unisafe - sitox.org · pdf fileunisafe - centro per la valutazione tossicologicadel rischio...
TRANSCRIPT
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 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
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.
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 %
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.
� 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
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);
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
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
� 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 oral toxicity
Class II – 28 - Substancesthat 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 toxicityClass III – 448 – Substances of
chemical structure that permit no strong initial presumption of
safety, or that may even suggestsignificant toxicity
OPs and
(carbamates)
With structural alert for
genotoxicity
546 µg/d
90 µg/d
18 µg/d
0,15 µg/d
1800 µg/d
� 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-genotoxiccarcinogens, bioaccumulative, with very large kinetic differences between animals and humans)
� Steroids (potent non-genotoxic carcinogens)
TTC should NOT be considered
� 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 = 0.0300 mg/kg b.w. day)
Cramer Class II (540 µg/day = 0.0091 mg/kg b.w. day)
Cramer Class III (90 µg/day = 0.0015 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.
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.
COMPOUNDConc 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 1.7 1.7E-03 3.97E-05 I 0.03 1.3-03
B 0.28 2.8E-04 6.53E-06 I 0.03 2.2E-04
C 1.1 1.1E-03 2.57E-05 I 0.03 8.6E-04
D 0.083 8.3E-05 1.94E-06 II 0.009 2.1E-04
E 3.8 3.8E-03 8.87E-05 II 0.009 9.7E-03
Ii 34 3.4E-02 7.93E-04 II 0.009 8.7E-02
G 0.076 7.6E-05 1.77E-06 III 0.0015 1.2E-03
H 0.13 1.3E-04 3.3E-06 III 0.0015 2.0E-03
I 0.18 1.8E-04 4.20E-06 III 0.0015 2.8E-03
J 6.1 6.1E-03 1.42E-04 III 0.0015 9.5E-02
HAZARD INDEX (sum of hazard quotients) 0.2
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
TRIGGERS FOR CONSIDERING TIER 2
� Systemic availability
� Toxicity in the 28/90-day study
� Genotoxicity in vitro
� ABSORPTION
� GENOTOXICITY
In vitro testing
� TOXICITY (28-day/90-day study)
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� 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