RIASSUNTO RISK.pdf

RISK ASSESSMENT = systema'c scien'ﬁc characteriza'on of poten2al health eﬀects resul2ng from human exposure to hazardous agents or situa2ons. It’s composed by compulsory steps: toxicologic research=> tests=> interpreta'on of data. i. RESEARCH: diﬀerent types of approach: a. Laboratory and ﬁeld observa'on of adverse eﬀects from par2cular agents b. New mechanis2c understanding of toxicity through lab experiments c. Field measurements of exposures, exposed popula2ons o HAZARD: intrinsic property of an agent or situa2on having the poten'al to cause adverse eﬀects when an organism, system or subpopula2on is exposed to that agent o RISK: the probability of an adverse eﬀect in an organism, system or subpopula2on caused under speciﬁed circumstances by exposure to an agent Shark is considered dangerous, a hazard and a risk to the human health. But if the human is outside the ocean there is a hazard but not risk. Hazard something that is poten2ally a risk, it becomes a risk in a speciﬁc circumstance (be in the water). In fact, the risk is given by the hazard x the exposure: RISK= HAZARD X ESPOSURE The risk depends on the extent of the exposure when there is no exposure, there is no risk. RISK ASSESSMENT REQUIRES 4 STEPS: 1. HAZARD IDENTIFICATION – evaluation of the toxic effects of the chemical 2. DOSE-RESPONSE information (=HAZARD CHARACTERIZATION) – evaluation of relationship between the exposure to the hazard and the adverse effect 3. EXPOSURE ASSESSMENT – determination of the level, frequency and duration of exposure of humans to the hazard 4. RISK CHARACTERIZATION – estimation of the incidence of adverse effects under human conditions exposure A. HAZARD IDENTIFICATION = 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. Approaches for HAZARD HARACTERIZATION: o SARs (structural activity analysis of a molecule): structure, solubility, stability, pH sensitivity, electrophilicity, volatility, chemical reactivity. find RELATIONSHIPS between CHEMICAL STRUCTURE and BIOLOGICAL ACTIVITY of studied compounds, including toxicity. The activity of molecules is reflected in their structure. Qualitative SARs and quantitative SARs, collectively are referred to as (Q)SARs. o Animal bioassays: o In vitro tests: mechanistic evaluation (=signal transduction). Validation of in vitro assays requires determination of their sensitivity, specificity and predictive value for the toxic endpoint under evaluation. o Epidemology: a positive association between exposure and disease has been observed o Cross-sectional tests: identification of risk factors and disease. Not for cause/effect o Cohort studies: you analyze the exposure agent and monitor the development of a disease o Case-control studies: retrospective studies based on the disease status B. HAZARD CHARACTERIZATION: DOSE/RESPONSE CURVE: evaluation of relationship between the exposure to the hazard and the adverse effect The curve illustrates the rela2onship between We can have different curves (linear, log, sigmoid..) the dose of a drug or chemical and the magnitude of the eﬀect it produces. Increasing the dose, you increase the eﬀect un2l you reach a threshold that gives a toxic eﬀect. Dose: The amount of a substance (e.g., drug, chemical) administered Eﬀect: The biological or physiological response elicited by the dose of the substance. ANALGESIC AND DEPRESSANT EFFECT OF MORFIN The dose makes the poison!!! According to the dose we can have diﬀerent eﬀects delimited by the margin of safety. The ﬁnal aim of RISK ASSESSMENT is to set up condi2ons to avoid risk. We experiment on animals and then we move to human (interspecies movement), we have to consider the safety factors that create human variability (sex, age) we have in this case an intraspecies movement. What is the rela6onship between dose and response? Suscep6bility. QUANTIFICATION OF ADVERSE HEALTH EFFECTS NOAEL= There are 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. It’s determined by using animal models. ADI= Admissible daily intake TDI= tolerable daily intake represents the amount of a FOOD ADDITIVE, a pesticide represents the amount of a CONTAMINANT or other or a veterinary drug residue, expressed on a body foreign chemicals, expressed on a body weight basis, weight basis, that can be ingested daily over whole that can be ingested daily over whole lifetime without lifetime without appreciable health risk. appreciable health risk. NOAEL 𝑵𝑶𝑨𝑬𝑳 )*+ ADI or TDI= = = 1,85 𝑺𝑭 ),, ADI/TDI = Admissible (Tolerable) Daily Intake mg/kg b.w. NOAEL = No Observed Adverse Effect Level (mg/kg b.w.) Theorically, it’s 10 or 100 because