Risk Assessment Lesson Notes PDF

RISK ASSESSMET Prof. Valentina Galbiati TAKE HOME MESSAGES – LESSON 1 HAZARD RISK DEFINITION DEFINITION Intrinsic property of an agent or The probability of an adverse effect in situation having the poten...

RISK ASSESSMET Prof. Valentina Galbiati TAKE HOME MESSAGES – LESSON 1 HAZARD RISK DEFINITION DEFINITION Intrinsic property of an agent or The probability of an adverse effect in situation having the potential to an organism, system or cause adverse effects when an (sub)population caused under organism, system or specified circumstances by exposure (sub)population is exposed to that to an agent. agent. TAKE HOME MESSAGES – LESSON 1 HAZARD vs RISK TAKE HOME MESSAGES – LESSON 1 RISK ASSESSMENT The process whereby hazard, exposure and risk are determined. RISK = HAZARD x EXPOSURE The likelihood of the occurrence of adverse effects on humans, animals, or the environment is primarily dependent on the extent of exposure to the given substance. Obviously, when there is NO EXPOSURE, there is NO RISK for harmful effects.  TAKE HOME MESSAGES – LESSON 1 Risk assessment requires 4 steps: HAZARD IDENTIFICATION – evaluation of the toxic effects of the chemical I DOSE-RESPONSE information – evaluation of relationship between the exposure II to the hazard and the adverse effect EXPOSURE ASSESSMENT – determination of the level, frequency and duration III of exposure of humans to the hazard RISK CHARACTERIZATION – estimation of the incidence of adverse effects IV under human conditions exposure TAKE HOME MESSAGES – LESSON 1 Hazard identification is the first stage in hazard assessment and the first of four steps in risk assessment. I HAZARD IDENTIFICATION – evaluation of the toxic effects of the chemical DEFINITION Is the identification of the type and nature of adverse effects that an agent has an intrinsic capacity to cause in an organism, system, or (sub)population. TAKE HOME MESSAGES – LESSON 1 RESEARCH RISK ASSESSMENT Laboratory and field HAZARD IDENTIFICATION observation of Does the agent cause adverse effects adverse effects? from particular agents Structure activity analysis Animal Bioassays In vitro tests New mechanistic understanding of toxicity Field measurements of exposures, exposed populations TAKE HOME MESSAGES – LESSON 1 DOSE-RESPONSE information – evaluation of relationship between the exposure II to the hazard and the adverse effect Toxicologic Pathology. 45. 10.1177/0192623316677068. RISK ASSESSMENT – quantification of adverse health effects RISK ASSESSMENT DOSE-RESPONSE HUMAN HUMAN ASSESSMENT variability population ANIMALS What is the relationship between dose and response? Susceptibility RESPONSE INTRASPECIES INTERSPECIES 10 10 1.85 18.5 185 DOSE (mg/kg body weight) RISK ASSESSMENT – quantification of adverse health effects RISK ASSESSMENT DOSE-RESPONSE HUMAN HUMAN ASSESSMENT variability population ANIMALS What is the relationship between dose and response? Susceptibility RESPONSE INTRASPECIES INTERSPECIES 10 10 NOAEL 1.85 18.5 185 DOSE (mg/kg body weight) RISK ASSESSMENT – quantification of adverse health effects NOAEL – NO ADVERSE OBSERVED EFFECT LEVEL DOSE-RESPONSE ASSESSMENT What is the relationship between dose and response? DEFINITION Susceptibility The no observed adverse effect level (NOAEL) is the greatest concentration or amount of a substance at which no detectable adverse effects occur in an exposed population RISK ASSESSMENT – quantification of adverse health effects RISK ASSESSMENT DOSE-RESPONSE HUMAN HUMAN ASSESSMENT variability population ANIMALS What is the relationship between dose and response? Susceptibility RESPONSE INTRASPECIES INTERSPECIES 10 10 ADI/TDI 1.85 18.5 185 DOSE (mg/kg body weight) RISK ASSESSMENT – quantification of adverse health effects ADI – ADMISSIBLE DAILY INTAKE DOSE-RESPONSE ASSESSMENT What is the relationship between dose and response? DEFINITION Susceptibility represents the amount of a food additive, a pesticide or a veterinary drug residue, expressed on a body weight basis, that can be ingested daily over whole lifetime without appreciable health risk. RISK ASSESSMENT – quantification of adverse health effects TDI – TOLERABLE DAILY INTAKE DOSE-RESPONSE ASSESSMENT What is the relationship between dose and response? DEFINITION Susceptibility represents the amount of a contaminant or other foreign chemicals, expressed on a body weight