Evaluation of Pesticide Mixture Interaction (Synergy) PPDC Meeting, May 3, 2017, Session 4d


Evaluation of Pesticide Mixture Interaction (Synergy)
PPDC Meeting, May 3, 2017, Session 4d

The long-standing ecological risk assessment approach for pesticides to support FIFRA regulatory
decisions has been based on a toxicological evaluation of single active ingredients. EPA's position that
regulatory decisions and risk mitigation efforts focused on the effects and therefore risks of individual
pesticides has been appropriate because:

1.	Toxicological interactions between active ingredients that produce significantly greater
toxicity than expected is a rare occurrence,

2.	Available environmental monitoring information (e.g. U.S. Geological Survey's ambient water
monitoring) indicates that, in a predominant number of cases across the country, the
potential toxic risk of contaminants is dominated by one to a few chemicals, and

3.	By focusing risk-based decisions using the chronic no effects thresholds and extreme low
probability acute thresholds for individual pesticide active ingredients, EPA would avoid much
of the concern for a potential of biologically significant mixtures effects (e.g. the combined
effect of exposure to two pesticides, both at no effect levels, is reasonably a no effect).

The National Research Council, in its review of Office of Pesticide Program's risk assessment methods
for endangered species effects determinations, supported the general opinion that synergistic
interactions between pesticides are rare (NRC 20131). The Council suggested that the Agency
consider pesticide active ingredient interactions when the best available scientific evidence supports
the quantitative evaluation.

Since 2015, the Agency has discovered a number of cases where pesticide producers have been
granted patents by the U.S. Patent and Trade Office (USPTO) for claims that selected mixtures of
pesticides produce toxicological effects in excess of expected additive effects (i.e., claims of
synergistic interactions). These claims are made primarily for effects seen in pest species (i.e.,
enhanced herbicidal, fungicidal, or insecticidal effects). However, under the Agency's risk assessment
approach using effects testing of surrogate plants and animals to represent flora and fauna in the
field, it is appropriate to consider the USPTO data with pest species to determine if the observations
are applicable to the Agency's pesticide ecological risk assessments. EPA has chosen to explore the
development of a process to review and, if necessary, account for these pesticide interaction claims
in ecological risk assessments. For the available patent data, EPA is addressing the suggestion by the
National Research Council1, that pesticide interactions be considered to the extent supported by
scientific evidence.

EPA has elected to begin the pesticide interaction evaluation with the USPTO patents for a number of
reasons:

1.	There are a large number of United States patents with claims of interactions;

2.	The supporting data are readily available and efficiently accessed;

1 National Research Council, 2013, Assessing Risks to Endangered and Threatened Species from Pesticides,
Washington, IDC: The National Academies Press. doii:https:://doi„org/10„17226/11

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3.	Pesticide producers have direct access to much of the data and underlying information;

4.	The USPTO has established which data sets, in their evaluation process, support interaction
claims;

5.	The extent of mixtures, conditions of testing, effects observed and organisms evaluated can
be readily determined in the majority of patent claims; and

6.	Many of the taxa tested and the effects reported are applicable to the ecological risk
assessment process.

The goal of the evaluation process for patent claims of pesticide interaction is to determine:

1.	If the available evidence would impact the risk conclusions and risk mitigation decisions for a
given pesticide, and if "yes"

2.	The methods the Agency may use to qualitatively or quantitatively incorporate this
information into the regulatory decision.

To support this effort, EPA has developed a process for rapidly searching and screening USPTO data
for interaction claims. The process is applicable to new chemicals proposed for registration as well as
pesticide registrations for proposed application to genetically modified crops. It assigns the searching
and sorting responsibilities to the pesticide producer as part of the submission package. The process:

1.	Outlines the suggested patent search use of available databases and a set of useful search
terms;

2.	Describes a series of criteria used to screen patents for the relevance to the EPA ecological
risk assessment;

3.	Presents a series of criteria for reporting data to EPA from patents meeting the relevance
criteria above; and

4.	Lists a set of information fields for the data reported to EPA. (EPA anticipates development
of a reporting template in the future)

EPA reviews and evaluates the reported information to determine:

1.	If the available evidence would impact the risk conclusions and risk mitigation decisions
for the pesticide registration; and

2.	The qualitative or quantitative process for incorporating the information in the supporting
risk assessment.

To date, EPA has completed, or is nearing completion, eight cases of patent searches and associated
data evaluation. The majority of patents discovered during the patent search did not contain
relevant information. The reasons for exclusion from further consideration included:

1.	Key words were identified in the text but no specific claims of interactions were actually
made;

2.	No effects test data were presented to support the patent claims;

3.	Tests supporting the patent were not conducted using the active ingredients under
regulatory consideration;

4.	Tests supporting the patent involved organisms for which EPA does not conduct ecological
risk assessments (e.g., fungi); or

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5. Tests supporting the patent involved effects information not relevant to the effects
considered in the ecological risk assessment (e.g., leaf damage from phytophagous
insects).

In two registration cases, available patent information was being used to evaluate pesticide
interaction for specific proposed formulations comprised of multiple active ingredients. The patents
in these two cases were relevant to the ecological risk assessment (tested taxa and endpoints were
relevant) and the tests involved mixtures of the pesticides directly applicable to proposed registration
of a mixture product. In both cases, the EPA and the pesticide producer determined that the most
direct and efficient way to address the observed effects was testing of the end-product formulations
using existing guideline effects studies and then directly use the effects information from those
studies in the ecological risk assessment.

In all the other cases, the submitted patent data has been insufficient to demonstrate a need for
further consideration of interactions in the ecological risk assessment because:

1.	The data did not support a statistical evaluation of any observed effects;

2.	The data from mixtures were statistically indistinct from the expected variability of
individually tested pesticides; and/or

3.	The effects interactions of mixtures, when qualitatively or quantitatively considered, would
not be expected to alter existing ecological risk conclusions or risk mitigation efforts.

EPA will continue to evaluate specific cases of patent claims. It is expected that the current process
will evolve as the Agency gains more experience with the data sets, their limitations, and the value of
the reviewed information in the context of regulatory decision making.

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