L01 Introduction Human & Environmental Toxicology PDF

3-6-2024 HUMAN & ENVIRONMENTAL TOXICOLOGY L01 INTRODUCTION TIMO HAMERS 1 1 GOAL OF THE COURSE To understand the biological effects of che...

3-6-2024 HUMAN & ENVIRONMENTAL TOXICOLOGY L01 INTRODUCTION TIMO HAMERS 1 1 GOAL OF THE COURSE To understand the biological effects of chemicals in the environment on organisms, including humans how to measure the effects (and chemicals) how chemical risk assessment is made 2 Vrije Universiteit Amsterdam 2 1  3-6-2024 TEACHERS OF THE COURSE Dr. Timo Hamers Dr. Samantha Hughes Prof.Dr. Pim Leonards Dr. Maria Margalef Course coordinator Guest lectures by Dr. Eva Sugeng Prof.Dr. Kees van Gestel 3 Vrije Universiteit Amsterdam 3 STUDENTS IN THE COURSE 51 participants Go to menti.com code 7823 4226 4 Vrije Universiteit Amsterdam 4 2  3-6-2024 CONTENT OF THE COURSE Exposure to chemicals Toxicity testing Effects of chemicals Risk assessment of chemicals 5 Vrije Universiteit Amsterdam 5 TEACHING FORMS AND TIME SCHEDULE Week 23 Mon Tue Wed Thu Fri Lectures 03/Jun/24 04/Jun/24 05/Jun/24 06/Jun/24 07/Jun/24 09:00-09:45 10:00-10:45 (L01-L22) 11:00-11:45 L01 Course intro L03 ADME L05 Bioaccumulation L07 Mixture toxicity L09 Ecotox studies Hamers Hamers Leonards Hamers Hamers NU-3B19 HG-06A33 NU-3A57 NU-3B05 NU-3A06 12:00-12:45 L02 Chemical properties and fate L04 Dose-response Leonards NU-3B19 Van Gestel NU-3A57 L06 Adverse Outcome Pathways Bouftas NU-3A57 L08 TEF concept Hamers NU-3B05 L10 in vitro bioassays Hamers NU-3A06 22 hours 13:30-16:30 WG01 Mixture toxicity Hamers 17:00 NU-3A06 Working groups Week 24 09:00-09:45 Mon 10/Jun/24 Tue 11/Jun/24 Wed 12/Jun/24 Thu 13/Jun/24 Fri 14/Jun/24 (WG01-WG03) 10:00-10:45 11:00-11:45 L11 Endocrine disruptors Bouftas L14 Epidemiology Sugeng L15 Carcinogenicity Hamers L17 Human biomonitoring Margalef L19 Alternative animal models: nematodes 10 hours NU-3B19 NU-3A57 NU-3A57 NU-3B05 Hughes NU-3A06 12:00-12:45 L12 Metabolomics L19 Animal models tox L16 Effect-based monitoring L18 Effect Directed Analysis L20: Alternative animal models: Leonards Hughes Hamers Margalef zebrafish, case studies Practicum compulsory! NU-3B19 NU-3A57 NU-3A57 NU-3B05 Baumann NU-3A06 13:30-15:15 WG02 VR-CALUX 15:30-17:15 Hamers NU-3A57 (P01-P02) 18:00 4 hours Week 25 Mon Tue Wed Thu Fri 17/Jun/24 18/Jun/24 19/Jun/24 20/Jun/24 21/Jun/24 09:00-09:45 P01A: Nematodes tox test Hughes WN-C255 P02A: Zebrafish embryo tox test Cenijn WN-C255 Practicum assignment 10:00-10:45 11:00-11:45 P01B: Nematodes tox test L21 Risk assessment Environment P02B: Zebrafish embryo tox test compulsory Hughes Van Gestel Cenijn WN-C255 NU-3A06 WN-C255 12:00-12:45 L22 Risk assessment Human Hamers 13:30 NU-3A06 WG03 Risk assessment Turn in the practicum assignment Quiz 18:00 Hamers NU-3A06 2 hours Week 26 Mon Tue Wed Thu Fri Exam 24/Jun/24 25/Jun/24 26/Jun/24 27/Jun/24 28/Jun/24 09:00-09:45 10:00-10:45 11:00-11:45 12:00-12:45 2:15 hours (+0:30 extra time) 13:30-15:15 QUIZ , Q&A HG-01A33 6 15:30-16:30 EXAM Theater1-NU-00C07 16:30-17:45 Vrije Universiteit Amsterdam 6 3  3-6-2024 EXAMINATION 1. Quiz (0%) Practice with multiple choice Possibility to ask questions 2. Practical (10%) Answers to assignments related to practical questions 3. Written exam (10 open questions) (90%) Test exam will be placed on Canvas Based on prescribed study material (next slide) On paper Closed book exam! 7 Vrije Universiteit Amsterdam 7 EXAM MATERIAL 1. Theory and skills of lectures, working groups, and practical 2. Online Textbook Environmental Toxicology Available through Canvas in e-book format Published in 2019, regularly updated! Covers most parts of the course, some more intensively than others Comments, feedback, and suggestions for improvement are welcome!!! Relevant sections announced on CANVAS 8 Vrije Universiteit Amsterdam 8 4  3-6-2024 Now for some content…. 