basis, that can be ingested daily over whole lifetime without appreciable health risk. RISK ASSESSMENT – quantification of adverse health effects ADI and TDI ADI TDI DEFINITION DEFINITION represents the amount of a FOOD represents the amount of a ADDITIVE, A PESTICIDE OR A CONTAMINANT OR OTHER VETERINARY DRUG RESIDUE, FOREIGN CHEMICALS, expressed expressed on a body weight basis, that on a body weight basis, that can be can be ingested daily over whole ingested daily over whole lifetime lifetime without appreciable health risk. without appreciable health risk. RISK ASSESSMENT – quantification of adverse health effects ADI/TDI NOAEL ADI/TDI = SF ADI/TDI = Admissible (Tolerable) Daily Intake mg/kg b.w. NOAEL = No Observed Adverse Effect Level (mg/kg b.w.) SF = Safety Factor (10, 100, n) RISK ASSESSMENT – quantification of adverse health effects SF – SAFETY FACTOR NOAEL ADI/TDI = SF Interspecies differences 10 Inter individual differences 10 RISK ASSESSMENT – quantification of adverse health effects RISK ASSESSMENT DOSE-RESPONSE HUMAN HUMAN ASSESSMENT variability population ANIMALS What is the relationship between dose and response? Susceptibility RESPONSE INTRASPECIES INTERSPECIES 10 10 NOAEL ADI/TDI = ADI/TDI SF 1.85 18.5 185 DOSE (mg/kg body weight) RISK ASSESSMENT – quantification of adverse health effects RISK ASSESSMENT DOSE-RESPONSE HUMAN HUMAN ASSESSMENT variability population ANIMALS What is the relationship between dose and response? Susceptibility RESPONSE INTRASPECIES INTERSPECIES 10 10 NOAEL ADI/TDI = NOAEL SF 1.85 18.5 185 DOSE (mg/kg body weight) RISK ASSESSMENT – quantification of adverse health effects SF – SAFETY FACTOR DOSE-RESPONSE HUMAN HUMAN ASSESSMENT variability population ANIMALS What is the relationship between dose and response? Susceptibility RESPONSE INTRASPECIES INTERSPECIES 10 10 NOAEL ADI/TDI = SF 1.85 18.5 185 DOSE (mg/kg body weight) TAKE HOME MESSAGES – LESSON 2 EXPOSURE ASSESSMENT – determination of the level, frequency and duration III of exposure of humans to the hazard Exposure assessment is one of the four major steps in risk assessment. Others include hazard identification, dose-response assessment, and risk characterization. RISK ASSESSMENT EXPOSURE ASSESSMENT EXPOSURE ASSESSMENT MEDIA Exposure may be estimated for any of the various exposure media: AIR FOOD AQUATIC SOIL AND DUST BIOTA CONSUMER WATER AND PRODUCTS SEDIMENTS RISK ASSESSMENT EXPOSURE ASSESSMENT - MEDIA CONSUMER Examples of consumer products include: PRODUCTS - cosmetics and other personal care products, - cleaning and home maintenance items, - furniture, - building materials, - pesticides, … and a variety of other items. RISK ASSESSMENT EXPOSURE ASSESSMENT - MEDIA CONSUMER Individuals who manufacture or use these products can be PRODUCTS exposed via ingestion, inhalation, and dermal contact. à Human exposure can occur through intentional direct contact such as applying cosmetics or other personal care products to the skin. ! Unintentional direct contact can also occur. For example, contact with laundry detergent or surface cleaner while in use, or contact with pesticides from products used for gardening. à Indirect contact (e.g., off-gassing from furniture or other materials; cleaning product residue on surfaces, clothing) can also occur. RISK ASSESSMENT EXPOSURE ASSESSMENT - MEDIA CONSUMER PRODUCTS CHILDREN Nonusers, including children, can also be passively exposed to chemicals in these products. Children are particularly susceptible via this indirect pathway. à This is because certain behaviors (e.g. tendency to mouth objects or hands*) and activities (e.g., crawling or playing on the floor indoors) may increase their contact with contaminant-laden surfaces or dust * Frequency of hand to mouth per hours: 9.5 events/h (EPA2001 RISK ASSESSMENT EXPOSURE ASSESSMENT - MEDIA CONSUMER EXPOSURE CHARACTERIZATION PRODUCTS For any of these scenarios, concentrations of the contaminants from consumer products are needed to estimate the exposure dose. Contact with consumer products may be infrequent, intermittent, or short term (e.g., use of household repair product) or continuous and long term (e.g., use of solid air freshener). After characterizing the exposed population and identifying exposure concentrations, it is important to define all appropriate exposure factor inputs to estimate potential exposures and risks.  