Nutritional Toxicology NFS488H1 - Week 2025 PDF

Nutritional Toxicology NFS488H1–W2025 DrDrJoan Joan Jory JoryRDRD PhDPhD (Dr J.) 1 1  Course Communications Announcements are posted on the Quercus course site. The Announcemen...

Nutritional Toxicology NFS488H1–W2025 DrDrJoan Joan Jory JoryRDRD PhDPhD (Dr J.) 1 1  Course Communications Announcements are posted on the Quercus course site. The Announcements contain important updates, clarifications and reminders important to student success in the course. It is critical, and each student’s responsibility, to check for new Announcements daily, and ensure Announcements notifications are turned on. Online Discussion Boards have been created for student questions about Course Content, Lecture Material, Tests and Assignments – Please post ALL questions about the course in the Discussion Boards (accessed via the Discussions tab in Quercus) Course Materials are organized in weekly Modules (Modules tab). Lecture slides, required readings, and other content will be posted there each week through the term. Assignments: Assignment and test information will be posted under the Assignment tab in Quercus. This will include descriptions, deadlines, instructions, and rubrics, where appropriate. Personal matters: questions about personal matters should be emailed to the Dr J. NFS488-2025-Week1 2 2 What do we study in NFS488 course? Applications of toxicology in the context of food science and nutrition Food and nutrient safety & regulation Fundamentals of toxicogenomics Fundamental and applied research Food industry Emerging topics: Application of the omics in toxicology Mercury and toxins in First Nations Food Artificial Sweeteners and Toxicity NFS488-2025-Week1 3 3 3  What do we study in NFS488 course? Gene-food toxicant Basics Concepts 1 5 interactions Applied Toxicology: Toxins and Toxicants 2 6 Mercury, POPs and First Nations peoples Toxicology tests 3 7 Toxicomicrobiomics Nutrient DRIs/ Regulation Drug-nutrient interactions Artificial Sweeteners/Toxicity 4 8 and genetic susceptibility NFS488-2025-Week1 4 4 4  Course Assessment Assessment Weight Date Research question 2% January 29 Term Test 1: (Open Book) 26% February 5 Group Project Outline 3% February 12 Group Research Paper 20% March 12 Term Test 2: (Open Book) 26% March 19 Group Oral Presentation 15% 5 March 26 + April 2 Participation 6% March 26 + April 2 Course engagement 2% January 8 - April 2 Total 100% *No Final Exam NFS488-2025-Week1 5 5  Term Tests 1.5 hours, open book In-person NO make-up tests (see Course Syllabus for course policies) NFS488-2025-Week1 6 6  Group Assignment Group Project Written Report Comparison of Studies and Scientific Evaluation Proposal Critical evaluation of a toxic substance in the food/beverage supply Developing writing skills Oral Presentation 12-minute Group Presentation (12 minutes oral presentation + 3-5 minute question period) Developing effective oral presentation skills NFS488-2025-Week1 7 7  Group Assignment Topics Topics Choose ONE topic related to a food or beverage toxic substance, either natural or synthetic, and how it relates to a health outcome Tutorial: TA Sabrina will present a Tutorial on how to be successful with the Group Assignment Written Report and Oral Presentation When: Wednesday, January 15 at 3 pm Groups: Groups will be made up of 2-4 students Make your group on Quercus NFS488-2025-Week1 8 8 8  Syllabus Reconnaissance Take 5 minutes to identify your items Individually Identify TWO important details in the syllabus Identify ONE item you are excited about! Identify ONE question that remains/ concern With your group, discuss your findings: What important details did you identify in the syllabus? What items are you excited about? What questions remain? NFS488-2025-Week1 9 9 9  Introduction to Nutritional Toxicology Lecture 1 January 8 2025 Objectives: 10 Understand the basic principles of toxicology Identify toxicology phases Understand the dose-response curves 10 NFS488-2025-Week1 10  Definitions Toxicology: The study of the adverse effects of chemicals or physical agents on living organisms….. Study of poisons, toxicants or toxins: Xenobiotics Food toxicology: emphasizes toxins