Pregnancy and birth cohort studies provide the possibility of repeated measurements of health outcomes and exposures at different time points from pregnancy through childhood and adolescence into adulthood. Therefore, they present an ideal framework for the prospective study of the effects of environmental exposures on the health and development of children. Furthermore, they allow the study of temporal variability in exposure. If temporal variability is sufficient, the relevance of exposure at different time points (e.g. prenatal and postnatal) and the health impact associated with changes in exposure can be investigated, which may help to focus preventive actions.

Currently, many European birth cohort studies of children’s environment-health relationships exist and provide evidence for relationships that can be used to develop strategies to reduce environmental exposures and to improve health. However, single studies often lack statistical power to lead to conclusive results on their own, in particular when health outcomes and/or exposures with low prevalence are studied. Combining data from different studies is a powerful remedy for this. Also, collaboration between birth cohorts enables us to replicate and corroborate or refute findings as well as to explore reasons for heterogeneity. Therefore, there is an urgent need to evaluate, and where possible combine, the existing data, methods and tools from European birth cohort studies in order to evaluate possible links between environmental exposures and health 1 .

The assessment of exposure is a crucial element of the study of the potential adverse effects associated with exposure. Error in exposure measurements reduces the statistical power of a study 2 and the estimated effect is likely to be smaller than the true effect 3 , both increasing the likelihood that real associations are not detected. Exposure can be assessed by means of direct approaches including biological and personal monitoring, by means of indirect approaches including environmental monitoring and modeling as well as the use of questionnaires and diaries or a combination thereof 4 . Exposure assessment by means of (repeated) individual environmental or biological monitoring, however, is costly and therefore usually not feasible in all participants of large cohort studies. This means that making informed decisions of what to measure in how many study subjects is crucial.

As part of the European Union funded Environmental Health Risks in European Birth Cohorts (ENRIECO) project, an inventory of the environmental exposure and health data in existing European birth cohort studies was made 5 . The objective of the present review is to analyze the environmental exposure assessment in the birth cohort studies in detail. The review covers established exposures (e.g. ambient air pollution, environmental tobacco smoke, allergens and biocontaminants, metals, persistent organic pollutants (POPs) and noise) as well as exposures that more recently became the focus of epidemiological research (e.g. electromagnetic fields, phthalates and phenols). The emphasis is on comparison of methods currently used in birth cohort studies leading to recommendations for improvement. We focus on methodological issues such as comparability, validity, (dis-)agreement between methods, ability to predict concentrations in earlier or later periods, and timing of exposure assessment that are relevant to several exposures rather than exposure-specific issues.

The inventory revealed that in the European birth cohort studies, rich and diverse data on environmental exposures exist. Several examples of successful collaborations were identified making use of exposure data obtained in several cohorts.

A number of methodological issues were identified as well. Often, indirect methods were used rather than measures of personal exposure. Temporal misalignment of exposure measurements relative to timing of health measurements was also identified, as was lack of information on time-activity patterns. All of these produce error in exposure measurements which may attenuate risk estimates and statistical power of a study and increases the likelihood that real associations are not detected 2 . The National Research Council ranked the different direct and indirect approaches of exposure assessment and considered personal exposure measurements as the best estimate of actual exposure 29 . Exposure assessment by means of (repeated) individual environmental or biological measurements, however, is costly and therefore usually not feasible in all participants of large cohort studies. Therefore, in many studies in this inventory, questionnaires were used to enquire about the exposure of interest, occasionally in combination with environmental measurements (water contamination).

Questionnaire reports were found to be an inexpensive and valid estimate of residential SHS exposure among preschool and school children 9 10 11 , whereas questionnaire-reported cat and dog ownership is a relatively poor measure of pet allergen levels in house dust 13 14 15 16 and cannot be used as a surrogate for measurements of specific microbial agents in house dust 17 18 19 . House dust collection by study participants instead of fieldworkers can reduce the costs associated with the collection of dust samples for the assessment of allergen and biocontaminant exposure. Several methods have been described in the literature including nylon socks 30 , electrostatic wipes 31 32 , and passive samplers 33 . For other exposures such as household use of pesticides and non-ionizing radiation, where exposure assessment also largely relies on questionnaires, such validation studies are still lacking. Also, for chemical exposures such as phthalates that are currently exclusively measured by biomonitoring, no validated questionnaires exist and predictors need to be identified 7 .

Likewise, there is still little validation of modeled exposures (ambient air pollution) or surrogate variables (e.g. proximity to agricultural activities as a proxy for bystander exposure to pesticides) against individual environmental monitoring.