RISK ASSESSMENT EXPOSURE ASSESSMENT - MEDIA CONSUMER PRODUCTS Examples of Exposure Scenarios Involving Consumer Products and Related Exposure Factors Handbook: 2011 Edition Tables RISK ASSESSMENT EXPOSURE ASSESSMENT - MEDIA CONSUMER EXPOSURE CHARACTERIZATION PRODUCTS To estimate human exposure to chemicals in consumer products, exposure factor information is needed. Exposure factors are human behaviors and characteristics that help determine an individual's exposure to an agent. RISK ASSESSMENT EXPOSURE ASSESSMENT - MEDIA CONSUMER EXPOSURE CHARACTERIZATION PRODUCTS Potential routes of exposure to chemicals released from consumer products include inhalation of particulates, vapors, or aerosols; dermal contact from direct application to the skin or contact with residues on surfaces; and incidental ingestion via hand-to- mouth or object-to-mouth contact. Depending on the scenario(s) being evaluated, inhalation rates, ingestion rates, dermal exposure factors such as body surface area, and/or activity-specific factors might be needed. RISK ASSESSMENT RESEARCH RISK ASSESSMENT Laboratory and field HAZARD IDENTIFICATION observation of Does the agent cause ROUTES adverse effects adverse effects? from particular agents Structure activity analysis An exposure route is the way that a In vitro tests Animal Bioassays contaminant enters an individual or Epidemiology population after contact (IPCS, 2004). New mechanistic DOSE-RESPONSE understanding of ASSESSMENT toxicity What is the relationship Typically exposure occurs by one of the between dose and response? three exposure routes: Susceptibility § INHALATION Field measurements EXPOSURE ASSESSMENT § INGESTION What types, levels and of exposures, exposed duration of exposures are § DERMAL experienced or populations anticipated? RISK ASSESSMENT EXPOSURE ASSESSMENT - ROUTES INHALATION Inhalation exposure can result from breathing air that is contaminated with particulate matter (e.g., dust), vapors (e.g., volatile or semivolatile contaminants), or aerosols. Individuals can be exposed via the inhalation route during a variety of activities outdoors and indoors. INGESTION Ingestion exposure can occur via consumption of contaminated food, water and other liquids. Food can contain chemical residues as a result of intentional application (e.g., pesticide use), deposition of particulate matter onto edible produce (e.g., from atmospheric pollutants), and/or biotic uptake and accumulation from contaminated soil or water (e.g., irrigation water, uptake of contaminants by fish or livestock). DERMAL Dermal exposure can result from skin contact with contaminated environmental media, including: water (e.g., during bathing, washing, swimming); sediment (e.g., while wading, fishing);outdoor soil or dust (e.g., during recreational, gardening, or construction-related activities); and indoor dust that has settled on carpets, floors, clothing, counter tops, or other surfaces. RISK ASSESSMENT EXPOSURE ASSESSMENT - APPROACH 3. Exposure reconstruction (biomonitoring) Exposure reconstruction uses internal body measurements rather than external measurements to estimate dose using biomarker data (U.S. EPA, 2012). evaluation of overall risk from a single chemical evaluation of overall risk from multiple chemicals considering all the possibile routes of exposure that have similar mechanism of action The primary benefit of reconstructing exposure using biomonitoring data is that both aggregate and cumulative exposure can be quantified. However, it may not be possible to identify specific sources or routes of exposure (e.g., inhalation, ingestion, or dermal). In contrast, scenario evaluation and direct measurement use information collected prior to exposure and "upstream" of the point of exposure. RISK ASSESSMENT EXPOSURE ASSESSMENT 3. Exposure reconstruction (biomonitoring) Biomonitoring data are necessary for exposure reconstruction: ! involves analyzing human samples, such as tissues and body fluids, to determine contaminant or biomarker concentrations Successfully performing exposure reconstruction requires modeling tools such as pharmacokinetic (PK) models. Biomonitoring data can be combined with PK models to reconstruct or estimate the amount of chemical a person was exposed to (i.e., the exposure dose). PK models simulate the distribution and movement of chemicals within a living system. RISK ASSESSMENT EXPOSURE