Peter Van Den Hazel

The Faroes statement: Human Health effects of developmental exposure to chemicals in our environment

The periods of embryonic, foetal and infant developmentare remarkably susceptible to environmental hazards. Toxicexposures to chemical pollutants during these windows ofincreased susceptibility can cause disease and disability ininfants, children and across the entire span of human life.Among the effects of toxic exposures recognized in the pasthave been spontaneous abortion, congenital malformations,lowered birthweight and other adverse effects. These outcomesmay be readily apparent. However, even subtle changes causedby chemical exposures during early development may leadto important functional deficits and increased risks ofdisease later in life. The timing of exposure during early lifehas therefore become a crucial factor to be considered intoxicological assessments.During 20–24 May 2007, researchers in the fields of environmentalhealth, environmental chemistry, developmentalbiology, toxicology, epidemiology, nutrition and paediatricsgathered at the International Conference on Fetal Programmingand Developmental Toxicity, in Torshavn, FaroeIslands. The conference goal was to highlight new insightsinto the effects of prenatal and early postnatal exposure tochemical agents, and their sustained effects on the individualthroughout the lifespan. The conference brought togetherresearchers to focus on human data and the translationof laboratory results to elucidate the environmental risks tohuman health.

The Human Early-Life Exposome (HELIX): Project Rationale and Design

Background: Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure–health effect relationships. The “exposome” concept encompasses the totality of exposures from conception onward, complementing the genome. Objectives: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the “early-life exposome.” Here we describe the general design of the project. Methods: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother–child pairs, and biomarkers will be measured in a subset of 1,200 mother–child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure–response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. Conclusions: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome. Citation: Vrijheid M, Slama R, Robinson O, Chatzi L, Coen M, van den Hazel P, Thomsen C, Wright J, Athersuch TJ, Avellana N, Basagaña X, Brochot C, Bucchini L, Bustamante M, Carracedo A, Casas M, Estivill X, Fairley L, van Gent D, Gonzalez JR, Granum B, Gražulevičienė R, Gutzkow KB, Julvez J, Keun HC, Kogevinas M, McEachan RR, Meltzer HM, Sabidó E, Schwarze PE, Siroux V, Sunyer J, Want EJ, Zeman F, Nieuwenhuijsen MJ. 2014. The Human Early-Life Exposome (HELIX): project rationale and design. Environ Health Perspect 122:535–544; http://dx.doi.org/10.1289/ehp.1307204

Cadmium and children: exposure and health effects.

Cadmium exposure and accumulation in the body start at young age. Exposure routes in children are mainly via food, environmental tobacco smoke and house dust. Excretion from the body is limited. Cadmium accumulation in the kidney is responsible for effects such as nephrotoxicity and osteoporosis which are observed at adult age. Cadmium exposure through inhalation is also associated with lung cancer in adulthood. Although transfer to the neonate through the placenta and through breast milk is limited, teratogenic and developmental effects were observed in experimental animals. The database on human studies involving children is limited, yet effects on motoric and perceptual behaviour in children have been associated with elevated in utero cadmium exposure. In school age children urinary cadmium levels were associated with immune suppressive effects. More studies are needed to confirm these results. Experimental data in vitro and in animals refer to effects of cadmium on the hypothalamus‐pituitary axis at different levels. This may lead to disorders of the endocrine and/or immune system. Cadmium exposure at early age should be limited as much as possible to prevent direct effects on children and to prevent accumulation of cadmium which may have serious health effects only becoming manifest at older age.

