UNISAFE - CENTRO PER LA VALUTAZIONE TOSSICOLOGICA DEL RISCHIO CHIMICO UNIVERSITÀ DEGLI STUDI DI MILANO - PDF

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UNISAFE - CENTRO PER LA VALUTAZIONE TOSSICOLOGICA DEL RISCHIO CHIMICO UNIVERSITÀ DEGLI STUDI DI MILANO VALUTAZIONE DEL RISCHIO PER ESPOSIZIONE COMBINATA A SOSTANZE CHIMICHE Federchimica - Milano 7 Luglio

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UNISAFE - CENTRO PER LA VALUTAZIONE TOSSICOLOGICA DEL RISCHIO CHIMICO UNIVERSITÀ DEGLI STUDI DI MILANO VALUTAZIONE DEL RISCHIO PER ESPOSIZIONE COMBINATA A SOSTANZE CHIMICHE Federchimica - Milano 7 Luglio 2015 Assess the intrinsic hazard of a chemical and establish a level of safety; Determine the level of exposure to a chemical; Compare the daily intake (exposure) with the health based guidance values to ensure that the risk is acceptable in light of all the existing scientific evidence. HAZARD is the potencial capacity of producing harm. is proportional to both the and the. Hazard identification Inherent biological activity Hazard assessment Assessment of relevance for humans Dose-response analysis EXPOSURE ASSESSMENT Active principle Dose of food additives Dose in individuals Dose in special population groups Max/min chronically/occasionally HAZARD IDENTIFICATION Identification of adverse health effects In silico methodologies In vitro toxicology data Animal-based toxicological studies Human observation HAZARD ASSESSMENT Quantification of adverse health effects Kinetic variability Dynamic variability Mode/mechanism of action Selection of critical data Dose-response for critical effect RISK CHARACTERISATION Biological Effect Dose (mg/kg body weight) Exposure Dose to target Interaction with target Interaction with target Toxic effect Toxicokinetic Toxycodynamic Absorption Distribution Metabolism Excretion Receptors Ionic Channels Enzymes Immuno System Detoxification Reactive Intermediates Cell damage Covalent binding/ox idative stress Immune Response The presence of a it is essential, so that the toxic agent could interact and to get the toxic response The concentration at the target of the toxic agent and/or its metabolits and/or its degration products is strictly related to the external dose mg/kg body weight of the administered toxic agent or the one present in the environment The toxic effect, either qualitative or quantitavive, is strictly related to the internal dose mg/kg body weight of the administered toxic agent or the one present in the environment and or its metabolits and or its degradation products reaching the target TOXICANT DELIVERY INTERACTION WITH TARGET DISFUNCTION/INJURY DYSREPAIR DDT (DDE) Central Nervous System Voltage-gated sodium channel proteins Slows the closing of sodium channels that open during depolarization Spasms, paralysis and eventual death EXTERNAL DOSE* Parent compound administered dose INTERNAL DOSE* Biologically and/or toxicologically active: parent compound metabolite(s) reactive product(s) *Expressed in mg/kg b.w. H 14 CHO MONTHS OF RIPENING HCHO free H 14 CHO in cheese H 14 CHO bound to casein 3 ppm 2 ppm 1. 4 ppm n.d. n.d. n.d. 73 ppm 70 ppm 63 ppm 64 ppm 64 ppm 64 ppm 60.4 % 58.9 % 53.2 % 52.0 % 48.8 % 48.4 % EXTERNAL DOSE Formaldeyde H C = O H INTERNAL DOSE Spinacine N COOH NH N H Toxicants Dietary supplements Botanicals Herbs Contaminants Toxicant and/or NON Genotoxic Carcinogen Reference points (RPs) in toxicology studies used to calculate a safe level for human intake: Benchmark Dose (BMD). ADI (Acceptable Daily Intake) ARfD (Acute Reference Dose) AOEL (Acceptable Operator Exposure Level) XYZ ecc. ecc ADI 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 a lifetime without appreciable health risk. ALLOCATION ADI ARfD -AOEL xxz.. TOXICOLOGICAL PROTOCOL Absorption Distribution Metabolism Excretion LD 50 oral LD 50 dermal LC 50 inhalation Skin irritation Eye irritation Skin sensitization Mutagenesis Clastogenesis Aneuploidy Teratogenicity tests (Rat-Rabbit) Mouse Rat Dog Dog 