Directorate-General for

Health & Food Safety

Presence of mycotoxins in feed and food in the EU: An increasing risk for animal and

public health and challenges for risk management

Frans Verstraete

1

Challenges as a consequence of changing weather conditions • Tension between MLs based on the application of

prevention / ALARA versus changing climate/weather conditions and year to year variation

• Approach to tackle the year-to-year variation of Fusarium toxins/mycotoxins from a legal point of view

• Increasing prevalence of aflatoxins in Europe (increased levels of aflatoxins in the South-East of Europe in 2012 – 2013)

• Increased levels of Fusarium toxins in maize in (large parts of the) EU in harvest 2013 and 2014

• …

Aflatoxins in maize (2012/13) Challenges identified

• Several notifications on high levels of aflatoxin in maize intended for feed

• Following issues/ challenges were observed :

* the complexity of the traceability

* the variability of the aflatoxin results (within a lot / at different stages in the distribution chain

* the representativeness of the samples taken the traders at loading

* the need for an early warning.

Fusarium toxins in maize (harvest 2013 and 2014)

• shortage of supply for food maize millers experienced/ expected

• Possible temporary derogation discussed – not granted

• Reasons:

- certain MS not convinced of shortage of supply

- exposure to certain mycotoxins already close or exceeding the health based guidance value

• Follow-up

- shortage of supply problems experienced following non-granting derogation

- root-cause analysis

MYCOTOXINS IN CEREALS USE OF CEREALS

Use of cereals, excluding rice, in period 2015-2016 - figures for EU-28 (losses

(market) not taken up in the table)

Cereal % for human

consumption

% for animal

feed

% for

seeds

% for industrial

use

Total cereals (100 %) 23.0 61.2 3.4 11.7

Common wheat (42.4 %) 39.6 46.4 4.1 9.1

Durum wheat (3.2 %) 87.0 6.6 5.0 1.0

Rye (2.9 %) 37.4 37.0 5.0 19.7

Barley (17.0 %) 0.7 75.3 4.5 18.6

Oats (2.4 %) 16.4 75.0 6.1 1.5

Maize (26.0 %) 6.5 77.2 0.6 14.8

Triticale (4.3 %) 0.4 90.3 5.0 3.5

Other cereals (1.5 %) 0.6 94.6 1.5 2.4

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MYCOTOXINS IN CEREALS USE OF CEREALS

• Large part of the production of cereals is used for animal feed

• Cereals for food production: by products intended for animal feed

• Cereals for bio-energy: by products intended

for animal feed

• Alternative uses for “non-compliant” cereals limited serious economic impact

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Major challenge for the future - MYCOTOXINS AND CLIMATE CHANGE

• Conference at the occasion of Milan EXPO 2015 on 5 June 2015 "Regulatory challenges following increased prevalence of mycotoxins in feed and food following climate change"

• Observations: Increased prevalence of mycotoxins at higher levels in cereals produced in the EU. Major cause is climate change and in particular the extreme weather conditions during critical growth stages of cereals in particular maize. However also other causes (agricultural practices) might contribute in depth

root-cause analysis appropriate

• Conclusion: For a sustainable solution, it was concluded that it would be appropriate to elaborate a comprehensive EU mycotoxiin (prevention) approach, including agricultural and environmental aspects

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NEED FOR A COMPREHENSIVE STRATEGY • Prevention

- Resistent/tolerant varieties - Agricultural practices (<-> environmental constraints) - Storage and transport conditions - …

• Mitigate the toxic effects of mycotoxins - Mycotoxin binders - Mycotoxin detoxifying products /additives - ….