Respiratory Effects of Commutersʼ Exposure to Air Pollution in Traffic

Background: Much time is spent in traffic, especially during rush hours, when air pollution concentrations on roads are relatively high. Controlled exposure studies have shown acute respiratory effects of short, high exposures to air pollution from motor vehicles. Acute health effects of lower real-life exposures in traffic are unclear. Methods: Exposures of 34 healthy, nonsmoking adult volunteers were repeatedly measured while commuting for 2 hours by bus, car, or bicycle. Particle number (PN), particulate matter (PM2.5 and PM10), and soot exposures were measured. Lung function and airway resistance were measured directly before, directly following, and 6 hours after exposure. Exhaled nitric oxide (NO) was measured directly before and 6 hours after exposure. Inhaled doses were estimated based on monitored heart rates. Mixed models were used to analyze effects of exposure on changes in health parameters after exposure compared with before. Results: PN, PM10, and soot were associated with decreased peak expiratory flow directly following but not 6 hours after exposure. PN doses were associated with decreases in maximum midexpiratory flow and forced expiratory flow (FEV1) 6 hours after exposure, whereas PN and soot exposures were associated with increased maximum midexpiratory flow and FEV1 directly after exposure. PN and soot were associated with increased exhaled NO after car and bus but not bicycle trips. PN was also associated with an increase in airway resistance directly following exposure but not 6 hours later. Conclusions: We found modest effects of 2-hour in-traffic exposure to air pollutants on peak flow, exhaled NO, and airway resistance.

Positive health effects of the natural outdoor environment in typical populations in different regions in Europe (PHENOTYPE): a study programme protocol

Introduction Growing evidence suggests that close contact with nature brings benefits to human health and well-being, but the proposed mechanisms are still not well understood and the associations with health remain uncertain. The Positive Health Effects of the Natural Outdoor environment in Typical Populations in different regions in Europe (PHENOTYPE) project investigates the interconnections between natural outdoor environments and better human health and well-being. Aims and methods The PHENOTYPE project explores the proposed underlying mechanisms at work (stress reduction/restorative function, physical activity, social interaction, exposure to environmental hazards) and examines the associations with health outcomes for different population groups. It implements conventional and new innovative high-tech methods to characterise the natural environment in terms of quality and quantity. Preventive as well as therapeutic effects of contact with the natural environment are being covered. PHENOTYPE further addresses implications for land-use planning and green space management. The main innovative part of the study is the evaluation of possible short-term and long-term associations of green space and health and the possible underlying mechanisms in four different countries (each with quite a different type of green space and a different use), using the same methodology, in one research programme. This type of holistic approach has not been undertaken before. Furthermore there are technological innovations such as the use of remote sensing and smartphones in the assessment of green space. Conclusions The project will produce a more robust evidence base on links between exposure to natural outdoor environment and human health and well-being, in addition to a better integration of human health needs into land-use planning and green space management in rural as well as urban areas.

In-Traffic Air Pollution Exposure and CC16, Blood Coagulation, and Inflammation Markers in Healthy Adults

Background: Exposure to traffic-related air pollution is a risk factor for cardiovascular events, probably involving mechanisms of inflammation and coagulation. Little is known about effects of the short exposures encountered while participating in traffic. Objectives: The objective of the study was to examine effects of exposure of commuters to air pollution on cardiovascular biomarkers. Methods: Thirty-four healthy adult volunteers commuted for 2 hr by bus, car, or bicycle during the morning rush hour. During the commute, exposure to particle number, particulate matter (PM) ≤ 2.5 µm in aerodynamic diameter (PM2.5), PM ≤ 10 µm in diameter (PM10), and soot was measured. We estimated inhaled doses based on heart rate monitoring. Shortly before exposure and 6 hr after exposure, blood samples were taken and analyzed for CC16 (Clara cell protein 16), blood cell count, coagulation markers, and inflammation markers. Between June 2007 and June 2008, 352 pre- and postexposure blood samples were collected on 47 test days. We used mixed models to analyze the associations between exposure and changes in health parameters. Results: We observed no consistent associations between the air pollution exposures and doses and the various biomarkers that we investigated. Conclusions: Air pollution exposure during commuting was not consistently associated with acute changes in inflammation markers, blood cell counts, or blood coagulation markers.