As the birth cohorts studies in this inventory were all funded locally, there was no initial harmonization of exposure assessment methods For example, different questionnaires were used in different cohorts; there were no standardized protocols for the collection and analysis of individual environmental samples and biomonitoring was done in different media such as breast milk, cord blood, placenta, serum and whole blood. Some exceptions include studies in which a standardized exposure assessment was part of a collaborative effort (e.g. TRAPCA (outdoor air pollution 21 ), ESCAPE (outdoor air pollution 22 23 34 ), HIWATE (water contamination 24 ) AIRALLERG (allergens, biological contaminants and indoor air pollution 25 26 ), and HITEA (indoor biological agents, http://www.hitea.eu/). In the absence of such prior harmonization of methods, data can still be combined after careful examination of the communalities and differences between methods. Moreover, it should be noted that harmonization of exposure assessment is not straightforward and may not be beneficial in all cases as for example for many exposures there is no gold standard, and questionnaires may be based on wrong hypotheses. This is more a concern for emerging exposures (e.g. radiation) than for established exposures (e.g. SHS). Furthermore, the development of internationally accepted standards is a complicated and lengthy process and often standards hinder the development and introduction of new methods. Especially for the assessment of emerging exposures and for new exposure assessment methods diversity is desired as it allows the evaluation and comparison of different methods. For exposures that are (mainly) assessed by means of biomonitoring (i.e. metals, pesticides, POPs, and other chemical pollutants), the performance of inter-laboratory comparisons and either the harmonization of the exposure assessment with regard to the sampling medium or the development of conversion factors has been recommended to facilitate combined analyses (Table 2).

Individual assessment of exposures experienced by the study subjects in different micro-environments by means of personal or stationary monitoring alone will generally not be feasible in birth cohorts, as the study populations generally comprise several hundreds to thousands of subjects. Therefore, environmental exposure assessment in the European birth cohorts currently is often limited to residential exposure although many study participants regularly spend considerable amounts of their time outside their homes for instance at day care centers or schools. Consequently, little is known about the role of non-residential exposure and time-activity pattern in the association between these exposures and health. Some recent publications on the effects of ambient air pollution where exposure was estimated as a time-weighted average of several addresses where the participants spent considerable amounts of time indicated little differences between the estimated exposure at the home address only and the time-weighted average of residential and non-residential (i.e. work or school) exposure 35 36 37 . However, this needs further evaluation.

For many exposures, we presently know very little about the relevance of the timing of the exposure in addition to the level of exposure, and it is unclear whether exposure during a specific period when organs develop and are considered being more susceptible, is more important than later exposure (e.g. for congenital anomalies early pregnancy and birth weight mostly likely late pregnancy). The window of susceptibility for reproductive outcomes is most likely short (days, months, trimesters of pregnancy) and depends on the type of outcome 38 . For asthma and allergies it has been hypothesized that there is a “window of opportunity” early in life where the development of asthma and allergies is initiated by a variety of factors 39 . However, we cannot rule out that there are multiple windows of susceptibility during fetal development and (early) childhood. As an example, one of the case studies performed within the ENRIECO project demonstrated that SHS exposure during pregnancy and during the first year of life are independent risk factors for childhood wheeze and asthma 28 .

Prospective birth cohort studies with repeated exposure and health outcome assessments offer a unique possibility to increase our knowledge with regard to the temporal variability of exposure and if variability is sufficient the relevance of exposure during different time periods. The need for repeated exposure assessments depends on the temporal variability and the toxicokinetics of the exposure of interest: if there is little variability, few repeated measures are needed; if there is a lot of variability many repeated measurements are needed. The number of measurements that can be performed in a cohort study, however, is limited, and therefore it will never be possible to continuously monitor exposure. Repeated exposure assessments, for part of the population if not possible for all study participants, however, can provide valuable information about the validity of a single exposure assessment for a longer period, i.e. its ability to predict concentrations in earlier of later periods. For example, land-use regression models that are currently used very often for assessments of long-term exposures to outdoor air pollution are based on one measurement campaign during which air pollution concentrations are measured at a number of locations. Few validation studies have been performed so far. Recently, it has been shown that land-use regression models were highly predictive of NO/NO₂ concentrations measured 10 and 13 years apart in The Netherlands, and Rome, Italy 40 41 . A high correlation has also been shown between measurements of POPs performed as much as 10 years apart 42 . Furthermore, there is some evidence that a single endotoxin 43 44 45 46 , mite or cat allergen measurement 46 47 is a valid estimate of exposure for longer time periods.

Collecting data before the occurrence of any adverse health event of interest is crucial when temporal variability of the exposure of interest is high or the presence of a certain disease or condition can result in changes in exposure (e.g. allergen avoidance in subjects with asthma and allergies). Furthermore, if exposure assessment relies on (parental) self-reporting a retrospective assessment may result in reporting bias or recall bias (e.g. due to increased awareness of certain exposures in diseased subjects). Nevertheless, also in prospective cohort studies, exposure assessment is sometimes done retrospectively, i.e. an exposure assessment is added to existing health data because time and money for exposure assessment at the beginning of a study are limited and often new exposures become of interest only after the study has been going on for some time. The storage of (part of) biological and environmental samples for later analyses as well as the use of historical data that has been routinely collected for other (e.g. monitoring) purposes can overcome the problems associated with retrospective exposure assessment. Another possibility included the use of GIS-based techniques and exposure modeling techniques, which are currently in particular, but not exclusively, used for air pollution exposure assessment. For example, within European birth cohort studies, GIS-based techniques have also being used for assessment of noise. Furthermore, outside European birth cohorts, GIS-based techniques have been used to assess pesticide exposures, e.g. 48 49 and more recently exposure to radiofrequency electromagnetic fields 50 .

