L17 Human biomonitoring and the exposome.pdf

15-6-2021 HUMAN AND ENVIRONMENTAL TOXICOLOGY L17‐HUMAN BIOMONITORING AND THE EXPOSOME MARJA LAMOREE 1 Learning goals In this lecture you will learn about human biomonitoring and the exposome. Af...

15-6-2021 HUMAN AND ENVIRONMENTAL TOXICOLOGY L17‐HUMAN BIOMONITORING AND THE EXPOSOME MARJA LAMOREE 1 Learning goals In this lecture you will learn about human biomonitoring and the exposome. Afterwards you are able to: Describe the concept of human biomonitoring Mention sources of chemicals/contaminants in the home situation Mention typical classes of compounds to which we may be exposed Describe how chemicals may be taken up and undergo biotransformation Give reasons why human biomonitoring should not always focus on parent compounds Indicate the considerations on collection of human samples and name a few different types of sample matrices Explain the analytical aspects related to human biomonitoring Name different human biomonitoring programmes in NL, Europe and worldwide Describe the concept of the exposome and mention the 3 different domains Indicate several important life phases that are of interest to carry out exposome studies ‹#› Het begint met een idee Department Environment & Health 1  15-6-2021 Mrs Wallström was checked for 77 man-made chemicals, which can be found in everyday products such as TV sets, carpets, furniture and food. The 77 chemicals fall into three groups: PBDEs (Poly Brominated Diphenyl Ethers), PCBs (Poly Chlorinated Biphenyls) and OCPs (OrganoChlorine Pesticides). Out of the 77 chemicals analysed, the laboratory in the UK found 28 chemicals in Mrs Wallström’s blood. ‹#› Het begint met een idee Department Environment & Health “On average, the MEPs had 1.7 micrograms/liter of glyphosate in their urine, 17 times higher than the European drinking water norm (0.1 microgram/liter). This means that everyone we tested was way above the limit for residues of pesticides in drinking water.” Newsweek (2016): Glyphosate is the best- selling herbicide of all time, and it's concerning scientists and health experts. Further details: http://www.greens-efa.eu/en/article/we-are-pissed-off/ ‹#› Het begint met een idee Department Environment & Health 2  15-6-2021 http://radar.avrotros.nl/uitzendingen/gemist/ 14-11-2016/hormoonverstorende-stoffen- in-urine-kamerleden/ ‹#› Het begint met een idee Department Environment & Health Human biomonitoring Human Biomonitoring (HBM) involves the analysis of natural and synthetic substances and their metabolites in the human body. Samples used in HBM can include blood, urine, breast milk or other tissues. It is an established method in occupational and environmental exposure assessment. HBM studies on the general population are playing an increasingly important role in the international debate on human health and the environment. ‹#› Het begint met een idee Department Environment & Health 3  15-6-2021 Exposure routes Chemicals enter the body via three major routes:  Ingestion  Dermal absorption  Inhalation Inhalation is the fastest route and dermal (skin) absorption the slowest Age, gender, health status and weight of an individual are also instrumental in determining the effect of a chemical Exposure occurs through: Diet Life style Occupation Environment! ‹#› Het begint met een idee Department Environment & Health Chemicals at home Chemicals Flame retardants Plasticizers Fluorinated compounds Pesticides Fragrances PCBs PAHs Products Electronics Carpets & textiles Indoor Dust Cosmetics Vacuum cleaner Health care products Floor dust Cleaning agents Settled dust Insect repellents Building materials ‹#› Het begint met een idee Department Environment & Health 4  15-6-2021 Drastic change in the use of chemicals since the 1950’s… ‹#› Het begint met een idee Department Environment & Health What happens after intake? See also: L02 on ADME  Absorption  Distribution  Metabolism  Excretion ‹#› Het begint met een idee Department Environment & Health 5  15-6-2021 Mechanisms for minimizing toxic effects Every compound can be poisonous under certain conditions.  Most chemicals have a safe threshold under which their effects are insignificant. Metabolic degradation, biotransformation  In mammals, the liver is the primary site of detoxification of both natural and introduced poisons. > However, sometimes compounds that are harmless can be broken down into products that are harmful. Effects of waste products and environmental toxins reduced by eliminating via excretion: faeces, urine, breath, sweat, respiration Cells, tissues and organs often have mechanisms for damage repair ‹#› Het begint met een idee Department Environment & Health Process of biotransformation Three phases: I Oxidation/reduction to create a “handle” to the compound (-OH), (=O); (-COOH) II Conjugation, by attaching a water-soluble molecule to the handle created in phase I III Elimination/excretion: removal of the conjugated product from the body ‹#› Het begint met een idee Department Environment & Health 6  15-6-2021 Phases in biotransformation XENOBIOTIC Hydrophilic Polar Lipophilic Very lipophilic and persistent SEQUESTRATION storage in fat tissue PHASE I