Spencer CI, Sham JS.
CV Therapeutics, Inc., 3172 Porter Drive, Palo
Alto, CA 94304. ian.spencer@cvt.com.
Due to increased global use, acute exposures to pyrethroid
insecticides in humans are of clinical concern. Pyrethroids
have a primary mode of action that involves interference with
the inactivation of Na(+) currents (I(Na)) in excitable cells,
which may include cardiac myocytes. To investigate the possible
cardiac toxicity of these agents, we have examined the effects
of a type-1 pyrethroid, tefluthrin,
on isolated rat ventricular myocytes. Under whole-cell current-clamp,
tefluthrin prolonged the mean action potential duration at 90%
repolarization (APD(90)) by 216 +/- 34% in 19 myocytes isolated
from 14 hearts. About one-third of this prolongation was apparently
due to persistent I(Na), with the balance associated with spontaneous
cytosolic Ca(2+) waves, and Na(+)-Ca(2+) exchange. In some action
potentials, tefluthrin also activated early after-depolarizations
(EADs). Using a selected EAD-containing action potential clamp,
we observed that EADs could evoke a Cd(2+)-sensitive membrane
current (I(EAD)) that triggered secondary sarcoplasmic reticulum
(SR) Ca(2+) release. The notion that EADs could stimulate Ca(2+)
current was strengthened by the persistence of I(EAD) in myocytes
exposed to extracellular Li(+) and Sr(2+) ions, used to minimize
Na(+)-Ca(2+) exchange and SR Ca(2+) release, respectively. Tefluthrin
inhibited I(EAD) by approximately 10%. Together,
our results support an arrhythmogenic model whereby tefluthrin
exposure stimulated Na(+) influx, provoking cellular Ca(2+)
overload by reverse Na(+)-Ca(2+) exchange. During Ca(2+) waves,
forward Na(+)-Ca(2+) exchange prolonged the action potential
markedly and kindled EADs by permitting the reactivation of
Ca(2+) current. Similar mechanisms may be involved in
pyrethroid toxicity in vivo, and also in type 3 long QT syndrome,
wherein Na(+) channel mutations prolong I(Na).
PMID: 15980056 [PubMed - in process]
Wolansky MJ, Gennings C,
Crofton KM.
National Research Council,
Research Triangle Park, NC.
The prevalence of pyrethroids in insecticide formulations has
increased in the last decade. A common
mode-of-action has been proposed for pyrethroids based on in
vitro studies, which includes alterations in sodium channel
dynamics in nervous system tissues, consequent disturbance of
membrane polarization, and abnormal discharge in targeted neurons.
The objective of this work was to characterize individual dose-response
curves for in vivo motor function and calculate relative potencies
for eleven commonly used pyrethroids. Acute oral dose-response
functions were determined in adult male Long Evans rats for
five Type I (bifenthrin, S-bioallethrin, permethrin, resmethrin,
tefluthrin), five Type II (beta-cyfluthrin,
lambda-cyhalothrin, cypermethrin, deltamethrin, esfenvalerate)
and one mixed Type I/II (fenpropathrin) pyrethroids [n=8-18
per dose; 6-11 dose levels per chemical, vehicle = corn oil,
at 1 ml/kg]. Motor function was measured using figure-8 mazes.
Animals were tested for one hour during the period of peak effects.
All pyrethroids, regardless of structural class, produced dose-dependent
decreases in motor activity. Relative potencies were calculated
based on the computed ED30s. Deltamethrin, with an ED30 of 2.51
mg/kg, was chosen as the index chemical. Relative potency ratios
ranged from 0.009 (resmethrin) to 2.092 (esfenvalerate).
Additional work with environmentally-based mixtures is needed
to test the hypothesis of dose-additivity of pyrethroids.
PMID: 16221961 [PubMed - as supplied by publisher]
Choi JS, Soderlund DM.
Department of Entomology, New York State Agricultural
Experiment Station, Cornell University, P. O. Box 462, Geneva,
NY 14456, USA.
Pyrethroid insecticides bind to voltage-sensitive sodium channels
and modify their gating kinetics, thereby disrupting nerve function.