9 Vrije Universiteit Amsterdam 9 TOXICOLOGY: SCIENCE OF POISONS  = from the bowman toxicum = arrow poison Typical questions that toxicologists try to answer: What compounds are poisonous? How are humans and the environment exposed? What is the mode of action of Chondrodendron tomentosum poisonous compounds? What are the risks? How can we prevent risks? 10 Vrije Universiteit Amsterdam 10 5  3-6-2024 SET UP (Very) short history of toxicology Characteristics of ecotoxicology/environmental toxicology Some generic principles in toxicology 11 11 SHORT HISTORY OF TOXICOLOGY Antiquity Poisonous animals and plants Ebers papyrus (±1500 bC) Hippocrates (± 400 bC) E.g. poisoned chalice of Socrates Hemlock Coniine 12 12 6  3-6-2024 SHORT HISTORY OF TOXICOLOGY Renaissance Paracelsus (1493-1541) Philippus Aureolus Theophrastus Bombastus von Hohenheim Alchemist and physician in Salzburg “Luther of medicine” Starting point is the compound (toxicon) and not the mixture 13 13 PARACELSUS (1493-1541) Starting points  Experiments are essential  Distinguish poisonous from therapeutic properties  These cannot always be distinguished  Compounds may have very specific effects Paradigm: Everything is poisonous and nothing is without poison; only the dose makes that something is not a poison. 14 14 7  3-6-2024 SHORT HISTORY OF TOXICOLOGY Industrial revolution Occupational toxicology  10000 newly synthetisized organic compounds in 1880 Environmental pollution 2015 2005 1975 1990 15 15 2023: >204 000 000 15 SHORT HISTORY OF TOXICOLOGY 20th century More environmental pollution Traffic Pesticides Plastics with additives “Chemical age” Chemical warfare Chemical weapons (mustard gas, sarin) Holocaust 16 16 8  3-6-2024 SHORT HISTORY OF TOXICOLOGY 20th century (continued) Scandals and disasters DDT (Rachel Carson) Thalidomide (softenon) Methylmercury (Minamata) Dioxin (Agent Orange; Seveso) Pesticides (River Rhine/Bhopal) Radioactivity (Tsjernobyl/Fukujima) Regulation Risk assessment of chemicals Criteria for food and environment 17 17 RACHEL CARSON (1962): SILENT SPRING There was a strange stillness. The birds, for example – where had they gone? Many people spoke of them, puzzled and disturbed. The feeding stations in the backyards were deserted. The few birds seen anywhere were moribund; they trembled violently and could not fly. It was a spring without voices. On the mornings that had once throbbed with the dawn chorus of robins, “a work that is credited as catbirds, doves, jays, marking the beginning of wrens, and scores of the environmentalist other bird voices there was now no sound; only movement” silence lay over the fields and woods and marsh. 