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Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. © The Author 2015.

Environmental justice research suggests that inequalities in the distribution of environmental quality systematically disadvantage the lower social strata of society. The effects of these inequalities on the human exposure to specific chemical pollution remain, however, to a large extend unknown, especially in hotspot areas where surrounding neighbourhoods are exposed to a mixture of diverse pollution. In Flanders, the northern part of Belgium, a community-based participatory approach was set up between 2009-2010 to collect blood, urine and hair samples of 197 socially and ethnically diverse adolescents (14-15 years of age) living in the close proximity of a non-ferro industrial area. We conduct a socio- stratification of human biomonitoring results by associating the internal body concentration of three types of chemical pollution (heavy metals, POPs and volatile compounds) with individual socioeconomic status (SES) and ethnic background. Social gradients in exposure to these chemicals are assessed with geometric means, using multiple regression models, controlling for covariates and confounders. Our results show that, depending on the (type of) pollutant, adolescents with a lower SES can either have higher or lower internal concentrations. Socially constructed factors, such as dietary and lifestyle habits, play an important role in these relations. We conclude that when assessing the human exposure concentrations of pollutants, more complex patterns of social stratification emerge than can be assumed on the basis of the environmental justice hypothesis. It therefore remains important to consider the chemical environment in relation to the social environment when monitoring environmental health risks. By emphasising on transparent communication and relevant interaction between residents, local stakeholders and scientists, monitoring environmental health could enhance the empowerment of socioeconomically disadvantaged communities.

Flanders, Belgium, is one of the most densely populated areas in Europe. The Flemish Environment and Health Survey (2002-2006) aimed at determining exposure to pollutants of neonates, adolescents, and older adults and to assess associated biological and health effects. This study investigated genome wide gene expression changes associated with a range of environmental pollutants, including cadmium, lead, PCBs, dioxin, hexachlorobenzene, p,p'-DDE, benzene, and PAHs. Gene expression levels were measured in peripheral blood cells of 20 adults with relatively high and 20 adults with relatively low combined internal exposure levels, all non-smokers aged 50-65. Pearson correlation was used to analyze associations between pollutants and gene expression levels, separately for both genders. Pollutant- and gender-specific correlation analysis results were obtained. For organochlorine pollutants, analysis within genders revealed that genes were predominantly regulated in opposite directions in males and females. Significantly modulated pathways were found to be associated with each of the exposure biomarkers measured. Pathways and/or genes related to estrogen and STAT5 signaling were correlated to organochlorine exposures in both genders. Our work demonstrates that gene expression in peripheral blood is influenced by environmental pollutants. In particular, gender-specific changes are associated with organochlorine pollutants, including gender-specific modulation of endocrine related pathways and genes. These pathways and genes have previously been linked to endocrine disruption related disorders, which in turn have been associated with organochlorine exposure. Based on our results, we recommend that males and females be considered separately when analyzing gene expression changes associated with exposures that may include chemicals with endocrine disrupting properties.

Personal care products (PCPs), such as soaps, perfumes, cosmetics, lotions, etc., contain a variety of chemicals that have been described as potentially hormone disrupting chemicals. Therefore, it is important to assess the internal exposure of these chemicals in humans. Within the 2nd Flemish Environment and Health Study (FLEHS II, 2007-2011), the human exposure to three classes of pollutants that are present in a wide variety of PCPs - i.e. polycyclic musks (galaxolide, HHCB and tonalide, AHTN in blood), parabens (urinary para-hydroxybenzoic acid, HBA) and triclosan (urinary TCS) - was assessed in 210 Flemish adolescents (14-15 years) and in 204 adults (20-40 years) randomly selected from the general population according to a stratified two stage clustered study design. The aim of this study was to define average levels of exposure in the general Flemish population and to identify determinants of exposure. Average levels (GM (95% CI)) in the Flemish adolescents were 0.717 (0.682-0.753) ?g/L for blood HHCB; 0.118 (0.108-0.128) ?g/L for blood AHTN; 1022 (723-1436) ?g/L for urinary HBA and 2.19 (1.64-2.92) ?g/L for urinary TCS. In the adults, levels of HBA were on average 634 (471-970) ?g/L. Inter-individual variability was small for HHCB and AHTN, intermediate for HBA, and large for TCS. All biomarkers were positively associated with the use of PCPs. Additionally, levels of HHCB and AHTN increased with higher educational level of the adolescents. Both in adults and adolescents, urinary HBA levels were negatively correlated with BMI. We define here Flemish exposure values for biomarkers of PCPs, which can serve as baseline exposure levels to identify exposure trends in future biomonitoring campaigns.