Oxidation, reduction or hydrolysis PHASE II Conjugation to water soluble molecule PHASE III Extracellular mobilization Excretion via bile Renal excretion ‹#› Het begint met een idee Department Environment & Health Which chemicals do we monitor – example of the phthalate DEHP only formed in vivo lipase/esterase in sample From: Calafat and Needham, EHP, 2009 ‹#› Het begint met een idee Department Environment & Health 7  15-6-2021 Hydrolysis of DEHP in breastmilk Hydrolysis of DEHP-d4 in 15 milk samples 80 70 60 50 Response ratio MEHP-d4 40 Humis samples (7) (tx/t0) Michalovce samples (8) 30 20 10 0 0 10 20 30 40 50 incubation time (h) ‹#› Het begint met een idee Department Environment & Health Different steps in chemical analysis e.g. urine, blood, breast milk, hair, saliva, nails, meconium… quantification of the levels of Sampling the analyzed compounds Further statistical evaluation, e.g. epidemiology e.g. removal of particles, centrifugation, sieving Sample pretreatment Data analysis isolation of the compound to be analyzed from the mass sample matrix spectrometry Extraction/cleanup/fractionation Detection Separation e.g. chromatography ‹#› Het begint met een idee Department Environment & Health 8  15-6-2021 Considerations for sampling The properties of the analytes should be taken into account:  Volatility: sampling containers should be airtight  Sensitivity to light: use amber coloured glass ware  Thermal instability: need to cool/freeze the sample rapidly  Biodegradability: e.g. remaining enzymes in the sample  Chemical reactivity: short-lived chemical species will disappear rapidly These properties are important for designing the optimum sampling strategy In general, in HBM studies we deal with: Low concentrations of the compounds that we want to quantify Small sample volumes Background contamination High accuracy High throughput ‹#› Het begint met een idee Department Environment & Health Ethics issues In HBM we are dealing with human materials that need to be sampled safely and adequately, without any harm for the person involved Participants in a HBM study have to give their consent before they can be involved in the study The results of the chemical analyses should be treated with great caution, privacy should be safeguarded Sample as well as data storage are important factors Advice and permission for the HBM study should be sought from a Medical Ethics Committee (we have one in the VUmc). ‹#› Het begint met een idee Department Environment & Health 9  15-6-2021 On-line analytical method Pump 1 Pump 2 Sample Protein/matrix Compound of interest Valve Trapping column Analytical column detector Department Environment & Health Sample loading and washing Pump 1 Pump 2 Sample Valve Trapping column Analytical column detector Department Environment & Health 10  15-6-2021 Transfer from trapping to analytical column Pump 1 Pump 2 Sample Valve Trapping column Analytical column detector Department Environment & Health Setting up a cohort for human biomonitoring HBM data will be used in combination with information from questionnaires and health surveys at defined time points for public health assessment ‹#› Het begint met een idee Department Environment & Health 11  15-6-2021 Setting up a cohort for human biomonitoring ‹#› Het begint met een idee Department Environment & Health The OBELIX project OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life  Hypothesis: perinatal exposure to endocrine disrupting chemicals (EDCs) may play a role in the development of obesity later in life  Objective: assessment of perinatal exposure in humans to major classes of EDCs in food, using mother-child cohorts EDCs? Early exposure Adult phenotype ‹#› Het begint met een idee Department Environment & Health 12  15-6-2021 Perinatal PFOS and PFOA exposure PFOS PFOA LINC Breast milk Cord blood LINC Country Name cohort Recruitment LINC period Belgium FLEHS II 2008-2009 Norway HUMIS 2003-2008 LINC Slovak Republic Michalovce 2003-2005 The Netherlands LINC 2011-2013 ‹#› Het begint met een idee Department Environment & Health Some scientific papers of the OBELIX project ‹#› Het begint met een idee Department Environment & Health 13  15-6-2021 Brief history of human biomonitoring – global perspective In 1999, this survey became a continuous program that has a changing focus on a variety of health and nutrition measurements to meet emerging needs. The survey examines a nationally representative sample of about 5,000 persons each year. The NHANES interview includes demographic, socioeconomic, dietary, and health- related questions. The examination component consists of medical, dental, and physiological measurements, as well as laboratory tests administered by highly trained medical personnel. Data from this survey will be used in epidemiological studies and health sciences research, which help develop sound public health policy, direct and design health programs and services, and expand the health knowledge for the US. Interesting video: www.cdc.gov/nchs/nhanes/nhanes-story.htm ‹#› Het begint met een idee Department Environment & Health NHANES NHANES covers ± 250 compounds Consider this: there are over 120 million unique organic