you multiply 10 X SF = Safety Factor (10, 100, n) 10 (Interspecies differences Inter X individual o Interspecies differences 10 differences) o Inter individual difference 10 How we assess the safety factor? (How I can say it’s 10, 100 etc). It depends on diﬀerent factors? Human data availability Quality of data for NOAEL setting Overall quality of toxicity data set (database) Type and characteristic of toxic response (e.g. reversibility/severity) Dose-response curve (stipness, pendenza=> variability) Comparative information on metabolism and Mode of Action (toxicokinetic and -dynamic between animals and humans) (There are cases in which I can add extra safety factors for extra toxicity reasons) C. EXPOSURE ASSESSMENT = determination of the level, frequency and duration of exposure of humans to the hazard. The primary objec2ves of exposure assessment are to determine SOURCE, TYPE, MAGNITUDE, DURATION of contact with the agent of interest. MEDIA: Exposure may be es2mated for any of the various exposure media: - Air: direct (inhala2on) or indirect (through other media: water, food, soil in contact with air). Indoor air and outdoor air (sta2onary ex. factories and mobile sources ex. cars). - Aqua2c biota: ﬁsh and shell ﬁsh that come in contact with contaminated water and then we eat them. - Consumer products: Individuals who manufacture or use these products can be exposed via inges2on, inhala2on, and dermal contact. The routes of exposure can be: o Inten'onal direct contact: such as applying cosme2cs or other personal care products to the skin. o Uninten'onal direct contact: contact with laundry detergent or surface cleaner while in use or contact with pes2cides from products used for gardening. o Indirect contact (e.g., oﬀ-gassing from furniture or other materials; cleaning product residue on surfaces, clothing …) o For children=> hand and mouth exposure For any scenarios we have to determine the dura2on and frequency of the contact with the item or contaminant-> can be 1 hour or 1 week. Aner that, we have to determine speciﬁc popula2on and to es2mate the poten2al exposure and risks. In the US they iden2ﬁed for every product type the kind of popula2on exposed, they highlighted the amount per day and how it is applied, to iden2fy the route of exposure and the period of exposure. To es2mate human exposure to chemicals in consumer product, EXPOSURE FACTOR is needed (= human behavior and characteris'cs that help determine individual’s exposure to an agent). - Food: from soil, water, air, pes2cized. Human milk from mothers exposed to contaminants. To dilute percentage of contaminated food, a variety of diﬀerent food must be consumed. - Soil and dust: direct exposure (inten2onal inges2on (geophagy), incidental inges2on, or via dermal contact); indirect exposure (transfer and subquent contact eith other media (food)). Children play with it. - Water and sediments: inges2on, dermal absorp2on, inhala2on, ﬁshing. ROOTS OF EXPOSURE: An exposure route is the way that a contaminant enters an individual or popula2on aner contact. Three main roots: o 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. Breath is the first way to be exposed. o 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). o 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 Exposure may be estimated using one of three approaches: 1. Direct measurement 2. Indirect estimation 3. Exposure reconstruction (biomonitoring): uses internal body measurements rather than external to estimate dose using biomarker data. In the first two we analyzed what could happen, now what happened to our body. 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)=> we use modeling tools such as pharmacokinetic (PK) models=> Biomonitoring data can be combined with PK models (math 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. 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: a. The simplest PK model is a one-compartment, first order model => 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. Actual exposures and human body physiology are more complicated than what is captured in a one- compartment, first-order model. b. In comparison to these simple models, a physiologically based PK (PBPK) model is a complex, multi- compartment model => It accounts for an organism’s physiology and the chemical properties of the contaminant. They simulate the movement and fate of chemicals within the body, considering transfers between tissues and organs, metabolism, and storage. Useful to decide the intake limits for human health. We can add a lot of info: speciﬁc 6ssue, speciﬁc organs, in order