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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

Transcript of UNISAFE - sitox.org · PDF fileunisafe - centro per la valutazione tossicologicadel rischio...

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

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 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