90 day toxicity 90 day toxicity 90 day toxicity 1 year toxicity Two generation reproductive toxicity Mouse 18 months Rat 104 weeks HUMANS sensitive subjects HUMANS population means ANIMALS ADI NOAEL 1 10 dose mg/kg bw 100 ADI = NOAEL SF ADI = Admissible Daily Intake mg/kg b.w. NOAEL = No Observed Adverse Effect Level (mg/kg b.w.) SF = Safety Factor (10, 100, n) Interspecies Differences 10 Interindividual Differences 10 Reference points (RPs) in toxicology studies used to calculate a safe level for human intake: No-Observed-Adverse-Effect-Level (NOAEL); Confidence Intervals 95% BMDL 10 BMD 10 Risk characterization for genotoxic carcinogens ALARA As low as reasonably achievable Cancer risk Estimation Based on low-dose extrapolation Margin of Exposure (MOE) Threshold of toxicological Concern (TTC) Based solely on hazard identification Does not take into account human exposure Does not take into account potency Risk characterization for genotoxic carcinogens Cancer risk Estimation Based on low-dose extrapolation Extrapolation Range * * Observed Range * * * * * DOSE % TUMOURS BEARING ANIMALS Risk characterization for genotoxic carcinogens Margin of Exposure (MOE) Confidence Intervals 95% BMD 10 PoD/BMDL 10 z MoE = PoD / EXPOSURE PoD = 25 mg/kg b.w. EXPOSURE (Dietary Intake) = mg/kg/day z MoE = 25 / = 50,000 Risk characterization for genotoxic carcinogens Threshold of toxicological Concern (TTC) Migrant substances from packaging materials (USFDA-TOR- 1993) Flavourings substances in food (WHO-JECFA 1993,1995,1999.) Endorsed for the risk assessment of chemicals (WHO-IPCS 1998) Non relevant plant protection product metabolites in ground water (EC-2002) Genotoxic impurities in pharmaceutical preparations (EMA 2003,2004) Flavourings substances in food (EFSA 2004) Genotoxic constituents in herbal preparations (EMA 2006) Suggested for REACH (Registr, Evaluat, Authoriz and restrict of Chemical substances) (ECHA 2008) Suggested for application to aquatic environmental exposure (2005) Suggested for application to the cosmetic ingredients and their impurities (2007) Suggested for prenatal developmental toxicity (2010) Suggested for mixture of substances potentially detectable in surface water (2011) Suggested for risk prioritization of trace chemicals in food. (2011) According to the TTC concept, a safe level of exposure can be identified for many chemicals based on their chemical structure and the known toxicity of chemicals that share similar structural characteristics. The TTC approach is exclusively designed where there is limited or no information on the toxicity of the compound and information on exposure indicates that human exposure is very low. TTC to set priorities in setting toxicity tests Hazard identification Inherent biological activity Hazard assessment Dose-response analysis Assessment of relevance for humans EXPOSURE ASSESSMENT Active principle Dose of toxicant Dose in individuals Dose in special population groups Max/min chronically/occasionally HAZARD IDENTIFICATION Identification of adverse health effects In silico methodologies In vitro toxicology data Animal-based toxicological studies Human observation HAZARD ASSESSMENT Quantification of adverse health effects Kinetic variability Dynamic variability Mode/mechanism of action Selection of critical data Dose-response for critical effect RISK CHARACTERISATION EXPOSURE ASSESSMENT Dose of toxicant Dose in individuals Dose in special population groups Max/min chronically/occasionally CHEMICAL STRUCTURE Structural information based on an algorithm developed in 1978 by Cramer Chemical grouped in three classes RISK PRIORITIZATION Class I- Substances with simple chemical structure and efficient modes of metabolism that would suggest a lower order of oral toxicity Class II Substances that are in structural class in which there is less knowledge of the metabolism, pharmacology and toxicology, but for which there is no clear indication of toxicity Class III Substances of chemical structure that permit no strong initial presumption of safety, or that may even suggest significant toxicity. 