Evaluation of the Common Mechanism of Action of Pyrethroid Pesticides 

Charge to the Panel 

Pyrethroids are a class of synthetic insecticides which are structurally
based on the pyrethrins, botanical insecticides extracted from
Chrysanthemum cinerariaefolium. Pyrethroid exposure can occur from food,
water, or non-occupational settings. Potential exposure of the general
public to pyrethroid pesticides has increased over the past decade, due
in part to a shift in usage away from the organophosphate and N-methyl
carbamate pesticides.

Pyrethroids are scheduled for re-evaluation under the Office of
Pesticide Program’s registration review program as required under the
Federal Insecticide, Fungicide, Rodenticide Act (FIFRA). Background
information on the program is provided at: http://www.epa.gov/
oppsrrd1/registration review/. The current schedule is available at:
http://www.epa.gov/oppsrrd1/registration_review/schedule.htm. An
explanation of the schedule is at:   HYPERLINK
"http://www.epa.gov/oppsrrd1/registration_review/explanation.htm" 
http://www.epa.gov/oppsrrd1/registration_review/explanation.htm .

With the passage of the FQPA (1996), EPA was required to consider
available information concerning the cumulative effects on human health
resulting from aggregate exposure to multiple chemicals that have a
common mechanism of toxicity. At this time, although some uncertainties
still exist, the Office of Pesticide Programs (OPP) believes that there
is sufficient scientific evidence to demonstrate that the pyrethrins and
synthetic pyrethroids share a common mechanism of action. The Agency’s
analysis and preliminary conclusions are provided in the document
titled: “Draft Science Policy Paper: Common Mechanism Grouping for the
Pyrethrins and Synthetic Pyrethroid Pesticides.” This draft issue
paper was developed by the Health Effects Division (HED) of OPP with
support from EPA’s Office of Research and Development (ORD).
Specifically, OPP is proposing that the naturally occurring pyrethrins
and synthetic pyrethroids form a common mechanism grouping based on 1)
shared structural characteristics; and 2) shared ability to interact
with voltage-gated sodium channels (VGSC), resulting in disruption of
membrane excitability in the nervous system, and ultimately
neurotoxicity characterized by two different toxicity syndromes. As
described in more detail below, OPP is further proposing to subgroup the
pyrethroid CMG into two subgroups representing Type I and II pyrethroids
based on differences in structure, sodium channel perturbations, and
neurobehavioral effects.

The Agency is soliciting comments from the Panel on science issues
related to the common toxicity pathway for pyrethroids, remaining
uncertainties, and the proposal to separate the pyrethroids into two
subgroups (Type I and II) 1. Pending the outcome of the June, 2009 peer
review, the pyrethroid pesticides are expected to be subject to
cumulative risk assessment during the forthcoming registration review. 

1. Common pathway to neurotoxicity: 

a.	OPP is proposing that the naturally occurring and synthetic
pyrethroids share the ability to interact with voltage-gated sodium
channels (VGSC) resulting in disruption of membrane excitability in the
nervous system, and ultimately neurotoxicity. The shared ability
provides the initial and common key event in the pathway to pyrethroid
neurotoxicity and thus provides a basis for forming a common mechanism
group. As described in Section 4.0 of the draft paper, the Agency has
determined that interaction with the VGSC is an initial and common key
event in the pathway to pyrethroid neurotoxicity. 

Unlike the cholinesterase inhibiting organophosphorous and N-methyl
carbamate pesticides, pyrethroids lack a readily measurable in vivo
biomarker for the initial key event (i.e., sodium channel interaction).
Despite this, the scientific evidence correlating pyrethroid-induced
changes in VGSC function with neurotoxicity for purposes of forming a
common mechanism grouping is substantial. Given the availability of
extensive studies on the mechanism of toxicity and toxic effects of
pyrethroids, the lack of an in vivo biomarker does not preclude grouping
via a common mechanism. 

Please comment on the evidence which does and does not support the
Agency’s proposal that sodium channel interaction provides the initial
and common toxic event in the pathway to neurotoxicity for the synthetic
pyrethroids and pyrethrins. As part of your response, please comment on
the uncertainty associated with lack of a readily measurable in vivo
biomarker for sodium channel interaction. 

b. 	The Agency is aware of studies which show that pyrethroids can bind
to other sites such as the calcium, chloride channels and ligand-gated
chloride channels currents. The Agency acknowledges that interaction
between the pyrethroids and these sites may mediate their potency.
However, the data which support interactions with the calcium, chloride,
and ligand-gated chloride channels are not sufficiently robust for
purposes of common mechanism grouping under the FQPA. Therefore, these
pathways do not provide the basis for establishing their binding as a
common key event leading to neurotoxicity. The Agency has concluded that
the evidence on pyrethroid interaction with the calcium and chloride
channels and ligand-gated chloride channels currents is limited and
inconsistent. The Agency has therefore concluded that the evidence does
not support characterizing these interactions as a common key event in
the pathway to neurotoxicity by the pyrethrins and synthetic pyrethroids
(Section 4.2.5). Please comment on the evidence which does and does not
support this determination. 