or toxicants present in foods that might be harmful to those who consume sufficient quantities of the food containing such substances Nutritional toxicology: the study of the nutritional aspects of toxicology The inter-relationships between toxins/toxicants and nutrients in the diet, which affect nutritional status. Encompasses food safety – toxicity issues related to our food supply NFS488-2025-Week1 11 11 11  History of Toxicology Paracelsus (1493--1541) "Father of Toxicology” “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” i.e.: “The dose makes the poison.” With increasing dose, there is increasing frequency and/or severity of adverse effects. Orfila (1787–1853) Established relationship between chemical properties and toxic effects ANYTHING has the potential to be a poison… NFS488-2025-Week1 12 12 12  Dose-Response It is the amount of exposure that determines toxicity! The relationship between the exposure dose of a substance and the response of the organism after ingesting the substance Determined by experiments, mainly conducted in animals. Groups of animals are dosed with the substance over a range of concentrations, and the animals are observed for symptoms of an endpoint (this must be measurable and quantifiable). Categories Adapted from Omaye (2004) Food and Nutritional Toxicology of Toxicity 13 NFS488-2025-Week1 13 13  Classification of Toxins/Toxicants Physical state - Gas, liquid, solid Toxicity - Extremely, slightly Chemical composition - Heavy metal, organophosphate Mechanism of action - Anticholinergic* - Enzyme inhibitor - Hepatotoxin - Carcinogen *Anticholinergic : A substance that blocks the neurotransmitter Acetylcholine in the brain NFS488-2025-Week1 14 14 14  Toxic Responses 1. Immediate vs. delayed a) Immediate: minutes to hours after a single exposure b) Delayed: days to years after exposure 2. Duration a) Acute: single exposure, short-term ( ½ life expectancy 3. Reversible vs. Irreversible a) Reversible: generally in rapidly regenerating tissue (eg. liver, intestinal mucosa, blood cells) b) Irreversible: CNS damage, carcinogenesis, teratogenesis CNS: central nervous system NFS488-2025-Week1 15 15  Local vs. Systemic Local – Site of first contact is the target tissues (e.g., inhalation of irritants affects the respiratory system) – Gastrointestinal irritant Systemic – Requires absorption and distribution to a distant site – Most toxicants are systemic – Some agents may act both locally and systemically NFS488-2025-Week1 16 16 16  MECHANISM SITES OF ACTION EXPOSURE NERVOUS SYSTEM DISTRIBUTION METABOLISM HEART EXCRETION 17 SKIN LIVER 17 NFS488-2025-Week1 17  Phases of Toxicological Effects TOXIC SUBSTANCE/ DOSE 1. Exposure phase Dissipation of toxicant or formation of active toxic substance Toxicant available for absorption Absorption, Distribution, 2. Toxicokinetic phase Biotransformation, Excretion Toxicant available for action Toxicant-receptor interaction in 3. Toxicodynamic phase target tissue Toxicant reaches sites EFFECT NFS488-2025-Week1 18 18 18  A toxic substance must be present in a molecular form that can be EXPOSURE dispensed and be relatively lipophilic to penetrate biological PHASE membranes Bioavailability and absorption of a 19 toxic substance depends on D° of ionization of the substance and the pH at the site of absorption MUST BE AVAILABLE 19 NFS488-2025-Week1 19 DURATION OF YOUR EXPOSURE ⚬ Acute (1 day) ⚬ Sub-acute (10 days) ⚬ Sub-chronic (2 weeks to 7 years) ⚬ Chronic (7 years to lifetime) ROUTE OF EXPOSURE Chemicals insoluble in the fluids of the GI tract (stomach, small, and 20 large intestines) are generally excreted. Chemicals that are soluble are absorbed through the lining of the GI tract and are transported by the blood to internal organs where they can cause damage. 