to understand the speciﬁc behavior of a contaminant in a speciﬁc organ. We have the instrument to elaborate but s6ll not the “fuel” -> we don’t have enough data, not enough literature, so we need to go on using both side: collec6ng data and working in silico. D. RISK CHARACTERIZATION: estimation of the incidence of adverse effects under human conditions exposure = 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. Final step of risk assessment: can be quan2ta2ve and qualita2ve. The ﬁnal aim is to have protec2ve assump2on for preven2on of human health. Not only for human but also for the environment. Risk Management is a distinctly different process from risk assessment. It’s the collateral step of risk characterization. =>RISK ASSESSMENT establishes whether a risk is present and, if so, the range or magnitude of that risk. =>In RISK MANAGEMENT process, the results of the risk assessment are integrated with other considerations, such as economic or legal concerns, to reach decisions regarding the need for and practicability of implementing various risk reduction activities. “Risk managers” decide how to protect humans and the environment from contaminants or other stressors and can be: o federal or state officials whose job it is to protect the environment (istituto della sanità) o business leaders who work at companies that can impact the environment, o private citizens who are making decisions regarding risk. Risk management is a process that evaluates options for protecting PUBLIC HEALTH and the ENVIRONMENT. 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. Sometimes fail for many reasons: too complex data to be communicated inadequate language different point of views and perception selective info from media lack of trust mental noise (from worry and upset) RISK PERCEPTION it is based on knowledge of the individual and on moral and political judgments; it should be considered as an integral part of the risk assessment. Risk percep2on: in some cases, is linked to the fear connected to the risk and is not objec2ve or is due to the fact that individuals beqer accept something under their control than under other control (level of knowledge or familiriaty with risk). In a lot of cases, the natural risk is more accepted than ar2ﬁcial. Voluntary risk is more easily accepted, number of people exposed can increase risk percep2on etc.. CAR > PLANE FALL FROM ATREE > A HIT FROM A THUNDER PAINKILLER OVERDOSE> ELECTROCUTION Genotoxic carcinogens: induction of cancer through interaction with DNA; every dose is potentially genotoxic, no threesold, no NOAEL. Non-genotoxic carcinogens: The genotoxic activity is not the primary biological activity of these compounds. These agents may yield to genotoxic evens as a secondary results. Non-genotoxic mechanisms of the compounds justify identification of NOAEL a present a threshold of genotoxicity. The assessment of genotoxicity is always required. According to European legislation no intentional exposure to mutagens is allowed, at any dose level. Pragmatic thresholds (e.g., TTC) only apply to unavoidable contaminants (UV and new substances). Once classified as genotoxic compounds, they cannot allow a threshold value. The registration of a new substance therefore requires a complete evaluation of its genotoxic potential. Mutagenic and/or genotoxic compounds CAN NOT be used in cosmetics, foods (if added), pesticides and biocides. Genotoxicity tests are not designed to derive point of departures (NOAEL, BMDL) for risk assessment. The assessment of human health risks from exposure to mutagenic substances is considered to cover the carcinogenic risk of these agents. There is considerable evidence of a positive correlation between the mutagenicity of substances in vivo and their carcinogenicity in long-term studies with animals. MUTAGENESIS STUDIES Objectives: o Identification of the substances able to induce genetic damage in progeny following interaction with the genetic material (hazard identification). Genotoxicity tests is just for this purpose. o Quantitative estimation of transmissible genetic damage (hazard characterization) o Prediction of the carcinogenic activity following interaction with the genetic material in somatic cells. o Evaluation of the mechanism of action of carcinogens. For a complete evaluation of the genotoxic potential, it is not sufficient to use a single test, but several tests are needed to identify the possible mechanism of action and the possible induction of the different types of mutations. Usually 2/3 tests are used (in vitro) and an in vivo test is conducted only in