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  • UNISAFE - CENTRO PER LA VALUTAZIONE TOSSICOLOGICA DEL RISCHIO CHIMICO

    UNIVERSIT 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

    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

    Active principle Dose of food additives Dose in individuals Dose in special population groups Max/min chronically/occasionally

  • 0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    BiologicalEff

    ect

    Dose (mg/kg body weight)

  • Exposure Dose to target Interaction with target

    Interaction with target Toxic effect

  • Absorption

    ToxycodynamicToxicokinetic

    Receptors

    Ionic ChannelsEnzymes

    Immuno System

    Distribution

    MetabolismExcretion

  • ReactiveReactiveIntermediates

    Covalentbinding/oxidativestress

    Detoxification

    Cell damage

    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 thatopen during depolarization

    Spasms, paralysis and eventual death

  • INTERNAL DOSE*

    Biologically and/or

    toxicologically active:

    parent compound

    metabolite(s)

    reactive product(s)

    EXTERNAL DOSE*

    Parent compound

    administered dose

    *Expressed in mg/kg b.w.

  • HH14 C O

  • MONTHS OF RIPENING

    1 4 7 10 13 16

    HCHOfree

    3 ppm 2 ppm 1. 4 ppm n.d. n.d. n.d.

    H14 CHOin cheese

    73 ppm 70 ppm 63 ppm 64 ppm 64 ppm 64 ppm

    H14 CHObound tocasein

    60.4 % 58.9 % 53.2 % 52.0 % 48.8 % 48.4 %

  • EXTERNAL DOSE INTERNAL DOSE

    Formaldeyde Spinacine

    C = OH

    H

    N COOH

    NNH

    H

  • Toxicant and/or NON Genotoxic Carcinogen

    Toxicants

    Dietary supplements

    Botanicals Herbs

    Contaminants

  • 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.

  • TOXICOLOGICAL PROTOCOL

    ADI ARfD -AOEL xxz..

    ALLOCATION

  • Absorption

    Distribution

    Metabolism

    Excretion

    Mutagenesis

    Clastogenesis

    Aneuploidy

    LD50 oral

    LD50 dermal

    LC50 inhalation

    Skin irritation

    Eye irritation

    Skin sensitization

    Mouse 90 day toxicity

    Rat 90 day toxicity

    Dog 90 day toxicity

    Dog 1 year toxicity Teratogenicity tests (Rat-Rabbit)

    Two generation reproductive toxicity Mouse 18 months

    Rat 104 weeks

  • dose mg/kg bw100101

    NOAEL

    ADI

    HUMANSsensitive subjects

    HUMANSpopulation means

    ANIMALS

  • NOAEL = No Observed Adverse Effect Level (mg/kg b.w.)

    SF = Safety Factor (10, 100, n)

    NOAEL

    SFADI =

    ADI = Admissible Daily Intake mg/kg b.w.

  • Interindividual DifferencesInterindividual Differences 1010

    Interspecies DifferencesInterspecies Differences 1010

  • Reference points (RPs) in toxicology studies used to calculate

    a safe level for human intake:

    No-Observed-Adverse-Effect-Level (NOAEL);

  • BMDL10

    Confidence Intervals 95%

    BMD10

  • Risk characterization for genotoxic carcinogens

    ALARA

    As low asreasonablyachievable

    Cancer riskEstimation

    Based onlow-dose

    extrapolation

    Threshold oftoxicological

    Concern

    (TTC)

    Margin ofExposure

    (MOE)

  • Based solely on hazard identification

    Does not take into account human exposure

    Does not take into account potency

  • Risk characterization for genotoxic carcinogens

    Cancer riskEstimation

    Based onlow-dose

    extrapolation

  • ***

    * *

    *

    *

    DOSE

    Extrapolation Range Observed Range%

    TU

    MO

    UR

    S B

    EA

    RIN

    G A

    NIM

    ALS

  • Risk characterization for genotoxic carcinogens

    Margin ofExposure

    (MOE)

  • PoD/BMDL10

    Confidence Intervals 95%

    BMD10

  • z MoE = PoD / EXPOSURE

    PoD = 25 mg/kg b.w.

    EXPOSURE (Dietary Intake) = 0.0005 mg/kg/day

    z MoE = 25 / 0.0005 = 50,000

  • Risk characterization for genotoxic carcinogens

    Threshold oftoxicologicalConcern

    (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

    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

    Active principle 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

    EXPOSURE ASSESSMENT

    Dose of toxicant

    Dose in individuals

    Dose in special population groups

    Max/min chronically/occasionally

  • 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.

  • Class I 137 -Substances with simplechemical structure and efficient modes of

    metabolism that wouldsuggest a lower order

    of or