20 NFS488-2025-Week1 20  The quantitation of the time course of toxic substances in the body during the processes of Absorption, Distribution, Metabolism (biotransformation), and TOXICOKINETICS Excretion or clearance of substances (ADME) PHASE Process Description Absorption Entrance into body 21 Distribution Movement to other parts of body Metabolism/ Chemical reactions that may change Biotransformation the substance Excretion Removal from body MUST BE ABSORBED INTO SYSTEM 21 NFS488-2025-Week1 21  Absorption of Substances Depends on: Dosage, form and dissolution of particles, Chemical and physical properties of the substance Stability of chemicals in gastric and intestinal juices and enzymes Toxicokinetic Phase Facilitated Simple Diffusion Diffusion Active Transport Endocytose ATP ABSORPTION NFS488-2025-Week1 22  Extent of Absorption = Bioavailability Destroyed Not Destroyed Destroyed in gut absorbed by gut wall by liver DOSE 23 Toxicokinetic Phase Absorption 23 NFS488-2025-Week1 23  Via the blood and lymphatic systems May attach to red blood cells or proteins in blood plasma and be distributed around the body and may target specific organs Depends on MW, solubility, Toxicokinetic polarity Phase Lipid-soluble, 24 small molecules cross cell membranes and enter body tissues (simple diffusion) Water-soluble chemicals either remain in solution in the plasma or are bound to other molecules for travel Highly fat-soluble substances will deposit and tend to Distribution remain in the body’s fat stores 24 NFS488-2025-Week1 24  DISTRIBUTION Excreted/ Stored/ Metabolised OR Once in the Metabolites may be excreted or stored bloodstream OR Metabolites 25 may interact or bind with cellular components. Toxicokinetic Phase The magnitude of a chemical’s distribution is given by the apparent volume of distribution (Vd) Distribution 25 NFS488-2025-Week1 25  Volume of Distribution (Vd) ⚬ The distribution of a xenobiotic, between plasma and the rest of the body, after dosing ⚬ ↑Vd: more diluted compound in plasma + more distribution in tissue. Administered dose (mg) Vd (l) = 26 Plasma concentration (mg/l) Compounds with high lipid solubility (non-polar), low rates of ionization or low plasma binding capabilities → ↑ Vd NFS488-2025-Week1 26  Take home test What would have higher VD? Compound with low lipid solubility vs. high lipid solubility High rate of ionization vs. low rate Low plasma protein binding vs. high plasma binding capabilities 27 NFS488-2025-Week1 27 27  Distribution: Plasma Protein Binding Some xenobiotics may bind to plasma proteins (especially albumin)→ Bound xenobiotic unable to leave the blood & enter tissues. Binding “removes" the toxicant from potential cell interaction → Because it remains in the blood Only free substances are able to pass through blood vessel membranes or interact with a target Albumin: binds many xenobiotics (especially drugs) Toxicokinetic Globulin: binds many endogenous substances Phase (vitamins, steroids, metal ions) 28 DISTRIBUTION NFS488-2025-Week1 28  Metabolism: Biotransformation vs Detoxification Process whereby a substance is changed (transformed) from one chemical to another by a chemical reaction, within the body. Phase I & Phase II Reactions Toxicokinetic Phase Result: - Detoxification - Bioactivation - No change METABOLISM 29 NFS488-2025-Week1 29  Biotransformation Sites Kidney & Lungs Toxicokinetic Liver -10-30% liver’s capacity Phase -High concentration of bio-transforming enzymes -First pass: blood leaves GI to liver through portal vein, before entering general circulatory system Skin, intestines & placenta - low capacity METABOLISM 30 NFS488-2025-Week1 30  Biotransformation Phases Phase I: production of more water-soluble and more reactive products Oxidation, Reduction, Hydrolysis → Cytochrome P450 enzymes Toxicokinetic Mixed Function Oxidase (MFO) system Phase Predominant biotransformation enzymes CYP450s: in Phase I Microsomal enzymes >50 enzymes -> most polymorphic METABOLISM 31 NFS488-2025-Week1 31  Biotransformation Phases Phase II: making the phase I product highly water-soluble Conjugation with another substance - Glucuronidation - Sulfation Toxicokinetic - Acetylation Phase - Amino acid conjugation - Glutathione conjugation Microsomal, lysosomal, mitochondrial or cytoplasmic enzymes -> Transferases (require co-factors) - Foods that induce enzymes: cruciferous vegetables, onions, garlic (phytochemical content) Larger molecules & ↑ polarity METABOLISM 32 NFS488-2025-Week1 32  Biotransformation Phase I Phase II Conjugated Metabolite metabolite Oxidation Toxic Conjugation Reduction substance Hydrolysis Toxicokinetic Phase METABOLISM 33 NFS488-2025-Week1 33 Biotransformation of Benzene 34 Benzene has Carcinogenic properties!!! → Metabolite more toxic 34 NFS488-2025-Week1 34 Biotransformation of Aspirin 35 It is Excreted in Urine. 