoxicants [28], [29]. Human studies have reported increased risks for the clear cell cancer of the vagina, cervix, and breast cancer in young women who were exposed

Epidemiological study design in children

Biomonitoring studies designed to evaluate genetic damage in children require careful evaluation of specific features that characterize pediatric populations. These may offer advantages and disadvantages for the investigators. The most evident difference between children and adults is the reduced impact of traditional confounding factors like cigarette smoking and occupational exposures. Children, at least until adolescence, usually do not smoke and are not exposed to any occupational genotoxic

Biological sampling in children

Biological samples needed for exposure assessment and evaluation of early biological outcomes can be obtained from many tissues and by a number of non-invasive as well as invasive methods (Table 1). The choice of biological specimens and mode of collection depends on the type of biological assay to be performed, the age of the study population(s), and the subjects’ health status. Exfoliated cells from the mouth (buccal) or urine (urothelial), may be adequate for some research purposes (e.g.,

Ethical issues

There are several reasons that justify conducting field studies in children, including needs to improve our knowledge of environmental risks at different stages of development, and to define baseline levels of genetic damage in children. However, despite scientific and public interest in these topics, none can provide immediate benefit to the study participants. In light of this fact, ethical considerations have led scientists to limit field studies on children to those that do not expose the

Examples from the field

To provide examples of typical problems encountered when studying pediatric populations, we will review three major field studies from Europe and the United States. Study descriptions are brief, but the reader will be introduced to arising issues and referred to the original publications. The first two examples focus on children exposed to specific and relatively well-defined agents. In the third example, a more general assessment of biomarkers of exposure and health effects is conducted in a

Concluding remarks

The critical issues addressed in this paper clearly show that biomarkers of genetic damage may play a major role in understanding and controlling the adverse health effects of environmental pollution in children. The most evident advantage of using biomarkers is the potential for a better exposure assessment in conditions that are difficult to study, such as when exposure occurs at low doses or there is a mixture of toxic substances. Other benefits are more subtle, but their impact on public

Acknowledgements

The study was supported by grants funded by the European Union 5th FP (QLK4-CT-2000-00628, QLK4-CT-2002-02831 and QLK4-CT-2002-02198) and the Associazione Italiana per la Ricerca sul Cancro (AIRC). The authors appreciated Ms. N. Bekarian's and Ms. L. Pfleger's help with the manuscript preparation.

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