18 18 9  3-6-2024 SILENT SPRING ON DDT Persistent and bioaccumulating Responsible for decrease in bird populations Eggshell thinning (mechanism only recently dissolved) Carcinogenic (still controversial) Resistance in malaria mosquitos Cl Cl Cl Cl Cl 19 Vrije Universiteit Amsterdam 19 DDT dichloro-diphenyl-trichloroethane Cl Cl 1,1'-(2,2,2-trichloroethane-1,1-diyl)bis(4-chlorobenzene) Cl Insecticide action discovered in 1939 Paul Hermann Müller: Nobel price 1948 Cl Cl In WW-II: lice control (typhus) After WW-II: Malaria control Agriculture 20 Vrije Universiteit Amsterdam 20 10  3-6-2024 21 21 22 22 11  3-6-2024 REDUCTION IN EGGSHELL THICKNESS www.falcoperegrinus.org 1947 23 23 EGGSHELL THICKNESS VS DDE LEVELS 24 Moriarty, 1988 24 12  3-6-2024 FROM HUMAN TO ENVIRONMENTAL TOXICOLOGY René Truhaut (1977): founder of ecotoxicology Ecotoxicology: the branch of toxicology concerned with the study of toxic effects, caused by natural or synthetic pollutants, to the constituents of ecosystems, animal (including human), vegetable and microbial, in an integral context Extension of human toxicology using organisms from the environment (fish, daphnids, birds, etc.) instead of rat and mice (surrogate for man) “Anthropocentric view” (Vasseur et al. 2021) 25 Vrije Universiteit Amsterdam 25 FROM HUMAN TO ENVIRONMENTAL TOXICOLOGY Frank Moriarty (1983): put “eco” (back) in Ecotoxicology Essential to Ecotoxicology is indirect relationship between effects on individual organisms and effects on populations in the natural environment Actually, already proposed in 1971 by Jean-Michel Jouany, who studied “how the constant changes in the relationships between individuals and their environment were decisive in the evolution, the species stability and the unsustainable equilibrium which 26 resulted.”” Vasseur et al. 2021 Vrije Universiteit Amsterdam 26 13  3-6-2024 FROM HUMAN TO ENVIRONMENTAL TOXICOLOGY Theo Colborn (1996) Our Stolen Future Are We Threatening Our Fertility, Intelligence, and Survival? A Scientific Detective Story Popular press publication With a foreword from vice-president Al Gore Development of the “endocrine disruption” hypothesis 27 Vrije Universiteit Amsterdam 27 ONE HEALTH APPROACH A collaborative, multisectoral, and transdisciplinary approach - working at the local, regional, national, and global levels - with the goal of achieving optimal health outcomes recognizing the interconnection between people, animals, plants, and their shared environment. An approach that recognizes that the health of people is closely connected to the health of animals and our shared environment. Understanding the interdependence of human and natural systems and promoting interdisciplinary collaboration. environmental contamination habitat use conflicts biodiversity loss emerging infectious diseases antimicrobial resistance ecosystem function degradation https://www.onehealthcommission.org/en/why_one_health/what_is_one_health/ Thddbfk Vrije CC Amsterdam Universiteit BY-SA 4.0 28 14  3-6-2024 ECOTOXICOLOGY AT DIFFERENT LEVELS OF BIOLOGICAL ORGANIZATION generic endpoints community population individual organ tissue cellular specific molecular endpoints mechanistic ecological understanding relevance 29 Vrije Universiteit Amsterdam 29 ECOTOXICOLOGY VS ENVIRONMENTAL TOXICOLOGY Environmental Exposure Emission distribution Environmental chemistry Uptake + direct interactions Indirect effects on effects on organisms organisms Environmental toxicology Effects on structure and functioning of ecosystem Ecology 30 Ecotoxicology Vrije Universiteit Amsterdam 30 15  3-6-2024 ECOTOXICOLOGY IS AN INTEGRATED SCIENCE Jan Koeman (1989) Ecotoxicology: 31 Vrije Universiteit Amsterdam 31 ENVIRONMENTAL CHEMISTRY Occurrence of chemicals in the environment Pathways of chemicals in the environment Effects of physico-chemical properties on environmental fate of chemicals Deposition and degradation processes Distribution in environmental compartments Intake in organisms Exposure Bioavailability Internal concentration