35 NFS488-2025-Week1 35  Excretion The elimination of the xenobiotic and/or its metabolites by specific excretory organs Urine -Kidney route -Only free toxicant (unbound) Toxicokinetic Phase Feces (https://www.toxmsdt.com/133-fecal-excretion.html) -Biliary route -Large molecular weight (>300 MW) & plasma protein-bound, water- soluble 36 -Direct excretion into the lumen of the gastrointestinal tract -Lipophilic substances if high lipid content in GIT Breast milk, sweat, saliva EXCRETION 36 NFS488-2025-Week1 36  Rate of EXCRETION can be described in terms of its half-life. Half-life: Time taken for the concentration of a chemical in the body (usually measured in blood) to fall by half Majority of excretion (~97%) completed within 5 half-lives. Longer in the body → greater potential for adverse effects 37 Toxicokinetic Phase Cadmium: 10-20 years Carbon monoxide: few hours EXCRETION 37 NFS488-2025-Week1 37  The interaction of toxic substances with a biological target (at specific sites of action) → A toxic effect/response Must reach target receptor/enzyme active site TOXICO-DYNAMIC Toxicant Interaction Cellular Organ Organism Response Response Response PHASE with Target Molecular Targets → Dose-Response Concept Concept 38 Toxic substance Mechanisms and mode of action Target molecule DNA—Aflatoxin 38 NFS488-2025-Week1 38 Mechanisms of Action of Toxic Substances Specific Non-specific Receptor-mediated events Necrosis of epithelial cells Action of receptors Most important for neurotoxins Interference with body metabolism or synthesis Enzyme-mediated events Interact directly with specific Carcinogenesis enzymes which catalyze specific 39 physiologic processes HCN in almonds↔ Cytochromes HCN: hydrogen cyanide 39 NFS488-2025-Week1 39  Factors that Modify Toxicity Dose/Concentration Age Gender Genetics Diet Health status Frequency/Duration of Exposure 40 Route of Administration (e.g. ingestion, inhalation, skin absorption) Synergists or Antagonists Form of Toxicant (e.g. gas, liquid, solid) Metabolism/Biotransformation 40 NFS488-2025-Week1 40 Nutritional Toxicology & Risk Assessment 41 41  WHAT IS RISK? Probability or likelihood that Hazard an adverse effect will occur Probability 42 Frequency Adverse effect Human health or the environment 42 NFS488-2025-Week1 42  WHAT IS HAZARD? An event, or attribute associated with an activity, product, process or site with the potential to cause harm or adverse impacts to environment and human health. Biological Chemical 43 Physical Natural Lifestyle choices 43 NFS488-2025-Week1 43  Actual or potential threat of adverse effects on living organisms and the environment by exposure to effluents, emissions, wastes, resource depletion, ENVIRONMENTAL etc., arising out of an organization’s RISK activities RISK = HAZARD X EXPOSURE 44 NFS488-2025-Week1 44 Process of Risk Assessment 45 NFS488-2025-Week1 45 HAZARD IDENTIFICATION & ANALYSIS What can go wrong? Possible sources of harm Identification of routes through which hazardous event can occur Estimating the probability or chance of occurrence Collection and analysis of data 46 NFS488-2025-Week1 46  Comparative Methods: Audits, inspections (what happened in past & what can happen in future?) Fundamental Methods: Methods Task analysis, Hazards and Operability studies (HACCP), Accident/incident and near miss reviews 47 etc. Failure Logic: Event Tree Analysis, Fault Tree Analysis 47 NFS488-2025-Week1 47  DOSE- RESPONSE ASSESSMENT Obtains relevant toxicity data Explores the relationship between dose of an agent and the incidence of adverse health effect in quantitative manner (dose–response relationship) All contaminants are not equal in their toxicity or capacity to cause harm; hence dose-response assessment is necessary Dose response assessment answers the question, “what are the health problems at different doses?” 