and inorganic compounds currently listed on the Chemical Abstracts Service (CAS) Registry ‹#› Het begint met een idee Department Environment & Health 14  15-6-2021 Germany German Environment Survey (GerES) The first German Environmental Survey took place between 1985 and 1986; each survey addresses ±5000 individuals. www.umweltbundesamt.de/en/topics/health/assessing-environmentally-related-health-risks/german-environmental-survey-geres ‹#› Het begint met een idee Department Environment & Health Canada and Japan Canadian Health Measures Survey The Canadian Health Measures Survey (CHMS), launched in 2007, is collecting key information relevant to the health of Canadians by means of direct physical measurements such as blood pressure, height, weight and physical fitness. In addition, the survey is collecting blood, urine, saliva and hair samples to test for chronic and infectious diseases, nutrition and environment markers and is storing blood, urine and DNA samples at the CHMS biobank for future health research projects. More info: http://www23.statcan.gc.ca/imdb/p2SV.pl?Function=getSurvey&Id=148760 Japan Environment and Children’s Study The Japan Environment and Children's Study (JECS) is a national birth cohort study in Japan. It is commissioned by the Japanese Government. It started in January 2011. It is the largest birth cohort study ever conducted in Japan that investigates the relationship between a wide range of environmental factors and children's health and development. > 100,000 recruits!!! Korea, China and Taiwan have similar programmes More info: https://www.env.go.jp/en/chemi/hs/jecs/ ‹#› Het begint met een idee Department Environment & Health 15  15-6-2021 World Health Organization WHO-Europe: 900 Million people, 53 nations Collaboration with UNEP: United Nations Environment Programme WHO does not collaborate with industry www.euro.who.int/en/data-and-evidence/environment-and-health-information- system-enhis/activities/human-biomonitoring-survey ‹#› Het begint met een idee Department Environment & Health Large Dutch children’s cohorts Generation R: Investigates the growth, development and health of 10,000 children in Rotterdam, born between 2002 and 2006. ABCD study: The ABCD – Amsterdam Born Children and their Development – study started in 2003 and is a long-term, large-scale cohort study, examining the health of children from the very beginning: 8,000 children are followed from the time of their mother’s pregnancy until adulthood. The ABCD study is carried out by the Academic Medical Centre (AMC). ‹#› Het begint met een idee Department Environment & Health 16  15-6-2021 Reporting of ABCD study results in peer-reviewed scientific journals like the European Journal of Endocrinology and in newspapers such as NRC ‹#› Het begint met een idee Department Environment & Health Large Dutch cohorts Lifelines: To move forward to more personalised health care and prevention, we need to understand why some people grow old in good health while others contract diseases. A longitudinal study among a large number of individuals offers the opportunity of collecting data with which the mechanisms of ageing and the development of (chronic) diseases can be studied. The Lifelines study follows over 167,000 participants over a 30-year period. Every five years, participants visit one of the Lifelines sites in the northern parts of the Netherlands for an examination. During this visit, several physical measurements are made and participants are asked to fill in questionnaires. In addition, participants are invited to complete a follow-up questionnaire once every 1.5 years. Lifelines collects data and biomaterials on a large scale, creating a unique biobank and databank. Wherever possible, the collected data and samples are made available for research and policies on healthy ageing. Video: www.youtube.com/watch?v=FQjKKvAhhjM ‹#› Het begint met een idee Department Environment & Health 17  15-6-2021 OBO – Onderzoek Bestrijdingsmiddelen en Omwonenden Public health issue brought to the attention by a documentary in the Zembla series on the Dutch television Advice of the Health Council (‘Gezondheidsraad’) in 2014 to the Ministries of Infrastructure and the Environment (I en M) and Economic Affairs (EZ) to investigate the relationship between the exposure to pesticides and health problems in areas of high pesticide use, such as the production of flower bulbs and fruit Project started in 2015, has just finished www.bestrijdingsmiddelen-omwonenden.nl/ ‹#› Het begint met een idee HBM4EU The European Human Biomonitoring Initiative: Human Biomonitoring for the EU Project started in January 2017, with a duration of 5 years Key objectives include: Harmonizing procedures for human biomonitoring across the 26 participating countries, to provide policy makers with comparable data on human internal exposure to chemicals and mixtures of chemicals at EU level Linking data on internal exposure to chemicals to aggregate external exposure and identifying exposure pathways and upstream sources Generating scientific evidence on the causal links between human exposure to chemicals and health outcomes Adapting chemical risk assessment