Lessons from collaborative efforts so far have been that combining data from various cohorts requires careful consideration of the aims, protocols, data (comparability and availability of exposure, health and relevant confounder data), ethical issues, analyses and management, and it is time and labor intensive but potentially fruitful. As an example, a challenge of the case study on POPs 6 was the development of conversion factors to facilitate combined analyses with persistent organic pollutant measurements performed in different media. Collaborative studies performed within the EU-funded CHICOS project (http://www.chicosproject.eu) currently build on these experiences. Both, existing collaborative studies as well as our recommendations regarding future meta-analyses and/or pooled analyses within the European birth cohort studies, so far, were very much focused on the study of one exposure at a time. Possible interactions between different exposures are of course of major interest as environmental exposure is not limited to a single agent and basically all cohorts have data on multiple exposures. Limited statistical power of single cohort studies is a much bigger issue in the study of interactions between exposures than in one-agent-at-a-time studies, resulting in an even greater need for collaborative studies here.

Substantive questions in environmental health that could potentially be answered by future collaborative efforts include health effects of ultrafine particles in air; pharmaceuticals, PFOS/PFOA and other endocrine disruptors in drinking water 51 ; and medical radiation exposure.

Improvement is needed of questionnaire instruments to assess water contamination, UV, non-ionizing radiation, second hand tobacco smoke, noise, and occupational exposures. Inter-laboratory comparisons are needed for methods to measure POPs and other chemicals through biomonitoring. Recommendations for future work include the use of new technologies such as GIS and satellite imaging for assessment of pesticide exposure and molecular methods or DNA fingerprinting for assessment of microbial exposures.

Lack of information on variables that are determinants of exposure and health outcomes can lead to confounding bias in epidemiological studies 8 . A discussion of relevant confounders for a wide range of exposure-health relationships is beyond the scope of this paper. However, there are two variables that may act as a confounders of many exposure health relationships and that we would like to mention here, namely socio-economic status (SES) and genetic predisposition. Socio-economic status has been shown to be an important determinant of several environmental exposures (e.g. air pollution and second-hand smoking) and susceptibilities (e.g. pre-existing health conditions, stress, behavior), which have been suggested to act together to influence the health response of groups classified by socioeconomic level 52 53 54 . Therefore information on SES has been collected in basically all existing cohorts. We strongly recommend to new cohorts to collect individual information on participants’ SES (e.g. parental education, income or occupation) to assess potential confounding and modifications of exposure-health relationships by SES. Likewise, information on genetic predisposition is very important and should be collected as genetic predisposition may act as a confounder (e.g. allergen-avoidance of allergic parents 55 ) or an effect modifier of the association of interest.

European birth cohorts are collecting a wealth of data on environmental exposures. Most data is currently available for outdoor air pollution, allergens and microbial agents, smoking and second hand tobacco-smoke, and occupational exposures. Collaborative analyses with data from several birth cohorts have been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and tobacco smoke exposure. This illustrates the large potential for collaborative analyses of other environmental health issues as well. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question. The main reasons for collaboration between population studies are replication, studying heterogeneity, and increasing statistical power to study small relative risks, rare events and/or complex interactions. Apart from subject-matter specific recommendations, progress can only be achieved with further harmonization of methods, including those for environmental exposure assessment. The ENRIECO project shows the potential as well as the limitations to use data from existing, locally funded studies for this. Assuming that the majority of future studies will continue to be locally designed and funded, there is a need to periodically review methods for exposure assessment as they become available. Investigators and funding agencies can then make use of this information to choose methods.

AAS: Atomic absorption spectroscopy; CT: Computer tomography; DDT: Dichlorodiphenyltrichloroethane; END: Environmental Noise Directive; ELF: Extreme low frequency; EMF: Electromagnetic field; ENRIECO: Environmental Health Risks in European Birth Cohorts; GIS: Geographic Information System; HPLC: High-Performance Liquid Chromatography; ICP-MS: Inductively Coupled Plasma Mass Spectrometry; JEM: Job Exposure Matrix; PCB: Polychlorinated Biphenyl; PFOA: Perfluorooctanoic Acid; PFOS: Perfluorooctanesulfonic Acid; POP: Persistent Organic Pollutant; RF: Radio Frequency; SES: Socio-Economic Status; SHS: Second Hand Smoke; UV: Ultraviolet.

The authors declare that they have no competing interests.

MN was the Principial Investigator of the ENRIECO project. MV and MC were responsible for the inventory that served as a basis for the evaluations presented in this paper. All authors were responsible for the evaluation of the information for one or more exposure topics including the writing of reports. UG wrote the manuscript; all other authors critically reviewed the manuscript and approved the final version of the manuscript for submission.