48 NFS488-2025-Week1 48  Dose is a measured amount of an agent (mg) administered per unit body weight (kg) of the individual over a period of one day. (Units: mg/kg/day) There is distinction between Exposure and Dose: Exposure is “outside” the body Dose is “inside” the body Response is a change in structure or function of organism, onset morbidity, or mortality LD50 (lethal dose 50%) is the basic measure of hazard Lethal dose in test animals (half of49 the test animals die) KNOWLEDGE Test: Which is more toxic? LD50 = 0.1 mg/kg LD50 = 5 mg/kg 49 NFS488-2025-Week1 49  DOSE-RESPONSE CURVES Dose-response curves are made from the results of dose-response assessment based on which threshold limits are established (cancerous substances=threshold is zero, dose-response plot’s origin is zero) Thresholds are represented by the Reference Dose (RfD), which is the intake or dose of the substance per unit body weight per day (mg/kg/day ) that is likely to pose no appreciable risk to human populations, including such sensitive groups as children. 50 NFS488-2025-Week1 50  Dose-Response: U-Shaped Curve (Also referred to as J-shaped curve or Bi-phasic curve) Hormesis: A biphasic dose-response to a xenobiotic, characterized by a low-dose stimulation or beneficial effect + a high-dose inhibitory or toxic effect” U-shaped Inverted U-shaped Hormetic region Hormetic region NFS488-2025-Week1 51 Example of end-point: Example of end-point: Longevity or growth Tumor incidence Modified from Edward et al. 2001. Trends in Pharmacological Sciences 51 NFS488-2025-Week1 51 Dose-Response: U-Shaped Curve The Lancet Public Health 2018 3e419-e428DOI: (10.1016/S2468-2667(18)30135-X) Atherosclerosis Risk in Communities (ARIC) U-shaped association between % of energy from carbohydrate and all- cause mortality. 52 Increased risk with carb 65% kcal/d Why? 52 NFS488-2025-Week1 52  Dose-Response: J-Shaped Curve The lowest risk of mortality is in the middle range of vitamin D (70 nmol/L or 28 ng/ml) with an increased risk at low levels (12.5 nmol/L or 5 ng/ml) and a slight increased risk at high levels (125 nmol/L or 50 ng/ml) 53 NFS488-2025-Week1 53  Dose-Response: S-Shaped Curve Expressed in relation to body weight (mg/kg/day) For most effects, small doses are not toxic. Threshold dose Threshold Dose: point at which toxicity first appears the point at which the reserve detoxification mechanisms are exceeded 54 NFS488-2025-Week1 54  Lethal Dose = LD50 Calculated in order to determine how toxic a substance is Lethal dose 50% (mg/kg) The dose causing death in 50% of test animals. LD50 tests not very useful for assessing low-dose long-term exposures. Measures acute toxicity NFS488-2025-Week1 55 55  No Observable Adverse Effect Level (NOAEL) Highest dose at which there is NO observed toxic or adverse effect. Determined by measuring a non- Adverse effect/health damage lethal end point (e.g. liver function enzymes) NOAEL Indicates lower systemic toxicity or lower chronic toxicity. Helps in estimating the Tolerable UPPER intake level (UL) DOSE The amount of exposure to chemicals 56 NFS488-2025-Week1 56 Lowest Observable Adverse Effect Level (LOAEL) Lowest dose at which there IS an observed toxic or adverse effect. Adverse effect/health damage LOAEL 57 DOSE The amount of exposure to chemicals 57 NFS488-2025-Week1 57  Dose-Response NFS488-2025-Week1 58 58 NFS488-2025-Week1 58  Acceptable Daily Intake = ADI Amount of a specific substance in food or beverage that can be ingested (eg: additive) on a daily basis over a lifetime without an appreciable health risk NOAEL (mg/kg/day) usually carried out in animals (rats/mice) Significant debate about extrapolating results to humans ADI calculated for chemicals in food based on NOAEL, following long-term dosing studies ADI = NOAEL SF *SF= Safety Factor (usually 1,000) = Uncertainty Factors (100) x Modifying Factor (usually 10) 59 NFS488-2025-Week1 59  Acceptable Daily Intake (ADI) Adverse effect/health damage ADI NOAEL 60 NFS488-2025-Week1 60  Tolerable Daily Intake (TDI) Tolerable Weekly Intake (TWI) Amount of substance in food that is consumed every day (TDI) or every week (TWI) for an entire lifetime that would not be expected to cause harm Used for chemical food contaminants that are not incurred as a normal part of food