To collect information on the concentration levels of Persistent Organic Pollutants (POPs) in the rural areas in Flanders (Belgium), 84 breastfeeding mothers were recruited in rural communities in East and West Flanders and Flemish Brabant in 2009-2010. Polychlorinated biphenyl (PCB) congeners, organochlorine pesticides, brominated flame retardants, perfluorinated compounds, polychlorinated dibenzodioxines and dibenzofurans, and dioxin-like PCBs were measured in individual milk samples and in a pooled milk sample, while some additional pollutants were only measured in the pooled sample. For most pollutants, the concentration levels in this study were lower or comparable to the levels measured in the pooled Belgian sample of the WHO human milk study of 2006, except for the pesticides dichlorodiphenyltrichloroethane DDT (+25% for ?DDT and metabolites) and trans-nonachlor (+94%), and for the brominated flame retardant hexachlorocyclododecane HBCD (+153%). Perfluorinated compounds were for the first time determined in human milk samples from Belgium and the levels were comparable to those from other European countries. Also, interesting associations were found between the levels of POPs measured in human milk and personal characteristics as well as dietary habits of the study population. PFOS en PFOA concentrations were significantly higher in milk of primiparous participants compared to mothers who gave birth to their second child. Lower brominated PBDE congeners increased with increasing BMI of the mothers (p=0.01 for BDE 47, p=0.02 for BDE 99 and p=0.02 for BDE 100). Participants consuming milk or dairy products daily had significant higher levels of sumDDTs (p=0.03) and oxychlordane (p=0.047) in their human milk samples.

Since 2002 a human biomonitoring network has been established in Flanders (Belgium) as part of a programme on environmental health surveillance. The human biomonitoring network should support environmental health policy by identifying priorities for further action. The first cycle of the programme (2002-2006) confirmed the hypotheses that living in areas with different environmental pressure is reflected in different loads of environmental chemicals in the residents. In the second cycle of the programme(2007-2011) the number of environmental chemicals for which human biomonitoring data were obtained was expanded substantially. The goal of the Flemish programme is to use and translate the scientific results into policy actions. Its further orientation in the second cycle to human biomonitoring in hot spots and sensitive age groups or susceptible persons with underlying complications (e.g.persons with diabetes) are linked to these goals. Interaction with stakeholders is embedded in the programmeemphasizing transparency of the choices that are made and direct communication. The Flemish human biomonitoring programme is organized centrally with major involvement of research partners from different disciplines which allows engrafting environmental health research on the programme. One of the major focuses is the question whether combinations of pollutants in the general population are associated with biological effects. The objective of this paper is to review and discuss the options that were taken in the human biomonitoring programme in order to achieve its goals.

Background We hypothesized that in Flanders (Belgium), the prevalence of at-risk genotypes for genotoxic effects decreases with age due to morbidity and mortality resulting from chronic diseases. Rather than polymorphisms in single genes, the interaction of multiple genetic polymorphisms in low penetrance genes involved in genotoxic effects might be of relevance. Methods Genotyping was performed on 399 randomly selected adults (aged 50-65) and on 442 randomly selected adolescents. Based on their involvement in processes relevant to genotoxicity, 28 low penetrance polymorphisms affecting the phenotype in 19 genes were selected (xenobiotic metabolism, oxidative stress defense and DNA repair, respectively 13, 6 and 9 polymorphisms). Polymorphisms which, based on available literature, could not clearly be categorized a priori as leading to an 'increased risk' or a 'protective effect' were excluded. Results The mean number of risk alleles for all investigated polymorphisms was found to be lower in the 'elderly' (17.0 ± 2.9) than the 'adolescent' (17.6 ± 3.1) subpopulation (P = 0.002). These results were not affected by gender nor smoking. The prevalence of a high (> 17 = median) number of risk alleles was less frequent in the 'elderly' (40.6%) than the 'adolescent' (51.4%) subpopulation (P = 0.002). In particular for phase II enzymes, the mean number of risk alleles was lower in the 'elderly' (4.3 ± 1.6 ) than the 'adolescent' age group (4.8 ± 1.9) P < 0.001 and the prevalence of a high (> 4 = median) number of risk alleles was less frequent in the 'elderly' (41.3%) than the adolescent subpopulation (56.3%, P < 0.001). The prevalence of a high (> 8 = median) number of risk alleles for DNA repair enzyme-coding genes was lower in the 'elderly' (37,3%) than the 'adolescent' subpopulation (45.6%, P = 0.017). Conclusions These observations are consistent with the hypothesis that, in Flanders, the prevalence of at-risk alleles in genes involved in genotoxic effects decreases with age, suggesting that persons carrying a higher number of at risk alleles (especially in phase II xenobiotic-metabolizing or DNA repair genes) are at a higher risk of morbidity and mortality from chronic diseases. Our findings also suggest that, regarding risk of disease associated with low penetrance polymorphisms, multiple polymorphisms should be taken into account, rather than single ones.