This paper describes the action of 11 structurally diverse commercial
pyrethroid insecticides on the rat Na(v)1.8 sodium channel isoform,
the principal carrier of the tetrodotoxin-resistant, pyrethroid-sensitive
sodium current of sensory neurons, expressed in Xenopus laevis
oocytes. All 11 compounds produced characteristic sodium tail
currents following a depolarizing pulse that ranged from rapidly-decaying
monoexponential currents (allethrin, cismethrin and permethrin)
to persistent biexponential currents (cyfluthrin, cyhalothrin,
cypermethrin and deltamethrin). Tail currents for the remaining
compounds (bifenthrin, fenpropathrin, fenvalerate and tefluthrin)
were monoexponential and decayed with kinetics intermediate
between these extremes. Reconstruction of currents carried solely
by the pyrethroid-modified subpopulation of channels revealed
two types of pyrethroid-modified currents. The first type, found
with cismethrin, allethrin, permethrin and
tefluthrin, activated relatively rapidly and inactivated
partially during a 40-ms depolarization. The second type, found
with cypermethrin, cyfluthrin, cyhalothrin, deltamethrin, fenpropathrin
and fenvalerate, activated more slowly and did not detectably
inactivate during a 40-ms depolarization. Only bifenthrin did
not produce modified currents that fit clearly into either of
these categories. In all cases, the rate of activation of modified
channels was strongly correlated with the rate of tail current
decay following repolarization. Modification of Na(v)1.8 sodium
channels by cyfluthrin, cyhalothrin, cypermethrin and deltamethrin
was enhanced 2.3- to 3.4-fold by repetitive stimulation; this
effect appeared to result from the accumulation of persistently
open channels rather than preferential binding to open channel
states. Fenpropathrin was the most effective compound against
Na(v)1.8 sodium channels from the perspective of either resting
or use-dependent modification. When use dependence is taken
into account, cypermethrin, deltamethrin and tefluthrin
approached the effectiveness of fenpropathrin. The selective
expression of Na(v)1.8 sodium channels in nociceptive neurons
suggests that these channels may be important targets for pyrethroids
in the production of paresthesia following dermal exposure.
PMID: 16051293 [PubMed - as supplied by publisher]
Culliford
SJ, Borg JJ, O'Brien MJ, Kozlowski RZ.
Department
of Pharmacology, School of Medical Sciences, University of Bristol,
Bristol and Nuffield Laboratory of Ophthalmology, University of
Oxford, Oxford, UK.
1.
There are no effective ways of screening for potential modulators
of volume-regulated anion channels in their native cell type.
Generally, cell lines are used for this purpose. Using HeLa and
C6 glioma cells, we identified the pyrethroids as a novel class
of compounds that inhibit taurine efflux through volume-regulated
anion transport pathways in these cells. Subsequently, we examined
their effects on volume-regulated anion channels in guinea-pig
ventricular myocytes to determine whether results obtained using
cell lines could be extrapolated to other tissues.
2.
Tetramethrin inhibited taurine efflux in both HeLa and C6 glioma
cells with Ki values of approximately 26 and 16 micro mol/L, respectively.
Bioallethrin and fenpropathrin inhibited volume-sensitive taurine
efflux from C6 glioma cells, but not from HeLa cells. The Ki values
for bioallethrin and fenpropathrin were 70 and 59 micro mol/L,
respectively.
3. Volume-sensitive I- efflux was observed in HeLa cells but not
in C6 glioma cells, suggesting that the taurine efflux pathway
in C6 glioma cells may be different to that of the I- efflux pathway.
Cyfluthrin, tetramethrin, fenpropathrin,
tefluthrin and bioallethrin all significantly
inhibited volume-sensitive I- efflux from HeLa cells at 100 micro
mol/L.
4.
Patch-clamp experiments have shown inhibition of ICl,vol in guinea-pig
ventricular myocytes by fenpropathrin, but not tetramethrin or
cypermethrin, at 100 micro mol/L. This revealed that further differences
exist between ICl,vol in guinea-pig ventricular myocytes and the
anion transport pathways in C6 glioma and HeLa cells.
5. In conclusion,
we have shown that pyrethroids differentially inhibit volume-regulated
anion and taurine efflux in a number of cell types. Because
these compounds have different effects in different cells, it
is likely that: (i) more than one pathway is involved in the
volume-sensitive transport of anions and organic osmolytes;
and (ii) the molecular identities of the channels underlying
anion transport are different. Finally, for the reasons given
above, care should be taken when extrapolating data from one
cell type to another. However, in the absence of an existing
high-throughput screen, taurine efflux still represents a viable
route for the identification of potential modulators of volume-regulated
ion channels.