Exposure to multiple environmental agents and their effect

Introduction: All children are exposed to multiple physical, chemical and biological challanges that can result in adverse health effects before and after birth. In this context, the danger of multiple exposures cannot be assessed from a single‐chemical approach as used in classical toxicology. Aim: To open up a ‘negotiation space’ for the problem of multiple exposure to environmental stressors, defined as any physical, chemical or biological entity that can induce an adverse response. In this context, two further questions obtain: to what extent can synergistic risks be assessed, and how far could potential adverse effects be prevented by enhanced regulation?Methods: A discussion of two general approaches is taken: 1 ) the investigation of mixtures such as smoking or air pollution without specifying the individual agents, and 2 ) the investigation of individual substances with a focus on possible interactions in the context of dose to receptor. Results: Although mixtures of compounds can have effects, it may not be possible to ascribe causation to a single compound. Furthermore, cumulative low‐dose insult can, in some circumstances, be more toxic than a single high‐dose exposure, e.g. endocrine disruptive effects of a combination of PCBs and dioxins which disrupt the thyroid hormone status; this tends to contradict elements of classical toxicology,. These cumulative insults may further combine with heavy metals and can disrupt the heme synthesis. It is possible that groups of pollutants could be used to test their cumulative capacity to multiple stress‐susceptible receptor targets as is done in smoking and air pollution. This methodology could be used for further groups of potential pollutants, for example those associated with cleaning products, or cosmetics. Testing individual substances with a focus on interactions means that not only chemicals but also concurrent diseases should be taken into account. We suggest that the enhanced regulation of potential multiple stressors falls into two discrete categories. The first comprises a more precautionary approach (as demonstrated by the banning of chemicals such as some brominated flame retardants in Europe). The second comprises a more ‘permissive’ liberal approach involving the initial study of an individual compound, and subsequent interrogation of that compound in combination with another (as demonstrated by lowering the carcinogenicity of aflatoxin by vaccination against hepatitis B).

Adverse health effects of children's exposure to pesticides: what do we really know and what can be done about it.

Children may be exposed to pesticides in several ways, such as by transplacental transfer during foetal life, by intake of contaminated breast milk and other nutrients, or by contact with contaminated subjects and areas in the environment such as pets treated with insecticides, house dust, carpets and chemically treated lawns and gardens. Exposure early in life, and particularly during periods of rapid development, such as during foetal life and infancy, may have severe effects on child health and development by elevating the risk of congenital malformations, cancer, malabsorption, immunological dysfunction, endocrine disease, and neurobehavioural deficiencies. As pesticides can also interfere with parental reproductive health, exposure of parents may have consequences for the offspring leading to reduced chance of male birth and increased risk of childhood cancer.

Today's epidemics in children: possible relations to environmental pollution and suggested preventive measures.

Background: Facts and hypotheses on the relationship between some childrens diseases or disorders and external stressors during the developmental stage of a child, both prenatally and postnatally are described in literature. In this paper the following changes in patterns and causes of the main childhood illnesses are summarized and recommendations for actions are made.

Lead neurotoxicity in children: is prenatal exposure more important than postnatal exposure?

Numerous studies indicate that low‐level lead poisoning causes mild mental retardation and low IQ scores in children. The general mean lead intake in the adult European population corresponds to a reassuring 14% (0.5–56%) of the tolerable daily intake: at this low level of exposure only few children (less than 10%) have blood lead levels (PbB) higher than 10μg/dl, previously considered the PbB of concern. In more recent years data now suggest that even when ‘the lifetime average blood lead concentration’ is below 10μg/dl an inverse association exists with intelligence quotient (IQ) scores. Two‐thirds (45–75%) of lead in blood, however, comes from long‐term tissue stores and this is especially true for newborn infants and pregnant women. Several data suggest that for lead the main toxic event is prenatal exposure: therefore we should focus our attention on maternal lead stores and whenever possible avoid their mobilization during pregnancy. In this regard we should design appropriate studies to confirm whether dietary supplementations can reduce bone resorption and lead mobilization during pregnancy. The hypothesis that the amount of maternal bone lead stores is the relevant parameter for predicting the level of neurotoxicity of this metal gives some optimism for the future: if we study children whose mothers never underwent high environmental pollution (born after the withdrawal of lead from gasoline) and hence have relatively low bone lead stores we could find that, at the population level, lead has little influence on children IQ scores