To collect regional information on internal levels of pollutants in humans in Flanders, 1196 mother–child pairs were systematically recruited in 2002–2003 via 25 maternities across Flanders. Cd, Pb, PCB congeners 118, 170, 138, 153 and 180, p,p′-DDE — a key metabolite of DDT- and hexachlorobenzene (HCB) were measured in cord blood or plasma. Cd was detected in 64% of the samples (geometric mean 0.21 µg/L cord blood). p,p′-DDE (110 ng/g plasma lipids) and Pb (14.7 µg/L blood), were measurable in nearly all samples. The individual PCB congeners could be detected in 40 to 81% of the newborns (138 + 153 + 180 = 64.4 ng/g plasma lipids). HCB (18.9 ng/g plasma lipids) and dioxin-like compounds measured by DR-CALUX® (23 pg CALUX-TEQ/g lipids) were above detection limit in more than 75% of the samples. Age and smoking habits of the mothers, did not influence the cord blood Pb and Cd levels. The organochlorines increased 4 to 9% per year of the mother's age (partial R2 = 0.05 to 0.22). Mothers had 2.6% less PCBs in cord blood (partial R2 = 0.02) for each unit increase in pre-pregnancy BMI. Season of delivery, breastfeeding previous children or consumption of local dairy products, were minor determinants. Up to 20% of the variability in organochlorine concentrations was explained by residence area. It was concluded that the place of birth in Flanders is an important determinant of the load of pollutants measured at the start of life. This underlines the validity of human biomonitoring on (relatively) small geographical scale.

ispartof: Neuron vol:13 issue:7 pages:374-379 status: published

Kanker berust in essentie op de accumulatie van mutaties in meerdere (n) genen, en de incidentie ervan stijgt met de nde macht van het mutatietempo. Doorheen levensstijl en leefmilieu zijn we blootgesteld aan lage dosissen van agentia die direct of indirect mutageen zijn. Voor direct werkende mutagenen bestaat geen kritieke drempel waaronder er helemaal geen mutageen effect is. Meestal hebben hoge en lage dosissen dezelfde mutagene activiteit per dosiseenheid; wanneer evenwel de herstelcapaciteit overschreden wordt, zijn hoge dosissen relatief sterker mutageen. Voorafgaande lage dosissen kunnen, middels inductie van herstelmechanismen voor exogene schade aan DNA, het effect van daaropvolgende hogere dosissen afzwakken (adaptatie). Sommigen stellen zelfs dat lage dosissen de gezondheid kunnen beschermen (hormesis). Dat hormesis optreedt bij de inductie van mutaties en kanker is echter onwaarschijnlijk. Daarentegen zijn zeer lage dosissen soms relatief sterker mutageen (“low dose hypersensitivity”), dit ten gevolge van het ontbreken van inductie van herstelmechanismen via het doorgeven van mutagene metabo- lieten doorheen cel-cel “gap junctions” (“bystander effect”) en door de inductie van dosisonafhankelijke genetische instabiliteit. Bij de inductie van kanker is de blootstellingsduur belangrijker dan de dosis, en de blootstelling in utero en op kinderleeftijd weegt zwaarder door. Subpopulaties met een verhoogde gevoeligheid vertonen vooral bij lage dosis een verhoogd kankerrisico. Synergetische effecten zijn belangrijk., Cancer results from the accumulation of mutations in several (n) genes and its incidence increases with the nth power of the mutation rate. Through life style and environment we are exposed to low or very low doses of mutagenic agents, interacting directly with DNA or indirectly with proteins involved in DNA replication or repair. For directly acting agents no threshold level does exist beneath which there is no mutagenic effect. A single alpha particle suffices to induce a mutation with high efficiency. Generally, high and low doses exert the same mutagenic activity per unit dose. Sometimes, when the repair capacity is exceeded, high doses are relatively more potent. Previous low doses can induce repair mechanisms for exogenous DNA damage and mitigate the mutagenic effects of subsequent high doses (adaptation). Some authors even state that exposure to low doses of mutagenic agents can protect against the development of cancer (hormesis). It is however unlikely that hormesis plays a role in induction of mutations and cancer. Sometimes low doses are relatively more mutagenic ("low dose hypersensitivity"). This can happen through lack of induction of DNA repair, by diffusion of mutagenic metabolites through gap junctions (bystander effect) and through induction of dose-independent genetic instability. In the induction of cancer, the duration of exposure is more important than the dose itself; also exposure in utero and during childhood are relatively more threatening. Mainly by exposure to low dose, subpopulations with higher sensitivity show a relative increase in cancer incidence. Synergistic effects are important.