production, processing or preserving (e.g. heavy metals) 61 Calculated the same way as ADIs, from toxicity data with applied safety factors 61 NFS488-2025-Week1 61 Adverse effect/health damage Acceptable Daily Intake (ADI) TDI NOAEL NFS488-2025-Week1 62 62 NFS488-2025-Week1 62  Maximum Residue Level (MRL) Maximum Limit (ML) MRL: maximum residue of a chemical that will occur in a crop following the use of an agrochemical (eg: pesticide) ML: relates to an environmental chemical contaminant (eg: lead) rather than intentional use MRLs and MLs set by Codex Alimentarius (FAO & WHO) 63 NFS488-2025-Week1 63  Take home test Assume the response is death, and that the dose is in mg for all 3. What do the intersection points (broken lines) represent? What can be said about substances A, B and C? Which is the most potent? Which have similar modes of action? What if the dose was not mg for all 3? 64 NFS488-2025-Week1 64  EXPOSURE ASSESSMENT It is an estimation of the extent to which environmental compartments are or may be exposed to a hazard If exposure is zero, then there will be no risk Very toxic substance -> zero exposure ->no risk Moderately toxic -> high exposure -> high risk 65 Exposure assessment involves: The assessment of potential consequences associated with exposure to hazardous event 65 NFS488-2025-Week1 65  Magnitude, frequency and duration of exposure to a hazardous agent over time Source: Nature and behavior of hazard (air dispersion, water dispersion) Receptor: Characteristics of exposed population (body weight, chemical absorption capacity, level of immunity etc.) Pathways: How a population will come in contact with hazard/hazardous agent Identification of Biological endpoints: A symptom of disease progression or death, an ultimate health effect that results from exposure to chemical. 66 NFS488-2025-Week1 66  RISK CHARACTERIZATION Risk characterization involves risk estimation and risk evaluation and can be defined as: “The estimation of the incidence and severity of the adverse effects likely to occur in a human population or environmental compartment due to actual or predicted exposure to a substance and includes the quantification of that likelihood.” Results of dose response relations and exposure assessment are combined in risk characterization 67 NFS488-2025-Week1 67  RISK ESTIMATION Risk estimation includes the estimation of the magnitude of risk spatial scale, duration and intensity of adverse consequences a description of the cause-effect links. Simplest form of risk estimation involves creating a risk matrix that can either be simple or complex, qualitative, semi- quantitative, or quantitative. 68 NFS488-2025-Week1 68  RISK EVALUATION Judgment is made about the significance and acceptability of risk consequences. Evaluation techniques compare risks against one another, and against benefits, as well as determining the social acceptability of risks. Social acceptability combines both political and managerial decisions -> involves a calculation of who is likely to benefit 69 and who will suffer, and what compensation, if any, should be paid. Risk characterization facilitates the judgment about risk acceptability 69 NFS488-2025-Week1 69  RISK MANAGEMENT Makes use of results of risk assessment to mitigate or eliminate unacceptable risks Decision making at program or agency level to decide about hazard, exposed population or adverse effects. Once the source and effects of potential failure have been identified, it is possible to determine where improvements can be made Risk management measures SHOULD NOT lead to secondary outcomes 70 NFS488-2025-Week1 70  The management decides what (and if any) corrective actions are needed to manage the risk as acceptable and as low as reasonably acceptable level (ALARP). Commonly taken steps are as follows: Prevention of hazards from occurring (elimination) to reduce the likelihood. Mitigation of consequences of such hazards which are inherent with some activity and cannot be prevented altogether 71 (reducing the effect). Recovery from the consequences of the incidents, and measures for all such foreseeable emergencies must be developed to prevent their escalation 71 Questions? 72 72