EFSA’s risk assessment of

contaminants in the food chain

Marco Binaglia

CONTAM Team Leader

15 December 2020

Introducing EFSAWhat is EFSA

How EFSA works

Assessment framework for contaminants in the food chain

Examples of risk assessment of food contaminants

Outline

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What is EFSA?

EU Agencies

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ECHA

EMA

ECDC

EFSA

EFSA is

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The reference body for risk assessment of food and feed in the European Union. Its work covers the entire food chain – from field to fork

One of the number of bodies that are responsible for food safety in Europe

Food Safety System in the EU

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Risk Management

Risk Communication

Risk Assessment

What EFSA does

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Provides independent scientific advice and support for EU risk managers and policy makers on food and feed safety

Provides independent, timely risk communication

Promotes scientific cooperation

And what EFSA does not do

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Develop food safety policies and legislation

Adopt regulations, authorise marketing of new products

Enforce food safety legislation

EFSA at a glance

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2002REGULATION (EC) N. 178/2002

> 450 staff

~ 1,300 experts

1,000 meetings/year

500 outputs/year

How EFSA works

Questions and Answers

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EU Commission

EFSA self mandate

Member States

EUParliament EFSA

receives a question

EFSA’s scientists evaluate, assess, advise

Adoption and communication

Appointment of an EFSA Scientific Panel

Output drafted by EFSA and external experts

The EFSA Scientific Panels

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Plant protection

GMO

Plant health

Animal health & welfare

Nutrition

Food Packaging

Animal feed

Biological hazards

Chemical contaminants

Food additives

How Risk assessment is performed for contaminants in

the food chain

Chemical contaminants in food and feed

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The EFSA Team and Panel on Contaminants in the Food Chain (CONTAM) provide scientific advice on contaminants in the food chain and undesirable substances such as natural toxicants, mycotoxins and residues of unauthorised substances.

The risk assessment framework

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RISK CHARACTERIZATION

HAZARD IDENTIFICATION & CHARACTERISATION EXPOSURE ASSESSMENT

Hazard identification

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Toxicokinetics in experimental animals, farm animals and humans

Toxicity in experimental animals or in vitro system

Observations in humans

Adverse effects in farm animals, fish, horses and pets

Mode of action

Aim: Identification of key effects and target organs

Role of toxicokinetics data

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The importance of TK data in risk assessment is often neglected. TK data can serve mutiple purposes:

Identify differences in toxicokinetics and toxicodynamics across species;

Inform on the Modes of Action;

Identify bioaccumulating chemicals;

Develop Physiologically Based Kinetics (PBK) models;

Support the use of in vitro toxicity data for hazard characterization.

Toxicity data

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Acute toxicity;

Repeated dose toxicity;

Genotoxicity;

Carcinogenicity;

Developmental and reproductive toxicity;

Other endpoints (e.g. immunotoxicity, neurotoxicity).

Case reports (e.g. poisoning cases);

Clinical studies;

Epidemiological data.

Case reports (e.g. poisoning cases);

Experimental studies (e.g. field studies).

Mode of Action (MOA) data

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The MOA is a sequence of key biological events and processes, starting with interaction of a substance with a cell, proceeding through operational and anatomical changes, and resulting in an adverse effect.

Information on Mode(s) of action are of key importance to understand the relevance of the effects identified in toxicity studies.

Identify difference in sensitivity across species and within species (e.g. sensitive groups of human population).

Used to take decisions on the hazard characterization approach (e.g. in case of carcinogenic substances).

Hazard characterization

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Aim: Definition of Reference Points (RPs)

Key Effects

Acute?

Non-thresholded?

Thresholded?

Chronic?

No/insufficient information

Dose-response analysis

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Key step for the establishment of the RP

Benchmark Dose (BMD) modelling is the preferred option for dose reponse analysis Independent from experimental design

Can be used both for thresholded and non thresholded effects

Uses all available information available in the study

Reference Point: BMDL = 95% lower confidence limit of the BMD extra risk of the critical effect

Dose-response analysis

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What if data are not sufficient to apply BMD modelling? Identification of No Observed Adverse Effect Levels (NOAELs);

Identification of Low Observed Adverse Effect Levels (LOAELs);

Linear extrapolation of tumour incidence (T25);

Lethality data (LD50).

What if no data are available at all? Read across with “structurally similar” substances?

In silico predictions (QSARs)?

Application of the Toxicological Threshold of Concern (TTC) approach?

UN

CERTAIN

TY

Approaches for hazard characterization

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Setting Health-Based Guidance Values (HBGVs)

For acute and chronic effects with a threshold of toxicity and adequate data HBGVs are established.

Tolerable Daily Intake (TDI) or Acute Reference Dose (ARfD) are derived by:

1. Identifying a RP (e.g. BMDL or NOAEL); 2. Applying uncertainty factors (UF) to the RP.

HBGV =Reference point

�UFi

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For non-thresholded effects (e.g. substances that are genotoxic and carcinogenic), or

For cases where no safe level can be identified (insufficient data).

Approaches for hazard characterization

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MOE =Reference point

Dietary exposure estimate

Margin of Exposure (MOE)

For genotoxic and carcinogenic substances MOEs ≥ 10,000 (based on a BMDL of 10% increase in tumour incidence) indicate low

concern for human health.