cases of uncertainty (for example when the substance is genotoxic if metabolically activated only in vivo). SHORT TERM TESTS FOR MUTAGENICITY In vitro Ames test=> on bacteria (mutated salmonella doesn’t grow in histidine), if the substance can revert the mutation we will have an high number of colonies on an absent histidine substrate=> substance is mutagenic. If there is not growth, not mutagenic substance. Sometimes is not the substance that is mutagen but the metabolites, so we had Fraction S9 for metabolic activation, if we see colonies => mutagenic. We used salmonella because there are more sensitive to single point mutations and frameshift mutations. In vitro Mammalian Cell Gene Mutation Test using the Hprt and Xprt genes => bacteria don’t contain nucleus and histones that protect genome, so we use mammalian cells. Normally the cells are not mutated and are sensitive to different types of substrates. The cells mutated can growth on those substrates, after exposure to the mutagen. They require an exogenous metabolic activation system (as fraction s9). Mammalian cell icronucleus assay=> micronucleus that can be found in the vicinity of the main nucleus containing chromosomes that can’t be equally divided between the cells, as a result of aberrant segregation of chromosomes from the mother cell. In vivo Chromosomal aberration=> lysis of the cell and analysis of metaphasic chromosomes in metaphases to see abnormal chromosomes, we count the most common mutations. Comet assay: it is based on the electrophoresis principle; the migration of DNA happens in relation to its size and conformation by analyzing DNA migration in single cells, it is possible to determine the presence of single (ssb), double (dsb) strand breaks and alkali labile sites (als), oxidative damage to DNA bases, dna-dna crosslink/dna-protein/dna- substance and DNA repair. Comet forms because the broken ends of negatively charged DNA molecules are free to migrate in an electric field towards the anode. There are two principles in comet formation: DNA migration depends on both the size and number of broken DNA ends. The tail length initially increases with damage and reaches a maximum that is dependent on the electrophoretic conditions, but not on the size of the fragments. If there is more migration of the tail, there is more damage. RESULTS WHO/IPCS harmonized scheme for mutagenicity testing => if we have positive results on the test, we can decide to not do in vivo tests. We can have three different responses to in vitro test: a. Negative in all tests b. Equivocal results in all tests in any test (in vitro genotoxic, in vivo no genotoxicity) c. Positive results in all tests in any tests In the two last cases we can consider in vivo studies. TTC The use of the TTC approach has been evaluated as a pragmatic tool that is based on the principle of establishing human exposure threshold values for all chemicals below which there is a very low probability of an appreciable risk of systemic adverse effects to human health. The TTC concept has been acknowledged by different organizations that concluded that the TTC approach should not be used for the following (categories of) chemicals: high potency carcinogens (i.e. aflatoxin-like, azoxy- or N-nitroso- compounds, benzidines and also nanomaterials; radioactive chemicals and mixtures of chemicals containing unknown chemical structures.hydrazines); inorganic chemicals; metals and organometallics; proteins; steroids; chemicals that are known or predicted to bioaccumulate; With respect to EDs, EFSA stated: ‘In addition, once the EU-wide approach for defining and assessing low-dose effects or endocrine disrupters are finalised it will be necessary to consider any impact they may have on the use of the TTC approach." In the ILSI monograph on TTC, Barlow disadvised the use of TTC for EDs (Barlow 2005). So far, this approach has been used in a regulatory context for substances migrating out from food contact material, food flavourings, fragrances, genotoxic constituents in herbal preparations and for pesticide metabolites in groundwater. It should, however, be noticed that the use of the TTC concept for chemicals with specific data requirements for their regulatory approval under a specific European regulation (e.g. Annex substances under Regulation (EC) N° 1223/2009) is currently not acceptable as a standalone alternative to a chemical-specific evaluation. The TTC approach aims to screen and prioritise chemical compounds, present in very small amounts, for which the chemical structure and exposure data are known, but for which no or limited toxicity data is available. An algorithm developed by Cramer (Cramer, 1978) is at the basis of the TTC concept, namely that substances, depending upon their chemical structure, were grouped into three structural classes (Class I=low, Class II=medium, Class III=high safety concern) in comparison with the toxicity data from available databases (about systemic effects after oral exposure) As with any risk assessment tool, application of the TTC approach requires a high level of confidence in: 1) the quality and completeness of the databases; 2) the reliability of the exposure data for the intended uses of the compound under study; and 3) the appropriateness of any extrapolations. 