• Detoxification - Acceptability criteria - …

• Last but not least – Regulation/regulatory measures - Maximum levels - Guidance levels - …

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NEED FOR A COMPREHENSIVE STRATEGY

Prevention • Prevention

- Resistent/tolerant varieties - Agricultural practices - Storage and transport conditions - …

- Drawbacks - Absence of economic incentives - Environmental constraints - Economic constraints - Triggers to effectively implement the good practices - Win-win situation: how to achieve this and how to

convince farmer and other food business operators of this

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Mycotoxin binders – detoxifying agents Regulation (EC) No 386/2009

* Regulation (EC) No 386/2009: establishes a new functional group of feed additives in the category of technological additives: "(m) substances for the reduction of the contamination of feed by mycotoxins: substances that can suppress or reduce the absorption, promote the excretion of mycotoxins or modify their mode of action"

Mycotoxin binders /detoxifying agents Regulation (EC) No 386/2009

• These binders/detoxifying agents are to be used in feed compliant with EU legislation (contrary to detoxification process Regulaiton 2015/786)

• These binders suppress or reduce the adsorption, promote the excretion of mycotoxins or modify their mode of action and thereby mitigate possible adverse effects of mycotoxins on animal health and public health"

• The use of such products may not result in an increase of existing maximum or guidance levels but should improve the quality of the feed for animal nutrition which is lawfully on the market, providing additional guarantees for the protection of animal and public health

Mycotoxin binders : detoxifying agents Regulation (EC) No 386/2009

Additional guarantees • To mitigate the risks related to the heterogeneous

contamination • In years of high prevalence at high levels (year-

to-year variance) • Co-exposure to several mycotoxins simultaneously • Modified mycotoxins • Sensitive breeds • ….

Mycotoxin binders – detoxifying agents Authorised additives Mycotoxin-adsorbing agents

• Bentonite (dioctahedral montmorillonite) – aflatoxin B1 – ruminants, poultry and pigs

• …

Mycotoxin-biotransforming agents

• Micro-organism strain DSM 11798 of the Coriobacteriaceae family – trichothecenes – pigs and all avian species

• Fumonisin esterase produced by Komagataella pastoris –fumonisins – pigs and avian species

• …

Feed: Criteria for detoxification processes

• Article 8 – Directive 2002/32/EC: The Commission may define acceptability criteria for detoxifciation processes as a complement to the criteria provided for products intended for animal feed which have undergone such processes.

• It is also provided that Member States shall ensure that measures are taken to guarantee the correct application of any acceptable detoxification process on products intended for animal feed and the conformity of those detoxified products with the provisions of Annex I of that Directive.

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Commission Regulation (EU) 2015/786 of 19 May 2015 : Criteria for detoxification processes

* In order to ensure a uniform assessment across the European Union of the acceptability of detoxification processes, acceptability criteria for detoxification processes are established at Union level.

* Detoxification of a contaminated batch of feed can be performed by a physical, chemical or (micro-) biological detoxification process.

* The acceptability criteria ensure that the detoxified feed should not endanger animal and public health and the environment and that the characteristics of the feed should not be adversely altered by the detoxification process

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Commission Regulation (EU) 2015/786 of 19 May 2015 : Criteria for detoxification processes

* The detoxification process has to be performed in an establishment approved for that purpose in accordance with Article 10 (3) of Regulation (EC) No 183/2005 of the European Parliament and of the Council of 12 January 2005 laying down requirements for feed hygiene.

* From the scope of this Regulation are excluded the physical detoxification process through which the contamination by an undesirable substance is reduced or eliminated solely by cleaning, sorting or mechanical removal of certain parts as such a process is in many cases part of the usual production process.

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Commission Regulation (EU) 2015/786 of 19 May 2015 : Criteria for detoxification processes

• * A detoxification process shall only be applied if the EFSA has performed, on request of the Commission, an scientific assessment of the detoxification process, concluding that the detoxification process complies with the acceptability criteria.

• * It applies as from 1 July 2017

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Applications for detoxification

Feed to be

decontaminated

Process Contaminants to be

detoxified

Groundnut meal Ammoniation Aflatoxin B1

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Regulation /regulatory measures

Issues

- Modified mycotoxins (DON, nivalenol, Fumonisins, Zearalenone, T-2 and HT-2 toxin)

- Lower HBGV (T-2/HT-2)

- Increased prevalence of certain mycotoxins: ochratoxin A , aflatoxins, Fusarium toxins

