Aquatic Risk Assessments for Pesticide Combination Products in the EU
Friday, February 27, 2015
Today in the European Union, mixture toxicity assessments have become an integral part of the evaluation of pesticides. However, there are several competing or complementary approaches that could be used, so, the outcome of regulatory decisions could prove controversial.
The new EU Regulation (EC) No. 1107/2009 was first published Nov. 24, 2009 and it entered into force Dec. 14th the same year. It has been applicable to all member states since June 14th, 2011. A stipulation of this new directive is the "expected cumulative and synergistic effects," meaning that environmental risk assessments shall include considerations on possible enhanced toxicities of chemical mixtures to non-target organisms.
Initial feedback drawn from experience indicates that a more sophisticated approach may be required to address this requirement.
All plant protection products containing an active ingredient and a number of additives can be considered as chemical mixtures where an enhancement of toxicity is possible. An aggravated toxicity can either be explained by an inherent toxicity of one or several co-formulants or by increasing the bioavailability of the active substance. Interestingly, an analysis by the Umweltbundesamt (UBA 2013) indicates that additives are mostly relevant for less sensitive organisms and, on the other hand, seldom significantly increase the toxicity for the most sensitive organisms. Therefore, mixture toxicity is usually not relevant for solo formulations.
The EFSA Scientific Opinion (2013) provides simplified approaches for considerations on combination toxicity. Accordingly, no mixture toxicity assessments are required if there are no indications of synergistic effects and if the risk quotient for all individual actives (here: Exposure-Toxicity-Ratio: ETRi) is lower than the trigger divided by the number of active substances in the mixture.
Likewise, if mixture toxicity can largely be explained by the toxicity of a single active substance, i.e. one active makes up for at least 90% of the overall toxicity, the risk assessment might be based on this single driver. The information on relative contributions to overall toxicity can be obtained from a ´toxicity per fraction´ assessment as detailed in the EFSA Birds and Mammals guidance document (2009). However, the theoretical contribution to overall toxicity of active substances might change dependent on the ratio of active substances which might deviate from the original ratio in the product.
For a comprehensive aquatic risk assessment, the observed toxicity of the mixture is compared to the predicted toxicity based on active substance data which can be done for any ratio of active substances by calculation of the Model Deviation Ratio (MDR). As the relative contribution to the predicted overall toxicity depends on the actual ratio of active substances, which might change over time and in dependence of entry route, it might not be sufficient only to focus on the product composition. The mode of toxic action of the actives if known should be considered as this information might be supportive of an unlikely synergism or even a potential antagonism. If one active substance drives the overall toxicity (≥ 90%) or if the MDR is within the range of 0.2 to 5 (i.e. it is in agreement with CA), product data are less relevant for risk assessments. In case of the unlikely indication of synergistic effects, co-formulants based on their known toxicity can be integrated in the CA model.
If no synergism is indicated, you may focus on concentration addition (CA). In deviation to the proposal by EFSA, risk assessments based on the available risk quotients may be preferred (based on TERs) from the assessments for individual actives calculating risk indicators (RI = Ʃ (Trigger/TER)), which should be prepared for each active, regardless of its contribution to overall toxicity. Taking into consideration the time course of exposure for each active substance as an RQmix (i.e. Ʃ PECSW/RAC) would be the logical higher tier approach, if a potential risk from combined action is still indicated.
Whole mixture vs. component-based approaches
For some organism groups and especially in regard to acute exposure scenarios, the most straightforward approach is mixture toxicity assessments based on data for the actual product ("whole mixture approach"). In contrast, for indirect exposure routes and within chronic exposure scenarios, however, effect data for the formulated product might become less relevant. Eventually, toxicity estimates are only meaningful for the specific exposure patterns in an effect study.
A reasonable alternative and/or supplement to the mixture toxicity assessments based on product data are assessments based on individual active substances ("component-based approaches"). Unlike in case of the whole mixture approach, assessments based on the combination of data for individual active substances have the advantage that toxicity endpoints are better defined.
Additive mixture toxicity approaches
Concentration Addition (CA) is a simple model for mixture toxicity assessments. Other approaches as Independent Action (IA) or Mixed Models (MM) are less relevant and more demanding in regard to data requirements.
CA assumes that the toxicity of several active substances adds up to an overall toxicity of the mixture dependent on the exposure to concentrations of the individual constituents. This approach is sufficiently protective or even conservative, unless there is a synergistic action of active substances. As synergisms are known to be very rare, CA qualifies as realistic worst-case approach and consequently is widely accepted in a regulatory context.
Concentration Addition (CA) was already implemented for acute mixture toxicity assessments in the EFSA Guidance Document for Birds and Mammals (2009). A comparable approach is now recommended in the EFSA Scientific Opinion on aquatic risk assessments (2013).
A disadvantage of this approach is that the risk quotient (TER or ETR as proposed in the EFSA Opinion) as explained above are only relevant for the ratio of active substances as in the formulated product. In order to account for differing ratios, surrogate endpoints have to be calculated for relative fractions as predicted in the environment.
Eurofins Regulatory AG has developed a software tool (´MixTox SW´) which easily facilitates time-resolved mixture toxicity assessments for combination products over entire FOCUS simulation periods. The assessments are based on FOCUS output files and defined RACs for individual active substances and are offered as service to clients. Tabular and graphical output can rapidly be produced. The tool in addition provides detailed statistics within the simulation period, duration of an event as well as the area under the curve above the trigger. These statistics might be used in combination with other information as for example data on recovery potential, onset of effects or periods where sensitive life stages are not prevalent, all potentially aiding weight-of-evidence argumentations.
More information may be requested from the authors.
Umweltbundesamt. Texte 92/2013: Ecotoxicological combined effects from chemical mixtures. Part 1: Relevance and adequate consideration in environmental risk assessment of plant protection products and biocides
European Food Safety Authority; Guidance Document on Risk Assessment for Birds & Mammals on request from EFSA. EFSA Journal 2009; 7(12): 1438. doi: 10.2903/j.efsa.2009.1438. Available online: www.efsa.europa.eu