in organisms 32 Vrije Universiteit Amsterdam 32 16  3-6-2024 ENVIRONMENTAL TOXICOLOGY Biotransformation Distribution of chemicals over organs/tissues → “target” Toxicokinetics & Toxicodynamics Mode of action Mechanisms of detoxification Mixture toxicity Effects at the individual level How does an organism cope with a chemical? What are the effects of a chemical, and by what mode of action? Dose-response relationships 33 Vrije Universiteit Amsterdam 33 ECOLOGY = The study of interactions between organisms and their environment (Haeckel, 1869) = The study of interactions determining the distribution and occurrence of organisms (Krebs, 1972) Factors regulating populations Genetic variability of populations Life cycles of organisms Interactions between species Role of organisms in ecological processes Etc. Effects on populations, communities and ecosystems 34 Vrije Universiteit Amsterdam 34 17  3-6-2024 SOME GENERIC PRINCIPLES IN TOXICOLOGY Routes of exposure Phases in toxic response Classification in toxic response Dose-response relationship 35 35 ROUTES OF EXPOSURE Oral exposure Absorption through gastrointestinal tract Dermal exposure Absorption through skin, cuticle, exoskeleton Respiratory exposure Absorption through lungs, gills Special routes Direct penetration of epithelial layer through injection, infusion, etc. 36 Vrije Universiteit Amsterdam 36 18  3-6-2024 PHASES IN TOXIC RESPONSE L02 Chemical properties and fate Exposure: L05 Bioaccumulation how does an organism get into contact with compound? Routes of exposure (previous slide) to what extend does an organism get into contact with compound? External (concentration in air, (drinking) water, soil, food) Dose (intake; quantity per bodyweight per day) Internal (concentration in body or body compartment) Toxicokinetics: what does the body do to the compound? Absorption, Distribution, Metabolism, Excretion L03: ADME Qualitatively and quantitatively Toxicodynamics: what does the compound do to the body? Hazard! Qualitatively: what type of effect? Endocrine disruptors, carcinogens,… 37 Quantitatively: dose-response relationship L04: dose-response Vrije Universiteit Amsterdam 37 CLASSIFICATION IN TOXIC RESPONSE Possibility for repair Reversible Irreversible Rate Acute toxicity occurs short after a single exposure to a compound Chronic toxicity occurs after prolonged and repeated exposure to a compound Site of action Local (at the site of exposure) Systemic (after systemic distribution of the compound) 38 Vrije Universiteit Amsterdam 38 19  3-6-2024 EXAMPLE OF SYSTEMIC TOXICITY Developmental toxicity Softenon-baby (late 1950s, early 1960s) Very serious structural birth defects related to use of thalidomide drug (sleep aid and amelioration of pregnancy nausea) during pregnancy Thalidomide is teratogenic causing Amelia: absence of limbs Phocomelia: reduction of long bones of limbs 39 DOSE-RESPONSE RELATIONSHIP Paracelsus paradigm: Everything is poisonous and nothing is without poison; only the dose makes that something is not a poison. See L06: Dose-response 40 40 20  3-6-2024 RISK ASSESSMENT OF COMPOUNDS Exposure assessment Effect assessment Compound Integration into a risk assessment Exposure Effect/Hazard Risk quotient 41 LEARNING OBJECTIVES After this lecture L01, you can Recall Paracelsus’ paradigm Paraphrase the story of DDT Explain the terms environmental toxicology and ecotoxicology Describe in your own words Main routes of exposure Phases in toxic response Classifications in toxic response 42 42 21