- "New"/not yet regulated mycotoxins : Alternaria toxins, sterigmatocystin …

- …

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Modified mycotoxins

Following a request from the European Commission, the risks

to human and animal health related to modified forms of the

Fusarium toxins zearalenone, nivalenol, T-2 and HT-2 toxins

and fumonisins were evaluated EFSA opinion December

2014

Modified (often called “masked”) mycotoxins are metabolites

of the parent mycotoxin formed in the plant or fungus, e.g. by

conjugation with polar compounds. Fumonisins, which are

difficult to extract from the plant matrix, are also termed

modified mycotoxins. 20

Modified mycotoxins

The CONTAM Panel considered it appropriate to assess human

exposure to modified forms of the various toxins in addition to

the parent compounds, because many modified forms are

hydrolysed into the parent compounds or released from the

matrix during digestion. For modified forms of

zearalenone, nivalenol, T-2 and HT-2 toxins and

fumonisins, 100 %, 30 %, 10 % and 60 % were added,

respectively based on reports on the relative

contribution of modified forms.

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Modified mycotoxins

Risk characterization was done by comparing exposure scenarios

with reference doses of the parent compounds. In humans, all

mean and 95th percentile exposures to the sum of modified and

parent toxins were below the respective provisional maximum

tolerable daily intakes (PMTDIs) and tolerable daily intakes (TDIs),

with two exceptions: for zearalenone and modified

zearalenone the UB 95th percentile exposure was up to 2.2-

fold the TDI. For fumonisins and modified fumonisins the

exposure of toddlers and other children exceeded the

PMTDI at both the LB and the UB estimates, which could be of

concern. 22

Modified mycotoxins –Follow up

• EFSA to be requested to assess if the health based guidance

value established for zearalenone, nivalenol, T-2 and HT-2 toxin

and fumonisins as parent compound can be considered as a group

health based guidance value (HBGV) for the parent compound and

its modified forms (for the modified forms identified in the

opinion).

• To include in the work programme 2016 for the EURL for

mycotoxins in feed and food the organisation of proficiency test

with a multi-mycotoxin method of analysis for the analysis of a

wide range of Fusarium toxins and their modified forms.

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HBGV for zearalenone and its metabolites - EFSA opinion April 2016

The CONTAM Panel found it appropriate to set a

group TDI of 0.25 µg/kg bw per day expressed as

ZEN equivalents for ZEN and its modified forms. To

account for differences in in vivo oestrogenic

potency, each metabolite was assigned a potency

factor relative to ZEN to be applied to exposure

estimates of the respective ZEN metabolites. 24

HBGV for zearalenone and its metabolites - EFSA opinion April 2016

• Relative potencies factors (RPFs) given on a molar basis for the metabolites of ZEN proposed by the EFSA CONTAM Panel

• ZEN 1.0; ZENGlcs and ZENSulfs 1.0; α-ZEL 60; α-ZELGlcs and α-ZELSulfs 60; β-ZEL 0.2; β-ZELGlcs and β-ZELSulfs 0.2; ZAN 1.5; ZANGlcs and ZANSulfs 1.5; α-ZAL 4.0; α-ZALGlcs, α-ZALSulfs 4.0; β-ZAL 2.0; β-ZALGlcs, β-ZALSulfs 2.0; cis-ZEN 1.0; cis-ZENGlcs and cis-ZENSulfs 1.0; cis-α-ZEL 8.0; cis- α-ZELGlcs and cis- α a-ZELSulfs 8.0; cis-β-b-ZEL 1.0; cis-β-ZELGlcs and cis-β-ZELSulfs 1.0

• ZEN: zearalenone; Glc: glucose; Sulf: sulfate; ZEL: zearalenol; ZAN: zearalanone; ZAL: zearalanol; ER: oestrogen

receptor. 25

HBGV for zearalenone and its metabolites - EFSA opinion April 2016

• Regulatory follow-up (Standing Committee 21 June 2016 and 13 September 2016)

• EURLs have to to work on the analytical methodology (including organisation at a later stage of a PT test)

• Further regulatory follow-up to be discussed once an EU-wide survey has been undertaken on prevalence of these modified forms (outcome survey, other monitoring results and EURL activities))

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HBGV for T-2 and HT-2 toxin and its metabolites - EFSA opinion 11/2016