ASSESSMENT 3. Exposure reconstruction (biomonitoring) PK models combine data about physiological and metabolic processes with biomarker concentrations or other biomonitoring data to mathematically estimate exposure or dose. Reconstruction can happen only after exposure has taken place. PK models vary in complexity: § The simplest PK model is a one-compartment, first order model à This assumes immediate distribution of a chemical within a single “compartment” such as blood or body lipids or even the whole body of the organism. § In comparison to these simple models, a physiologically based PK (PBPK) model is a complex, multi-compartment model à It accounts for an organism’s physiology and the chemical properties of the contaminant. RISK ASSESSMENT EXPOSURE ASSESSMENT - one-compartment (first-order PK model) 3. Exposure reconstruction (biomonitoring) A simple one-compartment, first-order PK model estimates the change in concentration (C) in one compartment over time given a specified exposure or intake. It takes what comes in (Dose); subtracts what goes out via an elimination rate constant (k); and calculates the change in concentration of a chemical (the body burden) over time (t). Simple models have minimal overall data requirements, but do not model the fate of the chemical in the body. A one-compartment PK model is most often applied for contaminants that bioaccumulate in body tissues (e.g., lead, dioxin, DDT). RISK ASSESSMENT EXPOSURE ASSESSMENT 3. Exposure reconstruction (biomonitoring) Actual exposures and human body physiology are more complicated than what is captured in a one- compartment, first-order model. More complex PK models account for an organism’s physiology in their equations and are called physiologically based pharmacokinetic (PBPK) models. à simulate the movement and fate of chemicals within the body, considering transfers between tissues and organs, metabolism, and storage. RISK ASSESSMENT EXPOSURE ASSESSMENT 3. Exposure reconstruction (biomonitoring) Multiple-compartment models are more complex and typically include the organs and tissues relevant for the specific chemical distribution, metabolism, or toxicity. These models might specify venous movement of blood (away from organs and back to the heart and lungs) and arterial movement of blood (away from the heart and lungs to the rest of the body). More complex models can also describe the formation and transport of metabolites. Creating these mathematical models requires specific physiological data. For many chemicals, such data are often unavailable to build these more complex models. TAKE HOME MESSAGES – LESSON 2 RISK CHARACTERIZATION – estimation of the incidence of adverse effects IV under human conditions exposure DEFINITION is the qualitative and, wherever possible, quantitative determination, including attendant uncertainties, of the probability of occurrence of known and potential adverse effects of an agent in a given organism, system, or (sub)population, under defined exposure conditions. RISK ASSESSMENT RISK MANAGEMENT Risk management is a process that evaluates options for protecting PUBLIC HEALTH and the ENVIRONMENT. Examples of risk management actions - deciding how much of a substance a company may discharge into a river; - deciding which substances may be stored at a hazardous waste disposal facility; - deciding to what extent a hazardous waste site must be cleaned up; - setting permit levels for waste discharge, storage, or transport; - establishing national ambient air quality standards; - determining allowable levels of contamination in drinking water - …. Appropriate risk management actions for sectors of industry or for local communities can be spelled out in risk management plans for day-to-day activities and for actions to be taken under emergency situations. RISK ASSESSMENT RISK COMMUNICATION AND PERCEPTION RISK COMMUNICATION is the interactive exchange of information and opinions throughout the risk analysis process concerning risk, risk-related factors and risk perceptions, among risk assessors, risk managers, consumers, industry, the academic community and other interested parties, including the explanation of risk assessment findings and the basis of risk management decisions. RISK PERCEPTION it is based on knowledge of the individual and on moral and political judgments; should be considered as an integral part