Review
Children's exposure to environmental pollutants and biomarkers of genetic damage: II. Results of a comprehensive literature search and meta-analysis

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Abstract

The present review is based on findings from 178 publications retrieved through an extensive search of the MedLine/PubMed database for a 25 years time period (1980–2004) and 10 manually identified papers. Among the cytogenetic biomarkers that are frequently used in field studies, chromosome aberrations (CA) and micronuclei (MN) but not sister chromatid exchanges (SCE) were found consistently increased in children exposed to environmental pollutants. Meta-analysis of the studies reporting SCE in cord blood showed similar levels of SCE in exposed and in non-exposed newborns. Exposure to airborne pollutants, soil and drinking water contaminants, mostly increased CA and, to a lesser extent, MN levels in children. The effect of exposure to airborne urban pollutants was consistently reported by field studies measuring DNA, albumin and hemoglobin adducts. Prenatal (in utero) and postnatal exposure (environmental tobacco smoke, ETS) to tobacco smoke compounds were associated with increased frequencies of DNA and hemoglobin adducts and CA. The limited number of field studies measuring DNA fragmentation (Comet assay), hypoxanthine-guanine phosphoribosyltransferase (HPRT) and the glycophorinA (GPA) mutation frequency in environmentally exposed children precluded a meaningful evaluation of the usefulness of these assays. Meta-analyses performed in children exposed to ETS and in newborns exposed in utero to their mothers’ smoke showed 1.3 and 7 times higher levels of hemoglobin adducts compared to referent subjects, respectively. These increases are consistent with the epidemiological evidence of higher lung cancer risks reported in adults who had never smoked and were exposed to ETS during childhood and with 7–15 times higher lung cancer risks reported in smokers than in non-smokers. Higher levels of PAH-DNA adducts were found in fetal than in maternal tissue, suggesting a specific susceptibility of the fetus to this class of ubiquitous environmental pollutants. According to these findings, future research and biomonitoring programs on children would greatly benefit from the inclusion of selected biomarkers that could provide biologically based evidence for the identification of intervention priorities in environmental health.

Introduction

In 2001, the European Network on children's susceptibility and exposure to environmental genotoxicants (CHILDRENGENONETWORK) [1] was planned, which was a research project focusing on the effects of environmental exposure to genotoxic agents during various developmental stages. This European network collects existing information from participating laboratories and reviews scientific literature to evaluate the evidence of the association between environmental exposure to genotoxic agents during the fetal, neonatal and infancy developmental periods, concentrating on exposures entailed by urban air, soil and water pollution, cigarette smoke and environmental tobacco smoke (ETS), and the level of selected biomarkers of genetic damage. Exposure to ionising radiation (accidental, environmental, therapeutic or diagnostic), a widely studied physical DNA damaging agent, is considered within the project and it will be evaluated separately. The network also explores the use of biomarkers to assess potential cancer risks of environmental exposures. Recommendations concerning the need for new research projects as well as ethical, legal, and social aspects of biomonitoring in children will be delivered to the European Commission and are expected to positively influence European research in the field.

The first step of the present systematic review includes the development of a protocol to conduct meta-analyses [2] on different biomarkers and the establishment of a database for pooled analyses. The following biomarkers were included as intermediate end-points related to the carcinogenesis process: DNA, hemoglobin and albumin adducts (evaluating the biologically effective dose), chromosome aberrations (CA), sister chromatid exchanges (SCE) and micronuclei (MN), DNA fragmentation by the Comet assay (evaluating early biological effect), the hypoxanthine-guanine phosphoribosyltransferase (HPRT) and the glycophorinA (GPA) mutation frequency assays (evaluating early biological response).

This review is aimed at identifying field studies conducted among children exposed to chemical environmental pollutants incorporating the above-mentioned biomarkers, evaluating and summarizing the evidence of specific exposure-biomarkers associations. For each study, the ratio of the mean levels (MR = mean ratio) of each biomarker detected in exposed and in referent children was computed as a point estimate of the relative effect of exposure. A more precise quantitative summary estimate of the exposure-biomarker association (meta-MR) was computed when feasible by conducting a meta-analysis to generalize single study findings [3].

Section snippets

Search strategy

We performed an extensive literature search without any language restriction by using the MedLine/PubMed database (National Library of Medicine, National Institutes of Health, Bethesda, MD, USA-http://www.ncbi.nlm.nih.gov/PubMed) and covering the time period between January 1, 1980 and November 30th, 2004. Table 1 shows the keywords selected from Medical Subject Headings (MeSH), (hereafter indicated as keyword [mesh]), and the combinations of search terms that have been used through the Boolean

Exposure-biomarker associations

The MedLine search strategy retrieved 178 studies. Cytogenetic biomarkers (CA, SCE and MN), were the most frequently found biomarkers through MedLine search (Table 2). CA were mentioned in 78 studies, SCE in 38 and MN in 27. Thirty-two studies measuring DNA adducts, 14 and 10 measuring hemoglobin and albumin adducts, respectively, were retrieved. The Comet assay was cited in 18 studies, the HPRT loci mutant frequency assay in 11, and the GPA human mutation assay in two field studies. The

Exposure-biomarker associations

The findings of the present review suggest that field studies conducted in children exposed to environmental pollutants may greatly benefit from the inclusion of biomarkers of genetic damage as study end-points. In fact, among the most frequently used cytogenetic biomarkers, CA and MN were consistently increased in children exposed to environmental pollutants regardless of the type of exposure. SCE appeared to be a less sensitive early biological effect marker capable of detecting only, and

Conclusions

The present review shows that biomarkers of genetic damage, including CA and MN, DNA adducts and DNA-surrogate hemoglobin and albumin adducts are capable of detecting early biological effects in children and newborns exposed to environmental pollutants. These biomarkers were consistently increased for postnatal exposures to urban air pollutants and ETS and transplacental exposure to chemicals contained in mainstream cigarettes smoke (i.e., smoking mothers) as well as in second-hand cigarettes

Acknowledgements

The study was supported by grants funded by the European Union 5th FP (QLK4-CT-2000-00628, QLK4-CT-2002-02198, and QLK4-CT-2002-02831) and the Associazione Italiana per la Ricerca sul Cancro (AIRC).

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