3-5.2.2 TTC APPROACH FOR HUMAN HEALTH RISK ASSESSMENT OF CHEMICAL SUBSTANCES AND COSMETIC SUBSTANCES The SCCS considers the TTC approach scientifically acceptable for human health risk assessment of systemic toxic effects caused by chemicals present at (1) very low levels for which (2) exposure and (3) chemical structure are known. Also, (4) the list of chemical classes for which TTC is not applicable should be consulted in detail in SCCP/1171/08 before applying the TTC tool. Practical application of the TTC approach to chemicals with no genotoxicity alert is thus done by analyzing their chemical structure and using Cramer classification as an indicator of systemic toxicity. The application of the TTC should be done on (5) a case-by-case basis and requires expert judgement. TOX TREE The Toxicological Tree (ToxTree) is a software tool used in the field of toxicology for risk assessment. It helps in predicting the toxicity of chemical compounds based on their structure. The tool uses decision tree approaches to classify chemicals into various toxicity categories, enabling users to understand potential health risks associated with exposure to these substances. Key Features of ToxTree: 1. Structure-Based Predictions: ToxTree analyzes the chemical structure of compounds to predict their toxicological properties. 2. Decision Trees: The tool employs predefined decision trees which are based on established toxicological knowledge and rules. 3. Endpoints: It can predict a variety of toxicological endpoints, such as mutagenicity, carcinogenicity, and skin sensitization. 4. User-Friendly Interface: Designed to be accessible to both experts and non-experts in toxicology. You can choose the appropriate decision tree model for your assessment. ToxTree offers multiple models tailored for different types of toxicity predictions. Examples: those for skin sensi2za2on, carcinogenicity, and general toxicity. The tool will analyze the structure and classify it into specific toxicological categories based on the decision rules. For risk assessment you can combine ToxTree results with other data such as exposure levels, usage scenarios, and population sensitivities to assess the overall risk. It’s efficient, cost/effect, help meet regulatory compliance, very detailed informations. It’s not accurate like experimental data, some complex chemical can be not evaluated properly, it requires regular updates to incorporate new toxicological knowledge and improve predic2on models. SKIN SENSITIZATION = it is defined as stimulation of cells involved in innate or acquired immunity as a result of chemical administration. Inappropriate immunos2mula2on: aberrant ac'va'on of immunity systems=> Hypersensi'vity reac2ons. The increase of ipersensi2za2on has due to more cleaned obsessive habits and the more chemicals produc2on (in food, at home etc). It’s an uncontrolled inﬂammatory response=> chronic inﬂamma2on is the underlying cause of all major clinical disorders. The two most frequent manifesta2on (in industrialized countries) of chemical-induced allergy are contact hypersensi'vity and respiratory sensi'za'on. HYPERSENSITIVITY: 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. 1) Type 1: IgE mediated (immediate type) 2) Type 2: IgM, IgG, cytolysis of cells 3) Type 3: IgM, IgG Immune complex mediated 4) Type 4: T-cell mediated (delayed-type) o skin sensitization=> Th1 o Respiratory => Th2 Allergic contact dermatitis (ACD) is a T-cell-mediated immune response to small molecular weight chemicals that contact and penetrate the skin. ACD MECHANISM: o Induc'on phase=> sensi2za2on for the ﬁrst exposure to the chemical o Elicita'on=> (or challenge phase) second exposure, you have the allergy reac2on 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 (haptenization) epidermal and dermal inflammation dendritic cell activation, migration to lymph nodes and recognition as antigenic by T cells. HYPERSENSITIVITY IV DC recognizes the hapten and presents it to T cell. The DC aner internaliza2on and exposure mature and migrate to lymphonodes with the help of kera2nocytes that with pro-inﬂammatory citokines guide the DC to the local lymphonode. We have the produc2on of T memory cells. The second 2me we will have the presenta2on and the T memory cells will remember the an2gen and starts the inﬂammatory reac2on. Data for hypersensi2vity were collected by animals un2l 2012 when there was the ban. QRA: QUANTITATIVE RISK ASSESSMENT FOR THE ASSESSMENT OF THE INDUCTION OF SKIN SENSITIZATION We need a threshold for the use of compounds, that can induce allergy. 