• Tolerable Daily Intake (TDI) for T2 and HT2 of 0.02

µg/kg body weight (bw) per day (from 0,1 µg/kg bw)and an

acute reference dose (ARfD) of 0.3 µg for T2 and HT2/kg

bw

• Group TDI and a group ARfD for T2 and HT2 and its

modified forms. Potency factors relative to T2 for the

modified forms were used to account for differences in

acute and chronic toxic potencies. Relative potency factors

(RPFs) assigned to the modified forms were all either 1 or

less than 1. 27

Exposure to T-2 and HT-2 toxin and its metabolites - EFSA report 07/2017

• In humans, the mean chronic dietary exposure to the sum of T2 and HT2 was highest in ‘Toddlers’ and ‘Infants’, with maximum upper bound (UB) estimates of 64.8 and 62.9 ng/kg body weight (bw) per day, respectively. The 95th percentile dietary exposure was highest in ‘Infants’ with a maximum UB estimate of 146 ng/kg bw per day.

• In the absence of data, potential modified forms were not included.

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Nivalenol an its modified forms 03/2017

• Tolerable daily intake (TDI) for nivalenol (NIV) of 1.2 µg/kg body weight (bw) and an acute reference dose (ARfD) of 14 µg/kg bw

• The only phase I metabolite of NIV identified is

de-epoxy-nivalenol (DE-NIV) and the only phase II metabolite is nivalenol-3-glucoside (NIV3Glc).

• NIV3Glc can occur in cereals amounting up to about 50% of NIV. There are no toxicity data on NIV3Glc, but as it can be assumed that it is hydrolysed to NIV in the intestinal tract it should be included in a group TDI and in a group ARfD with NIV.

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Deoxynivalenol and its modified forms adopted 01/2017 – published 11/09/17

• EFSA assessed the risk to animal and human health related to DON, 3-acetyl-DON (3-Ac-DON), 15-acetyl-DON (15-Ac-DON) and DON-3-glucoside in food and feed.

• Since 3-Ac-DON and 15-Ac-DON are largely deacetylated and DON-3-glucoside cleaved in the intestines the same toxic effects as DON can be expected. The TDI of 1 µg/kg bw per day, that was established for DON was therefore used as a group-TDI for the sum of DON, 3-Ac-DON, 15-Ac-DON and DON-3-glucoside.

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Deoxynivalenol and its modified forms adopted 01/2017 – published 11/09/17

• A group-ARfD of 8 µg/kg bw per eating occasion was calculated.

• Estimates of acute dietary exposures were below this dose and did not raise a health concern in humans.

• The estimated mean chronic dietary exposure was above the group-TDI in infants, toddlers and other children, and at high exposure also in adolescents and adults, indicating a potential health concern.

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Deoxynivalenol and its modified forms adopted 01/2017 – published 11/09/17

• Based on estimated mean dietary concentrations in ruminants, poultry, rabbits, dogs and cats, most farmed fish species and horses, adverse effects are not expected.

• At the high dietary concentrations, there is a potential risk for chronic adverse effects in pigs and fish and for acute adverse effects in cats and farmed mink.

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Outlook Fusarium-toxins

• Health based guidance value for fumonisins

and modified forms : EFSA opinion awaited

• Zearalenone , nivalenol and modfied forms: no immediate regulatory follow-up

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Outlook Fusarium-toxins

• Follow-up Recommendation 2013/165/EU on T-2 and HT-2 toxin (lower TDI, exposure > TDI)

• Deoxynivalenol: updated risk assessment from EFSA available : feed and food, acetylated derivatives, DON-3-glucoside: potential health risk (food and feed)

regulatory follow-up feed and food, including analytical aspects comprehensive strategy

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Regulatory outlook other mycotoxins

• Ergot alkaloids

• Ochratoxin A

• Alternaria toxins

• Citrinine

• Enniatins

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CONCLUSIONS

• Huge (regulatory) challenges ahead to continue to ensure a high level of human health protection and this in light of increasing levels in staple crops due to climate change. Modified forms major additional challenge

• Challenges EU but also global • Fusarium toxins (DON, T-2/HT-2, Zearalenone,

fumonisin, …) • Increased prevalence aflatoxins and ochratoxin A

• « Emerging » mycotoxins

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Thank you for your

attention ! 37