methodologies to use human biomonitoring data and account for the contribution of multiple external exposure pathways to the total chemical body burden Feeding information on exposure pathways into the design of targeted policy measures to reduce exposure ‹#› Het begint met een idee Department Environment & Health 18  15-6-2021 Exposome The exposome is composed of every exposure to which an individual is subjected from conception to death. Therefore, it requires consideration of both the nature of those exposures and their changes over time. ‹#› Het begint met een idee Department Environment & Health Exposome From: C.P. Wild, International Journal of Epidemiology 2012;41:24–32 ‹#› Het begint met een idee Department Environment & Health 19  15-6-2021 Exposome “Within this continuum, there will be periods of only gradual change in the exposure profile; periods with dramatic changes in specific components, e.g. a change in occupation, or a course of medical treatment; and periods when there is a radical change in global exposure profile in a short period, for example, when one is born or migrates.” ‹#› Het begint met een idee Department Environment & Health How to measure the exposome…? “A ‘one-agent-at-a-time’ approach, using different methods to measure each individual exposure, is clearly unrealistic. A common feature therefore of the approaches to define the exposome is the integration of a wide range of individual exposures in a single measurement… …The assimilation of the known and unknown is a primary goal of the new generation of methods to assess the exposome.” ‹#› Het begint met een idee Department Environment and Health 20  15-6-2021 Omics sciences Latest addition to the omics field: Epigenomics General omics: Genomics Transcriptomics Proteomics Metabolomics Epigenomics From: Wu R et al. J DENT RES 2011;90:561-572 ‹#› Het begint met een idee Department Environment & Health Exposome “The application of general omics technologies to biological samples in epidemiological studies has been described as a ‘top–down’ approach to measuring the exposome… …However, the ‘top-down’ approach lacks a crucial link between exposure to a given agent and the molecular profiles observed. To identify risk factors and implement prevention strategies such a link is a requirement. Therefore, …, the link between a biomarker and an exposure will frequently require two additional steps: chemical or structural identification and establishment of a relationship with an exposure.” Chemical analysis Targeted omics: Adductomics – the simultaneous analysis of a broad range of different chemical DNA and protein adducts Lipidomics – the simultaneous analysis of lipids to study the pathways and networks of cellular lipids in biological systems Immunomics – the study of immune system regulation and response to pathogens ‹#› Het begint met een idee Department Environment & Health 21  15-6-2021 Exposome centers and projects Health and Exposome Research Center: Understanding Lifetime Exposures At Emory University in Atlanta, US, was funded in May, 2013 for $4,500,000 over four years HEALS: Health and Environment-wide Associations based on Large population Surveys HELIX: EXPOsOMICS: The EXPOsOMICS project aims to develop a new approach to assess environmental exposures, primarily focusing on air pollution and water contaminants. Using ‘omic’ techniques the collected exposure data can be linked to biochemical and molecular changes in our body. The results will help to improve our understanding on how these pollutants influence the risk of developing chronic diseases. Video: https://www.youtube.com/watch?v=WpEFk_kgVMs ‹#› Het begint met een idee Department Environment & Health Exposome “The challenge therefore is to recognize, understand and interpret the interplay between the exposure and the biological responses to that exposure. “ Multidisciplinary nature of exposome research: involvement of experts from a wide number of disciplines, including among others molecular techniques, bioinformatics, biostatistics, epidemiology, social sciences and clinical research. “Training researchers to have the linguistic skills to order more than a beer outside their discipline of origin is an important goal.” ‹#› Het begint met een idee Department Environment & Health 22  15-6-2021 Exposure assessment Use of personal monitors that capture a wide range of environmental pollutants Monitors for physical activity or physiological measures such as heart rate and blood pressure Devices that track location through GPS technology Electronic diaries to capture psychosocial stress Tracking of social interaction through new/social media Dietary assessment through apps on portable devices, including biosensors ‹#› Het begint met een idee Department Environment & Health Summary of topics Media attention for human exposure What is human biomonitoring Exposure routes and biotransformation to enhance excretion Chemical analysis Setting up a cohort for HBM Brief history of HBM The Human Biomonitoring for EU project: HBM4EU Exposome Omics sciences Current exposome research Personal exposure assessment ‹#› Het begint met een idee Department Environment & Health 23