Pyrethrins and Developmental

Neurotoxicity

Meeting Between the Pyrethrins

Joint Venture (PJV) and the EPA

July 24, 2008

Slides from the PJV 1
Science Strategies & PJV

Agenda

 Thank you...

 Introduction

Slides from the PJV 2
Science Strategies & PJV

The Bases for Requiring a DNT

 Are there sufficient “triggers” in the current

database that suggest the potential for

developmental neurotoxicity?

 Are there reports in public literature that raise

the concern for developmental neurotoxicity

of pyrethrins?

 Will the new data be likely to alter the

regulation of pyrethrins in any significant

way?

Slides from the PJV 3
Science Strategies & PJV

Science Triggers? Is there...

 Evidence of significant neuropathological

effects observed in toxicology studies on

adult animals;

 Clear indication of behavioral alteration in

studies at doses close to or less than those

producing clear systemic toxicity, and/or;

 Indication from developmental or

reproduction/fertility studies that suggests

there may be increased sensitivity in prenatal

or juvenile animals.

Slides from the PJV 4
Science Strategies & PJV

Science Triggers? Pyrethrins

“The developmental neurotoxicity study

is an upper tier study which would only

be required if effects observed (e.g.

lesions of the CNS) in the acute and 90-

day neurotoxicity studies indicate

concerns for potential increased

sensitivity of the infant or neonate.”

- HED Revised Risk Assessment for Pyrethrins

Slides from the PJV 5
Science Strategies & PJV

Science Triggers? Pyrethrins

“Based on the finding of neuropathy in

the acute neurotoxicity study in rats, a

developmental neurotoxicity study is

required (for pyrethrins).”

- HED Revised Risk Assessment for Pyrethrins

Slides from the PJV 6
Science Strategies & PJV

Evidence of significant neuropathological

effects observed in toxicology studies on

adult animals? No

 Reread of slides from original neurotoxicity

study

 Confirmed original finding of mild-moderate

 peripheral axonopathy in only 3/10 high dose

females - 200 mg/kg)

 Sporadic degeneration in other groups as well

(including controls)

 No axonopathy in central fiber tracts, nerve

somata, nor neuronopathy or myelinopathy

Slides from the PJV 7
Science Strategies & PJV

Evidence of significant neuropathological

effects observed in toxicology studies on

adult animals? No

 Reread, continued

 Myelin vacuolation - unequivocally

artifactual

 No central nervous system (CNS) effects

Slides from the PJV 8
Science Strategies & PJV

Indications of Behavioral Alterations?

No

 Functional observational battery (FOB) and

motor activity (MA) data

 Correlation of 2 high-dose female rats showing

behavioral changes with the more pronounced

axonopathy (still only mild-to-moderate)

 Only after 1st post dosing interval (3-4 hr)

 Clinical observations - animals prostrate - inability

to perform FOB to be expected

 Animals completely recovered - no other effects

Slides from the PJV 9
Science Strategies & PJV

Indications from Developmental or

Reproductive/Fertility Studies? No

 No evidence of persistent gross or

behavioral effects on successive

generations after in utero exposure

even at the highest dose tested

Slides from the PJV 10
Science Strategies & PJV

Science Triggers? No

Slides from the PJV 11
Science Strategies & PJV

Published Reports Relevant to

the DNT Requirement? Yes

 Extensive review by Shafer et al, (2005)

 More research is needed

 No clear and consistent pattern of post-natal

effects from prenatal/perinatal exposure to

compounds that target VSSCs

 Data suggest that Type II pyrethroids (like

deltamethrin) are significantly more lethal in

young animals that adults (Sheets et al. 1994)

Slides from the PJV 12
Science Strategies & PJV

Published Reports Relevant to

the DNT Requirement? Yes

 Two Type I pyrethroids (cismethrin and

permethrin; pyrethrins are also Type I) did not

have any age-dependent toxicity (Sheets

(2000)

 No age-dependent differences in the

behavioral toxicity of either Type I or Type II

pyrethroids at doses below those causing

overt toxicity (Sheets (2000)

Slides from the PJV 13
Science Strategies & PJV

Likely Importance of the DNT to

Regulation of Pyrethrins? Not likely

 NOAEL for neuropathology -

 63 mg/kg females, 125 mg/kg males

 RED Endpoints for risk assessments

 4.3-20 mg/kg - EPA Assessment assumes NOAEL

from DNT to be 6.3 mg/kg/day

 Work on other pyrethroids

 Unlikely that a DNT study will provide any

revelations about increased susceptibility or

persistent effects on nervous system

development

Slides from the PJV 14
Science Strategies & PJV

The Bases for Requiring a DNT

 Are there sufficient “triggers” in the current database

that suggest the potential for developmental

neurotoxicity? No.

 Are there reports in public literature that raise the

concern for developmental neurotoxicity of

pyrethrins? No.

 Will the new data be likely to alter the regulation of

pyrethrins in any significant way? Not likely.

Slides from the PJV 15
Science Strategies & PJV

Conclusion

 Threshold for the DNT requirement has

not been met for pyrethrins and that

such a requirement should be waived.

Slides from the PJV 16
Science Strategies & PJV

Discussion

Slides from the PJV 17