of the risk assessment RISK ASSESSMENT RISK PERCEPTION TAKE HOME MESSAGES – LESSON 4 DEFINITION excessive humoral or cellular immune response to an antigen which can lead to tissue damage. Hypersensitivity reactions are the result of normally beneficial immune responses acting inappropriately. ALLERGIC CONTACT DERMATITIS § Allergic contact dermatitis (ACD) is a cell-mediated immune response to small molecular weight chemicals that contact and penetrate the skin. § There are a variety of characteristics that determine whether a chemical can function as a contact sensitizer (or allergen): § ability to penetrate into the skin § reactivity with protein § epidermal and dermal inflammation § dendritic cell activation, migration to lymph nodes and recognition as antigenic by T cells.  SKIN SENSITIZATION QUANTITATIVE RISK ASSESSMENT Contact allergy to fragrance materials is a topic of considerable interest for consumers, clinicians, industry and regulatory authorities. Mixtures of fragrance materials are used in a wide variety of consumer products at varying levels, leading to a wide range of exposures. Some of these fragrance materials have been identified as contact allergens and they express varying degrees of sensitizing potency. These potency differences, the demonstration of induction dose responses and the determination of induction thresholds have been explored in a number of publications.  SKIN SENSITIZATION QUANTITATIVE RISK ASSESSMENT The aim of the QRA process, as with risk assessments for other toxicological endpoints, is to take data on the sensitisation potency of a chemical in an experimental situation and extrapolate this to consumer exposure in an in- use situation and thereby define a safe exposure level. The QRA is founded on the principle that induction of skin sensitization is threshold based (Kimber et al., 1999, 2008; Boukhman and Maibach, 2001; Basketter et al., 2002). That is, there is a level of dermal exposure to a skin sensitizer at, or below which, sensitization induction will not occur in an individual. This is consistent with the principles used for assessing many other non- genotoxic endpoints.  QRA IS BASED ON 1. Hazard identification: Determination of the No Expected Induction Sensitization Level (NESIL) 2. Application of Sensitization Assessment Factors (SAF 10-1000) 3. Determination of the Acceptable Exposure Level (AEL): AEL = NESIL/SAF 4. Determination of Consumer Exposure Level (CEL) 5. Acceptable Risk: AEL>CEL or AEL/CEL ratio > 1 6. Risk management (e.g. allergy warning labels) i.e. hair dye (PPD and resorcinol can induce skin sensitization and allergy à warning on the product) PARALLELS WITH ‘CLASSICAL’ CHEMICAL RISK ASSESSMENT No No Observed Expected Adverse Effect Induction Sensitization Level Level NOAEL NESIL ADI/TDI = AEL = Admissible SF Acceptable SAF Daily Safety Exposure Sensitization Intake Factor Level Assessment Factor  CONSIDERATIONS A reduction of ACD can be achieved by: Correct identification of skin sensitizers; Characterization of potency; Understanding of human skin exposure; Application of adequate risk assessment and management strategies. Only improved quantitive risk assessment, better education of risk assessors, better education of consumers on the proper use of cosmetic products (following instructions), better marketing surveillance by authorities to control proper cosmetic product safety evaluation, could help to 'make contact allergy history’. Other sources: food, flowers – can contain the same sensitizers contains in cosmetics (different exposure).  TAKE HOME MESSAGES – LESSON 7 FRAGRANCES & ALLERGY Allergic contact dermatitis to fragrance ingredients is most often caused by exposure to cosmetics and predominantly involves the: Face Hands Armpits https://andymillward-facialist.co.uk/how-to-treat-an-allergic- https://foradermatology.com/hand-rash https://www.sciencedirect.com/science/article/pii/ reaction-to-skin-care-products/ S1578219014002455  HEALTH AND CONSUMERS – NANOMATERIALS NANOMATERIALS IN COSMETIC PRODUCTS Cosmetics placed on the EU market are regulated by the Regulation on cosmetic products. It provides a safety framework and established a central notification system for cosmetic products placed on the EU market. Colourants, preservatives and UV filters must be authorised by the European Commission prior to their use in cosmetics. Before authorisation, the Scientific Committee on Consumer Safety (SCCS) reviews the toxicological data related to the substance for which the authorisation is sought. You can find out if the cosmetic product you are using contains nanomaterials by looking at the list of ingredients on the package of the product. Nanomaterials in a cosmetic product must be labelled with the word ‘nano’ in brackets after the name of the ingredient.  