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. 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. PARAMETERS OF QUANTITIVE RISK ASSESSMENT IN SKIN SENSITIZATION: o HAZARD IDENTIFICATION. This involves the use of experimental data to determine the skin sensitization potential of the fragrance ingredient. o DOSE-RESPONSE: The dose–response for induction of skin sensitization is typically determined in the first instance using animal assays such as the LLNA. Confirmatory human assays such as the Human Repeat Insult Patch Test (HRIPT) may also be subsequently conducted to provide substantiation of the NOAEL. Relative skin permeability and integrity are also considered in this section. o EXPOSURE ASSESSMENT. Exposure to the fragrance ingredient is determined using habits and practice data for consumer product use and human parameters data. o RISK ASSESSMENT. The data from the previous steps are used to determine an acceptable exposure level to a fragrance ingredient against which the real life consumer exposure to that fragrance ingredient in a specific product type can be compared. The acceptability or unacceptability of real life exposures can then be determined accordingly. 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) ADI/TDI=NOAEL/SF AEL=NESIL/SAF Depending on the concentration of chemicals and skin surface involved I can have different responses: - NO MIGRATION, NO SENSITIZATION - MIGRATION, SKIN SENSITIZATION DOSE MAKES THE VENOM More the area, less the substance is concentrated. The point of departure for skin sensitivization is NESIL: No Expected Sensitization Induction Level Weight of evidence approach to use of data Uses all of the available scientifically robust data (must employ a published methodology, well documented and involve 100 subjects) Can be derived from animal and human data 2 Uses a defined dose metric - dose/unit area (μg/cm ) NESIL must be express in mg/cm2 Guidelines established for NESIL determination Hierarchy of human data (well run HRIPT) Use of guinea-pig tests as secondary data sources LLNA data only Hierarchy of human versus animal data: the NOAEL from HRIPT will have precedence over all other NOEL. Diagnostic Patch Test (DPT) data cannot be used LLNA => gives good potency info vs guinea pigs test Sensitisation Assessment Factor (SAF) 1. Inter-individual Variability (10) (Age, gender, ethnicity, inherent dermal barrier function and genetic predisposition) 2. Vehicle or Product Matrix Effects (1-3)(e.g. presence of irritants, penetration enhancers) 3. Use Considerations (1-3, 3-10)(Site of contact, barrier function, occlusion) The parameters tha compose the SAF is not precisely from 1 to 10 SAF = VARIABILITY X VEHICLE X CONSIDERATION The first values is always 10. When we have two same values (of factors 2 and 3) we approximate it ex 10x3x3=100 CONSUMER EXPOSURE LEVEL (CEL) § Based on the different cosmetic products § Exposure assessment § Understand human exposure to a material through characterization of: o Exposed populations o Magnitude of exposure under various conditions o Duration and frequency of exposure § Important to use reliable data e.g. habits & practices data to calculate consumer exposure. 2 § Important to use common units of exposure (μg/cm /day) § The topical dose is taken to be the delivered dose. 1. Calculation of CEL Reten'on factor depends if it’s a leave on or rinse oﬀ product. 