PMID: 15008955
[PubMed - indexed for MEDLINE]
From Science Direct
Biochemical and Biophysical Research Communications; Volume
292, Issue 1 , 22 March 2002, Pages 208-215
Tefluthrin
Modulates a Novel Anionic Background Conductance (IAB) in Guinea-Pig
Ventricular Myocytes
John J. Borg (a), Jules
C. Hancox (b), C. Ian Spencer (a), and Roland Z. Kozlowskia (2)
a Department of Pharmacology, School of Medical
Sciences, University Walk, University of Bristol, Bristol, BS8
1TD, United Kingdom
b Department of Physiology and Cardiovascular Research Laboratories,
School of Medical Sciences, University Walk, University of Bristol,
Bristol, BS8 1TD, United Kingdom
This report describes for the first time a novel
anionic background current (IAB) identified in guinea-pig isolated
ventricular myocytes. It also shows that IAB has both novel and
differential pharmacology from other (cardiac) chloride currents.
Using the whole-cell patch-clamp technique and external anion
substitution, IAB was found to be outwardly rectifying and highly
permeable to NO-3, with a relative permeability sequence of NO-3
> I- > Cl-. IAB was not blocked by 50 M DIDS, by hypertonic
external solution, or by the nonselective protein kinase inhibitor
H7-DHC. Exposure to the pyrethroid agent
tefluthrin (10 M) increased the current density of IAB significantly
at positive voltages (P < 0.05), but had no significant effect
on other cardiac chloride currents. We conclude that IAB possesses
a distinct pharmacology and does not fall into the three major
classes of cardiac chloride conductance commonly reported.
Water Research
Volume 31, Issue 1 , January 1997,
Pages 75-84
Desorption of tefluthrin insecticide from soil in simulated
rainfall runoff systems—Kinetic studies and modelling
Jun
L. Zhou*(a, b), Steve J. Rowland (a), R. Fauzi, C. Mantoura (b)
and Mike C. G. Lane (c)
a
Department of Environmental Sciences, University of Plymouth,
Plymouth PL4 8AA, U.K.
b Plymouth Marine Laboratory, Prospect Place, The Hoe, Plymouth
PL1 3DH, U.K.
c Jealott's Hill Research Station, Zeneca Agrochemicals, Bracknell,
Berkshire RG12 6EY, U.K.
The sorption and subsequent desorption from soil particles, of
tefluthrin, a widely used soil-active pyrethroid insecticide,
were studied in a simulated rainfall runoff system. Experimentation
was facilitated by use of the 14C-labelled compound. The desorption
of such highly hydrophobic organic compounds from soils has rarely
been reliably determined previously. Sorption results showed that
the partition coefficients (Kp and Koc) were determined with good
precision, although the resultant coefficients were shown to be
underestimates of true adsorption to soil due to non-attainment
of true equilibrium and the presence of colloidal material in
the aqueous phase supernatants analysed. Once the adsorption slurries
were diluted (30 ml of aqueous phase to 3.51) to simulate transport
of soil to a larger water body after heavy rainfall, kinetic studies,
using a centrifugation method, indicated that the soil phase concentration
decreased once more, whilst at the same time a biphasic re-equilibration
process occurred in the aqueous phase. A direct particle counting
method was used to rapidly and reproducibly measure desorption
of 14C-tefluthrin from soil under contrasting experimental conditions.
Initial re-equilibration was shown to be
rapid when soil-to-water ratios were changed significantly, temperature
having a pronounced effect on this desorption. The results are
important for the accurate modelling of tefluthrin behaviour in
the environment.
* Corresponding author. Author to whom correspondence should be
addressed at: Plymouth Marine Laboratory, Prospect Place, The
Hoe, , Plymouth PL1 3DH, , U.K. [Tel. 01752 633457; Fax: 01752
633101].
From Toxline at Toxnet
Source: 23RD ANNUAL MEETING OF THE JAPANESE SOCIETY OF TOXICOLOGICAL
SCIENCES, FUKUOKA, JAPAN, JULY 24-26, 1996. JOURNAL OF TOXICOLOGICAL
SCIENCES; 21 (5). 1996. 373.