HEALTH AND CONSUMERS – NANOMATERIALS NANOMATERIALS IN COSMETIC PRODUCTS COLORANTS UV FILTERS OTHER FUNCTIONS Carbon black Titanium dioxide Alumina Titanium dioxide Zinc oxide Copper Zinc oxide Gold Silver Platinum Fullerene Silica  HEALTH AND CONSUMERS – NANOMATERIALS NANOMATERIAL IN COSMETIC PRODUCTS COLORANTS – CARBON BLACK Carbon Black, CI 77266, is a known cosmetic ingredient that is often used as a colorant for eye decorative cosmetic products, skin products, and mascaras. Nail polish Eyeliner Mascara Lipstick Foundation Eye shadow Blush Face mask  HEALTH AND CONSUMERS – NANOMATERIALS NANOMATERIAL IN COSMETIC PRODUCTS UV FILTER – ZINC OXIDE How have ZnO nanoparticles been tested for safety? There are now results from a wide range of standardised toxicological assessments of zinc oxide nanoparticles. They include tests for skin irritation, and other tests explored a range routes for internal exposure, including swallowing, breathing, or direct injection. Are sunscreens using zinc oxide nanoparticles safe? This report concludes that products containing up to 25 per cent nanoparticles are as safe for use on the skin as those containing micro-preparations of zinc oxide. It is probably a bad idea to swallow sun lotion, but this is not likely to pose a major hazard. There remain some doubts about possible effects of breathing in zinc oxide nanoparticles. At the moment, however, there should be no sprayable sunscreens using nano-zinc oxide on sale in Europe.  HEALTH AND CONSUMERS – NANOMATERIALS TOXICOLOGY EVALUATION – TITANIUM DIOXIDE The SCCS opinion was adopted in 2023 In light of the EFSA Opinion on genotoxicity concerns for E171, does the SCCS consider Titanium dioxide safe in oral cosmetic products? Having considered all the information (including that evaluated by EFSA, 2021), the SCCS considers that the available evidence is not sufficient to exclude the genotoxicity potential of almost all of the types of TiO2 grades used in oral cosmetic products. […] More information is, however, needed on the potential uptake and cellular effects of the nano grades in the oral mucosa to consider them safe for use in oral-care products. It is worth highlighting that the SCCS approach to risk assessment of TiO2 ingredients in orally-used cosmetic products is slightly different from that of EFSA. This is because cosmetic products are not meant to be ingested orally, and any ingestion via the oral route can only be unintended and incidental. Keeping this in mind, the amounts of orally-ingested cosmetic ingredients can only be expected to be far lower than the amounts ingested when a TiO2 material is used as a food additive, which is consumed via intake of the food products. For the SCCS, the potential absorption/retention, translocation and adverse effects of nanoparticles in the buccal mucosa are therefore important considerations for safety evaluation.  HEALTH AND CONSUMERS – NANOMATERIALS TOXICOLOGY EVALUATION – TITANIUM DIOXIDE The SCCS opinion was adopted in 2023 SCCS Conclusions Studies have indicated that oral mucosal cells are prone to the uptake of nanoparticles (including TiO2 nanoparticles), as they may penetrate the mucous layer and may be internalised by the epithelial cells. Considering that some oral products containing TiO2 nanoparticles, such as toothpastes and mouthwashes, will be used every day and potentially more than once a day, further investigations are needed to exclude the risk to the consumer from long-term repeated exposures of the oral mucosa to TiO2 nanoparticles. On the basis of the available evidence, the SCCS has concluded that the use of TiO2 nanomaterials at a concentration up to 25% as a UV-filter in sunscreens, can be considered to not pose any risk of adverse effects in humans after application on healthy, intact or sunburnt skin. This, however, does not apply to applications that might lead to inhalation exposure to TiO2 nanoparticles (such as powders or sprayable products).