1800 µg/d Class I Substances with simple chemical structure and efficient modes of metabolism that would suggest a lower order of oral toxicity 546 µg/d Class II 28 - Substances that are in structural class in which there is less knowledge of the metabolism, pharmacology and toxicology, but for which there is no clear indication of toxicity Class III 448 Substances of chemical structure that permit no strong initial presumption of safety, or that may even suggest significant toxicity 90 µg/d 18 µg/d OPs and (carbamates) 0,15 µg/d With structural alert for genotoxicity TTC should NOT be considered For specific structural alerts: i.e. aflatoxin-like, azoxy and N-nitroso-compounds (potent genotoxic carcinogens) Polyhalogenated dibenzo-p-dioxins, -dibenzofurans and dioxin like PCB s (non-genotoxic carcinogens, bioaccumulative, with very large kinetic differences between animals and humans) Steroids (potent non-genotoxic carcinogens) Inorganic chemicals, metals and organometallics (not included in the data base) High molecular weight chemicals such as polymers (not included in database) Nanomaterial (not included in database) Radioactive substances (not included in database) Organo-silicon compounds (not included in database) Proteins (not included in database and..risk of allergenicity) 10 compounds potentially detectable in surface water, assuming that no toxicological information, other than structure, is available, were classified into Cramer Classes TTC values for each substance assigned Cramer Class I (1800 µg/day = mg/kg b.w. day) Cramer Class II (540 µg/day = mg/kg b.w. day) Cramer Class III (90 µg/day = mg/kg b.w.day) Exposure (mg/kg b.w. day) = Surface water concentration (mg/l) x 0.42 L day/18 Kg (children) (Drinking water assumption made for children to be conservative) Hazard Quotient (HQ) for each substance = Exposure/TTC value ILSI Health and Environmental Sciences Institute (HESI) Mixtures Project Screening-level, Tier 0 approach. COMPOUND Conc in surface water (µg/ml) Conc in surface water (mg/l) Exposure (mg/kg bw/day) (a) Cramer class TTC value (mg/kg bw/day) (b) HAZARD QUOZIENT (HQ) BASED ON TTC (a/b) A E E-05 I B E E-06 I E-04 C E E-05 I E-04 D E E-06 II E-04 E E E-05 II E-03 Ii E E-04 II E-02 G E E-06 III E-03 H E E-06 III E-03 I E E-06 III E-03 J E E-04 III E-02 HAZARD INDEX (sum of hazard quotients) 0.2 The calculated Hazard Index of 0.2 is less than 1.0, and therefore the results of this Tier 0 assessment would suggest that advancement to higher assessment tiers is not necessary in this case. ILSI Health and Environmental Sciences Institute (HESI) Mixtures Project Screening-level, Tier 0 approach. ABSORPTION GENOTOXICITY In vitro testing TOXICITY (28-day/90-day study) TRIGGERS FOR CONSIDERING TIER 2 Systemic availability Toxicity in the 28/90-day study Genotoxicity in vitro Guidance for submission for food additive evaluations EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) - EFSA Journal 2012;10(7):2760 ADME Single dose GENOTOXICITY In vivo testing TOXICITY (stand alone or combined) Chronic toxicity Carcinogenicity REPRODUCTIVE & DEVELOPMENTAL TOXICITY Extended One Generation Reproduction Toxicity Study PRENATAL DEVELOPMENTAL TOXICITY (Teratogenicity) TRIGGERS FOR CONSIDERING TIER 3 Bioaccumulation Positive in vivo genotoxicity Chronic toxicity/carcinogenicity Reproductive & developmental toxicity Guidance for submission for food additive evaluations EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) - EFSA Journal 2012;10(7):2760 ADME Repeated doses CARCINOGENICITY Mode of action REPRODUCTIVE & DEVELOPMENTAL TOXICITY Endocrine Disruptor? SPECIALIZED STUDIES Immunotoxicity Neurotoxicity Endocrine activity Mode of Action Guidance for submission for food additive evaluations EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) - EFSA Journal 2012;10(7):2760
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