2. Comparison of acceptable exposure level (AEL) to calculated consumer exposure level (CEL) ACCETABLE RISK = AEL/CEL ratio > 1 AEL > CEL The quan'ta've risk assessment it’s not completely accepted by SCCS 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. CONCLUSIONS o Several in vitro methods to assess contact hypersensitivity are available. o Ten methods for contact hypersensitivity have been successfully validated, and their integration allow appropriate classification and labeling. o GAPs: bioavailability information (extrapolation of in vitro concentration to in vivo dose), applicability domains (solubility, metabolism, chemistry, respiratory allergens, mixtures, biologicals), potency. o The identification of the mechanisms influencing the vigor of T cell responses, that can explain the strength of contact hypersensitivity reactions to weak, moderate, strong, and extreme sensitizers is a challenge still to be solved. o Accurate evaluation of skin sensitizing potency to support effective quantitative risk assessment using non- animal tests is still open. PERFUMES AND ALLERGIES Fragrance substances are naturally or synthetically derived organic compounds with a characteristic, usually pleasant smell. They are ubiquitously found in perfumes and other perfumed cosmetic products, but also in detergents, fabric softeners and other household products where fragrances may be used to provide the consumer with a fresh smell or to mask unpleasant odours from raw materials. Fragrance substances are also used in aromatherapy and are sometimes present in herbal products. A fragrance formula (‘perfume’) may contain up to several hundred or more different ingredients. Special fragrance databases lists more than 2,587 fragrance ingredients used for perfuming. Contact allergy to fragrance ingredients occurs when a susceptible individual has been exposed on the skin to the fragrance allergen, for example through their presence in a cosmetic product. It is a life-long, specifically altered reactivity of the immune system involving recognition of the fragrance allergen(s) by immune cells. Once a contact allergy has been developed, cells capable of recognizing and reacting towards the allergen will always be present in the immune system. As a consequence, symptoms of allergic contact dermatitis characterized by erythema (‘redness’), swelling and vesicles occur upon re-exposure to the fragrance allergen in question. If exposure continues over a longer period of time, it may develop into a chronic condition with scaling and painful fissures of the skin. Allergy susceptibility can be cause by genetics or the repetitive presence of that allergens in different products (so chronological exposure) § HANDS: Contact sensitization may be the primary cause of hand eczema or may be a complication of irritant or atopic hand eczema. The number of positive patch tests has been reported to correlate with the duration of hand eczema, indicating that long-standing hand eczema may often be complicated by sensitization § ARMPITS: Bilateral axillary dermatitis may be caused by perfume in deodorants and, if the reaction is severe, it may spread down the arms and to other areas of the body. (Lyral) § FACE: Facial eczema is an important manifestation of fragrance allergy from the use of cosmetic products. IRRITATION AND URTICARA= Irritant effects of some individual fragrance ingredients, e.g. citral, are known. Many more people complain about intolerance or rashes to perfumes/perfumed products than are shown to be allergic by testing PIGMENTARY ANOMALIES: It refers to increased pigmentation, usually on the face and neck, often following sub- clinical contact dermatitis. Many cosmetic ingredients were patch tested at non-irritant concentrations and statistical evaluation showed that a number of fragrance ingredients were associated. In India, Filippine.. PHOTOXIC REACTIONS: Musk ambrette (synthetic musk) produced a considerable number of allergic photocontact reactions (in which UV-light is required) in the 1970s and was later banned from use in the EU. Special attention is paid to synthetic musks, especially musk ambrette, which are shown to be linked to different types of dermatitis, carcinogenic effects and endocrine dysfunction. Nowadays, photoallergic contact dermatitis is uncommon. Furocoumarins (psoralens) in some plant-derived fragrance ingredients caused phototoxic reactions with erythema followed by hyperpigmentation resulting in dermatitis. There are now limits for the amount of furocouumarins in fragrance products. RESPIRATORY ALTERATION: Fragrances are volatile and therefore, in addition to skin exposure, a perfume also exposes the eyes and naso-respiratory tract. It is estimated that 2–4% of the adult population is affected by respiratory or eye symptoms by such an exposure. It is known that exposure to fragrances may exacerbate pre-existing asthma. Asthma- like symptoms can be provoked by sensory mechanisms. In an epidemiological investigation, a significant association was found between respiratory complaints related to fragrances and contact allergy to fragrance ingredients, in addition to