2. Sodium channel structural heterogeneity: 

Briefly, mammalian sodium channels are comprised of α and β subunits
that exist in multiple isoforms, giving rise to tissue, regional and
lifestage heterogeneity in sodium channel expression (Goldin 2001;
Plummer and Meisler 1999). Mammalian neurons typically express multiple
isoforms of both α and β subunits, making it difficult to determine
the composition of subunits comprising sodium channel currents in native
neurons. Evaluation of specific alpha- and beta-subunits (either alone
or in combination) may be interesting for purposes of evaluating species
differences, potential population pharmacodynamic variability, and
lifestage differences. With respect to the proposal to form a CMG,
however, incomplete knowledge of the role of the α and β subunits in
pyrethroid toxicity does not discount the role of sodium channel
interaction as a key event in pyrethroid toxicity. As described in
Sections 4.2 and 5.0, the Agency has concluded that although there is
heterogeneity among the subunit combinations, the pathway of toxicity
remains the same---namely that sodium channel interaction as a critical
and initial key event in toxicity of pyrethroids. Please comment on the
scientific support for and against the Agency’s conclusions with
respect to the sodium channel structural heterogeneity information. 

3. Sub-grouping the Type I and II pyrethroids: 

a.	The Agency has proposed to separate the pyrethrins and synthetic
pyrethroids into Type I and Type II subgroups as discussed in detail in
Section 5.0 of the Draft Science Policy Paper. Briefly, this proposal is
based on the structural difference in Type I and Type II pyrethroids,
i.e, the absence or presence of an α-cyano group, respectively1. This
structural difference is correlated with length of time the sodium
channel is inactivated (-CN=shorter; +CN=longer) which in turn
corresponds with the 2 distinct toxicity syndromes (-CN=T syndrome;
+CN=CS syndrome). This separation is based on a weight of the evidence
evaluation that considered both historical and newer studies from in
vitro (i.e., intact and transected sodium channels and microelectrode
array) and in vivo studies (i.e., motor activity and functional
observational battery). 

Please comment on the evidence which does and does not support this
determination.

b.  	With respect to assigning the pyrethroids to sub-groups;

The Agency’s preliminary designation for 11 pyrethroids and pyrethrin
is based on a weight of the evidence assessment utilizing three key
lines of evidence:  presence/absence of the alpha-cyano group, effects
on sodium channel kinetics, and in vivo toxicity syndromes.

Five additional pyrethroids are being characterized in a special FOB
study.  For these five the structure is also known.  Thus for
tetramethrin, cyphenothrin, imiprothrin, phenothrin, and prallethrin,
information from two lines of evidence will be available (structure,
toxicity syndrome) for assigning these.

Tralomethrin is metabolized to deltamethrin in vivo and is also
converted in the environment to deltamethrin.  As such, given the
presence of the alpha-cyano group and its relationship to deltamethrin,
the Agency expects tralomethrin to be assigned a designation of Type II.

Cinerin and jasmolin are naturally occurring pyrethrins and do not have
the alpha-cyano group on their structure.  Thus, the Agency expects
cinerin and jasmolin to be assigned a designation of Type I.

Two other pyrethroids, metofluthrin (non-cyano) and fluvalinate (cyano)
have scant databases.  With respect to their toxicity, the Agency is
unaware of detailed characterization of their profiles which would allow
designation.  Moreover, the Agency is unaware of studies describing
their interactions with sodium channels.   The Agency expects
metofluthrin and fluvalinate to be designated as Type I and Type II
compounds, respectively, based on structure.

Please comment on the Agency’s approach to assigning the pyrethroids
to the Type I and Type II sub-groups.  Please include in your comments
consideration for those without special FOB information and for which
structure will be the major determinant in their designation.

Two pyrethroids, fenpropathrin and esfenvalerate, exhibit
characteristics of Type I and Type II compounds (i.e., “mixed”
Type).  In the anticipated cumulative risk assessment, the Agency must
determine the appropriate approach for these two.  In performing
exposure assessment and ultimately in estimating human risk, several
options have been identified—include fenpropathrin and esfenvalerate
in the Type I sub-group, in the Type II subgroup, or in both subgroups.

Please comment on these possible options and any others identified by
the Panel.  

4. Evaluation of Dose-Addition of pyrethroids 

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萏Ũ葞Ũ摧絘°ሀ 4.4, there are a limited number of mixture studies
on pyrethroids. Electrophysiological studies have evaluated mixtures of
two pyrethroids but used excessive doses and/or lack robust study
designs and statistical analyses. As such, these studies preclude
thorough evaluation of dose or effect addition. More recent studies
include Wolansky et al (2009) and Shafer et al (in prep) which evaluate
motor activity in vivo and micro electrode arrays, a newer assay for
mammalian neural networks, in vitro. The Wolansky et al (2009) and
Shafer et al (in prep) studies were specifically designed to test dose
additivity but endpoints measured in both studies lack in their ability
to establish dose additivity specifically at the level of the sodium
channel. Please comment on additional research which could be undertaken
to evaluate the assumption of dose-addition as it relates to the
proposed common mechanism pathway. 

1The Agency acknowledges that at least two pyrethroids (esfenvalerate
and fenpropathrin) appear to exhibit characteristics of both Type I and
Type II. In the coming months and as the Agency moves into developing
the preliminary cumulative hazard and exposure assessments, the Agency
will make a determination as to how to handle these two pyrethroids in
the actual cumulative risk assessment. The public will have
opportunities to comment on this issue in the future. 

