Mind Those Metabolites!
Safety Assessment
Mary Parker

Mind Those Metabolites!

New regulations from the European Food Safety Authority target the dietary risk of agrochemicals

We all know the benefits of eating healthy, which means lots of fruits, vegetables, and maybe some locally raised meat. However, even these healthy options can contain hidden risks.

While the demand for fresh produce has grown, regulatory agencies across the world recognize the importance of protecting our food supplies. Add to that the risk of second-hand consumption of pesticides through meat from livestock raised on agrochemical-treated crops, and the problem grows more complicated.

The European Food Safety Authority (EFSA) and other regulatory agencies have kept pace with research on the effects of agrochemicals in diet by updating their product testing guidance. Testing is now recommended for both the active agrochemical substances and any metabolites, which are the chemical products of the metabolism of agrochemicals. Possible metabolites must be identified and tested separately in order to ensure the safety of crop for both human and animal consumption.

“Plant residues are all the chemicals that are on or in the plant after an agrochemical is applied,” said Marloes Busschers, Senior Regulatory Toxicologist at CRL’s Den Bosch facility. “So it can be the active chemical itself, or the active can be broken down to metabolites, which then can be left in the plant as residues. [The metabolites] of the active can be less, equal or more toxic than the parent chemical itself. Therefore, toxicological information on the metabolites that are left as residues in the plant is needed.”

For regulatory purposes, “residue definitions” are set by the regulatory organization to refer to which agrochemical residues will be chosen for dietary risk assessment and for testing and enforcing Maximum Residue Limits (MRLs).

“The requirements for metabolite identification have become more thorough,” said Simon Chapleo, manager of the crop metabolism group at CRL’s Edinburgh site. “More toxicological testing of metabolites is required, and identification of the metabolites is required to a greater degree. As I see it the big changes are increased requirements for metabolite identification, toxicology of metabolites, inclusion of metabolites in residue analytical methods, and focus on unique human metabolites.”

In July 2016, the EFSA’s Panel on Plant Protection Products and their Residues adopted new guidance on which residues should be included for dietary safety testing, though the new recommendations have not yet been voted on and accepted by the larger organization. Using a stepwise approach to identify all potentially genotoxic metabolites, the panel now recommends testing all relevant metabolites for general toxicity. Each metabolite is tested to generate an inventory of toxicity and dietary exposure information for both humans and livestock. These steps eventually result in estimates for the overall toxicological burden of each metabolite, which can then be used to produce the residue definition. Once the residue definitions are identified, the agrochemical in question can be given a proper risk assessment.

According to Chapleo, scientists at CRL’s Edinburgh site offer facilities for investigating the metabolism of agrochemicals in crops and animals, including livestock and fish, and also using in vitro systems which investigate interspecies differences and indicate any unique human metabolites. They also cover mammalian toxicology testing of metabolites where necessary. In Busschers’ facility, CRL scientists provide regulatory support and toxicological assessment of the identified metabolites.

“This new guidance gives more practical tools on how to assess toxicological relevance,” said Busschers. “It indicates in more detail what kind of information can be used. For example, for the first time for plant protection products (PPPs) the regulations describe how quantitative structure activity relationships (QSARs) can be used. QSAR are a quite common tool to be used to estimate toxicological properties, but it was never accepted for PPP.”

As usual, CRL has been able to adapt and thrive on these new regulations, using them to improve results for client companies. The facilities in Edinburgh and Den Bosch remain prepared for new testing requirements in order to integrate them seamlessly into their routines. Between improved regulations and efficient testing, consumers can feel secure in the safety of their food.