Exposure assessment

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Exposure Assessment

Chemical Occurrence

Food consumption

Research institutes/ Universities

Food and feed industry

European Countries

Based on a collection of EU national surveys on food consumption

Data divided by age classes

The most recent data within the country

The most complete/detailed data currently available in EU

Comprehensive Food Consumption Database

Exposure assessment, how it works

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Occurrence of toxin A in rice

µg/kg

Mean occurrence

95th percentile

Mean consumption

95th percentile

Consumption of rice by toddlers in country B

g/kg body weight

Chronic exposureMean occurrence levels are combined with consumption data. Exposure levels are generally calculated for average and 95th consumption within each survey.

Acute exposure95th percentile occurrence levels are combined with consumption data. Exposure levels are generally calculated for average and 95th consumption (‘consumers only’) within each survey. In alternative: probabilistic approach (random iterative combinations of consumption and occurrence data).

Risk characterization

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In case of HBGVs:• Comparison of ARfDs with acute exposure levels (e.g. after a 1-day

exposure or a single consumption episode), or

• Comparison of TDIs with chronic exposure levels.

Or MOE calculation:

MOE =Reference point

Dietary exposure estimate

Examples

Example 1: Pyrrolizidine alkaloids (PAs)

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PAs are substances biosynthesised exclusively by (mostly non-edible) plants.

600 known PAs, as result of combinations of different necine bases and necic acids.

PA contamination can occur in several foods, including tea and herbal infusions, honey, spices and food supplements.

Hazard identification and characterization:

Tested 1,2-unsaturated PAs show a consistent picture indicating genotoxic potential

Toxicity in experimental animals is characterized by liver toxicity and carcinogenicity anddevelopmental toxicity.

Dose-response data on liver carcinogenicity are available only for 2 PAs.

Necine base Necic acid

Mode of action supporting read-across

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Bioactivation to reactive electrophilic pyrrolic species is a key event both for genotoxicity and liver toxicity

Pyrrolic species from several PAs alkylate nucleophilic groups forming a common set of DNA and protein covalent adducts.

Strong evidence for a genotoxic mechanism for hepatocarcinogenicity of riddelliine in rodents: concomitant DHP adduct formation induction of liver cell mutations formation of liver haemangiosarcomas and hepatomas.

Risk assessment approach

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A BMDL10 of 237 µg/kg bw per day was calculated for the incidence of liver haemangiosarcoma in rats exposed to riddelliine and selected as RP.

Riddelliine is not commonly detected in food in the EU

Using read across, the RP is applied to the sum of PAs, assuming they are all equally potent to riddelliine.

PAs are genotoxic and carcinogenic substances:

TDI MOE

Chronic exposure levels ranged from <0.2 to ~200 ng/kg bw per day across surveys and age groups.

MOEs < 10,000 were calculated, in particular for high consumers of tea and herbal infusions, indicating a possible concern for human health.

Example 2: 3-MCPD fatty acid esters

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2- and 3-monochloropropandiol (MCPD), their fatty acid esters and glycidyl fatty acid esters (GEs) are process contaminants derived from glycerol.

Free 3- and 2-MCPD are found in particular in hydrolysed vegetable proteins (HVP) and soy sauce .

3- and 2-MCPD fatty acid esters and GEs are mainly formed during high-temperature processing of vegetable oils and fats (e.g. deodorisation).

(free) 3-MCPD Glycidyl ester

Hazard identification and characterization

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Main target organs identified in laboratory animals following repeated exposure to 3-MCPD: Kidney and male reproductive system.

Kidney toxicity: progressive nephropathy leading to tubular hyperplasia and adenomas following chronic exposure to ≥ 2 mg/kg bw per day (LOAEL).

Fertility effects: decreased sperm motility and male fertility after short-term exposure above 1 mg/kg bw per day (NOAEL).

Sustained exposure to higher doses causes decreased sperm count and histopathological changes in testes.

Genotoxicity: 3-MCPD is not genotoxic in vivo. Neoplastic changes observed following chronic exposure are likely mediated by non-genotoxic modes of action.

3-MCPD esters cause effects similar free 3-MCPD, supporting the view that toxicity is primarily exerted by 3-MPCD following cleavage of ester bonds.

Risk assessment approach

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0.20 1.95

0.44 3.88

1.34 4.25

1.30 8.50

1.50 14.00

0.10 1.00 10.00

Kidney tubular hyperplasia(chronic, 10%)

Decreased sperm motility (subacute, 5%)

Decreased sperm count(subchronic, 23%)

Epididymal epithelium vacuolization(subacute, 10%)

Seminiferous tubular atrophy(chronic, 10%)

Derivation of HBGV: TDI of 2 µg/kg bw per day established for the sum of free 3-MPCD and 3-MCPD esters (expressed as 3-MCPD equivalent).

Based on the selected Reference Point of 0.2 mg 3-MCPD/kg bw per day, and

Overall UF of 100 (10 for extrapolation from rats to humans, 10 for inter-individual variability)

Comparison of BMDLs calculated for different effects for the RP selection

mg 3-MCPD/kg bw per day

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Risk assessment approach

Chronic exposure levels for average consumption ranged from 0.2 to 1.5 µg 3-MCPD/kg bw per day. For high (95th percentile) consumption ranged from 0.3 to 2.6 µg 3-MCPD/kg bw per day.

A specific exposure scenario for infants receiving infant formula only led to exposure estimations ranging from 2.4 to 3.2 µg 3-MCPD/kg bw per day.

Considering exposure levels estimated in the previous opinion, the established TDI of 2 µg/kg bw per day is not exceeded in the adult population (mean and high exposure levels). A slight exceedance of the TDI was observed in the high consumers of the younger age groups and for the scenarios on infants receiving formula only.

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