ACUTE TOXIC PROFILES OF
PYRETHROID TEFLUTHRIN IN RATS AND MICE
SUZUKI M, TAKAHASHI H
BIOSIS COPYRIGHT: BIOL ABS. RRM MEETING POSTER RAT MOUSE TEFLUTHRIN
TOXICITY PYRETHROID MEPHENESIN ANTIDOTE AGENT PRETREATMENT PENTOBARBITAL
URETHANE HALOTHANE CARDIORESPIRATORY FAILURE TOXICOLOGY HEART
DISEASE RESPIRATORY SYSTEM DISEASE
From Toxline at Toxnet
Source: BRITISH CROP PROTECTION COUNCIL. BRIGHTON CROP PROTECTION
CONFERENCE: PESTS AND DISEASES, 1990, VOLS. 1, 2 AND 3; INTERNATIONAL
CONFERENCE, BRIGHTON, ENGLAND, UK, NOVEMBER 19-22, 1990.
XXII+396P.(VOL. 1); XXII+482P.(VOL. 2); XXII+386P.(VOL. 3) BRITISH
CROP PROTECTION: FARNHAM, ENGLAND, UK. ILLUS. MAPS. PAPER. ISBN
0-948404-46-9(VOL. 1); ISBN 0-948404-47-4(VOL. 2); ISBN 0-948404-48-8(VOL.
3); ISBN 0-948404-45-0(SET).; 0 (0). 1990.
975-980.
THE EFFECTS OF TEFLUTHRIN
ON TERRESTRIAL NON-TARGET ORGANISMS
COULSON JM, BROWN RA, EDWARDS PJ, LEWIS
FJ
BIOSIS COPYRIGHT: BIOL ABS. RRM SOIL MICROBES
EARTHWORMS BENEFICIAL ARTHROPODS BIRDS MAMMALS
From Science Direct
Journal
of Fluorine Chemistry Volume 45, Issue 1 , October 1989,
Page 107
Routes to the insecticides tefluthrin: unusual steps
on the road to the 4-methyl-2,3,5,6-tetrafluorobenzyl unit
D.
J. Milner
Imperial
Chemical Industries
Plc, Fine Chemicals Research Centre, Blackley, Manchester U.K.
The choice of route for manufacture of Tefluthrin is strongly
influenced by the presence of four halogeno substituents on the
aromatic nuclei of its potential precursors.
Direct routes, which would be straightforward for halogen-free
species, are rendered useless, but other, novel processes become
practicable. Thus p-C6C14(No2)2 undergoes cyanodenitration [1],
treatment of p-C6F4(CN)2 with RMgBr affords RC6F4CN [2] and p-C6F4(CH2OH)2
can be readily monobrominated [3].
From Toxline at Toxnet
PESTIC SCI; 25 (4). 1989. 375-390.
THE METABOLISM OF TEFLUTHRIN
IN THE GOAT
HEATH J, LEAHEY JP
BIOSIS COPYRIGHT: BIOL ABS. RRM FORAGE RESIDUE TOXICITY KIDNEY
LIVER LIVESTOCK INDUSTRY
From Toxline at Toxnet
BULL ENVIRON CONTAM TOXICOL; 42 (2). 1989.
172-176.
PERSISTENCE
AND DEGRADATION OF PP993 [Tefluthrin]
PYRETHROID FONOFOS AND CHLORPYRIFOS IN A QUEBEC CANADA CORNFIELD'S
SOIL
ELHAG FA, YULE WN, MARSHALL WD
BIOSIS COPYRIGHT: BIOL ABS. RRM DIABROTICA-BARBERI INSECTICIDE
PESTS CROP INDUSTRY AGRICULTURE
CAS Registry Numbers:
79538-32-2 - Tefluthrin
2921-88-2
944-22-9
From Toxline at Toxnet
J ENVIRON SCI HEALTH PART B PESTIC FOOD CONTAM AGRIC WASTES;
24 (1). 1989. 57-64.
EFFECTS OF SOME EXPERIMENTAL
INSECTICIDES ON MICROBIAL ACTIVITIES IN MINERAL AND ORGANIC SOILS
TU CM
BIOSIS COPYRIGHT: BIOL ABS. RRM BACTERIA FUNGI POPULATION DYNAMICS
NITRIFICATION OXYGEN CONSUMPTION TOXICITY AGRICULTURE CROP INDUSTRY
CAS Registry Numbers:
79538-32-2 - Tefluthrin
54593-83-8 - Chlorethoxyfos
12407-86-2 - trimethacarb