hand eczema, which were independent risk factors in a multivariate analysis. A 1999 opinion by the SCCNFP identified 26 substances that needed to be identified on the label of consumer products to help prevent allergic reactions. Since that time, the review of the clinical and experimental data published after 1999 revealed that many more fragrance substances have been shown to be sensitizers in humans NANOMATERIALS A natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1nm – 100 nm” Nanomaterials give a better performance of the finished product: matte effect of makeup, mascara sunscreens are an example. NANOTOXICOLOGY=> TOXICOLOGY OF NANOMATERIALS The study in vivo, in vitro, in silico, in chemical prediction Colorants, 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. Nanomaterials can be used as colorants (carbon black), UV filters, other functions (antiseptic, antibacterial, matt effect, delivery systems). Carbon black in nanoform has a better performance in mascara, nail polish, foundation, mask… SCCS: the product is safe on healthy, intact skin. - with a size of 20 nm or larger - at a concentration up to 10% as a colorant in cosmetic products, This opinion, however, does not apply to applications that might lead to inhalation exposure to carbon black nanoparticles, where the preparation might lead to inhalable particles. The purity of carbon black nanomaterials used in cosmetic products should be >97%. This opinion is based on the currently available scientific evidence, which shows an overall lack of dermal absorption of carbon black nanoparticles. Since the skin absorbance studies have only been performed with carbon black nanoparticles ≥ 20 nm, the current opinion applies to nano-structured form of carbon black with a particle size of 20 nm or larger. Purity is important, generally is more than 95%, so that you know you are studying that material and not a mixture MINERAL UV FILTERS The concentration levels are controlled and, should not exceed 25% of the final product composition for mineral filters or 10% for chemical filters. 1. ZnO= Zinc oxide is a largely inert, white compound which is used very widely as a bulking agent or filler, and as a white pigment. It is also used in a many cosmetic and medical products and in toiletries, as it has antibacterial and deodorant properties. It is often found in, for example, baby powder and anti-dandruff shampoos. Its strong absorption of ultra-violet (UV) light has led to its use in sunscreen lotions, for both adults and children. How have ZnO nanoparticles been tested for safety? There are now results from a wide range of standardized 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. § The nanoparticles themselves do not appear to penetrate the skin. § They release a small amount of zinc into the sunscreen’s formulation, and a portion of this solubilized zinc might be absorbed through the skin. § The amounts involved are small compared with the amount of zinc normally in the body. § There is evidence that ZnO nanoparticles can cause inflammation in the lungs if they are inhaled. This means that any products which spray such particles cannot be considered safe at present. § ZnO as a colorant in cosmetic products applied to the skin is also considered safe for use. TiO2= nano TITANIUM DIOXIDE (TiO2) is used in sunscreens due to its ability to block ultraviolet radiation while remaining transparent on the skin. TiO2 particles used in sunscreens typically have sizes in the range 5–50 nm. Titanium dioxide is a food additive without any nutritive value and added in processed foods to provide a whitening effect in US. In UE is banned 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. SCCS CONCLUSION ON TiO2 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 internalized 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). SCCS General considerations It should also be noted that the risk assessment of nanomaterials is currently evolving. ð In particular, the toxicokinetic aspects have not yet been fully explored in the context of nanoparticles (e.g. the size dependency). ð Also, long term stability of the coatings remains unclear. At the moment, testing of nanomaterials and the present assessment, are both based on the methodologies developed for substances in non-nano form, and the currently available knowledge on properties, behaviour and effects of nanomaterials. To study nanoparticles you have to start on the toxicology profile of the bulk, to move on the collection on data on other fields and on vitro tests.

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