Addressing Potential Age-related 

Sensitivity to Pyrethroids and Pyrethrins

Thomas G. Osimitz, Science Lead

Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA)

EPA – FIFRA Science Advisory Panel

May 19, 2015

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 1
Agenda

• Introduction

– Benefits of Pyrethroids

– CAPHRA Conceptual Framework

• Science Program

– Pharmacodynamics

– Pharmacokinetics

• Read Across

• Conclusions

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 2
CAPHRA Members

AMVAC

BASF

Bayer Animal Health

Bayer CropScience

Botanical Resources of Australia

Central Life Sciences

Cheminova

Du Pont

FMC

LG Life Sciences

MANA Crop Protection 

MGK

SC Johnson

Sumitomo Chemical Company

Syngenta

Valent Companies

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 3
Leadership and Oversight

• Business Committee

– Chair - Monty Eberhart, Bayer CropScience

• Technical Committee

– Chair - Moire Creek, Valent USA

• Technical Lead

– Thomas G. Osimitz, Science Strategies, LLC

• QA/Data Auditing – “Spirit of GLP” 

– Renee Daniels - Perspective Consulting, Inc.

• Administrative

– Susan Little, Jessica Bartlow -Consumer Specialty Products 

Association

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 4
Leadership and Oversight

• Science Working Groups

– Neurotoxicology 

– Physiologically-based Pharmacokinetics

– Member scientists and collaborators

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 5
Pyrethroids: Vital tools for 

agricultural and residential pest 

control and for 

public health protection

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 6
Highly effective products for a wide 

range of use sites*

• Agriculture

– Wide range of pests controlled on many crops – 200 million 

acres treated between 2009 and 2012 (PWG evaluation of GfK

Agrotrak data)

• Public Health

– for control of mosquitos and associated disease vectors such as 

West Nile virus (and of course, malaria)

– for control of ticks (Lyme disease)

– Only organophosphate insecticides offer an alternate chemistry/ 

mode of action

• Residential and Vector Control

– For control of e.g. grubs, chinch bugs in lawns

– Indoor uses for control of cockroaches, ants, termites, spiders, 

bedbugs, fleas etc. 

*All data are for US only Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 7
Pyrethroids in Agriculture: Percent distribution of the 

200 million acres treated in 2009 to 2012

From PWG evaluation of GfK

Agrotrak data

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 8
Pyrethroids in Agriculture: Percent of crop 

acres treated with a pyrethroid

• Top 5 crops:

– Sweet corn (100%)

– Citrus (72%)

– Tree nuts (64%)

– Sunflowers (61%)

– Vegetables, ground fruits (41%)

From PWG evaluation of GfK Agrotrak data

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 9
Pyrethroids protect health and structures 

from multiple urban pests

• Termites cause >$5 billion in damages/yr (homeowner loss $3,000 on 

average; can be $30,000 - $80,000; generally not covered by insurance ) 

• Nearly 35,000 cases of tick-borne Lyme disease reported to CDCP/yr

• Cockroaches and ants transmit bacteria like Salmonella into homes, 

restaurants and food processing facilities

• Allergens from cockroaches one cause of asthma in children (37 percent 

inner city children allergic)

• Fire ants inflict painful venomous stings; serious health issues, including 

death

• Wasps, bees can trigger severe allergic reactions; > 100 deaths/yr 

• Survey on resurgence of bed bugs (NMPA and U. of Kentucky): 95% of pest 

management companies encountered infestations in 2010

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 10
Residential Uses

• With decline in organophosphate and methylcarbamate uses, pyrethroids represent ca. 

60% of residential use pesticides*

• Poses greatest potential exposures to children

*From Kline Survey of PCOs/LCOs sponsored by PWG

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 11
Background

• Neurotoxicology of pyrethroids

• Pyrethroids - 6 developmental neurotoxicity 

studies (870.6300)

• EPA Conclusion (2009-10)

– “It has been determined that, for pyrethroid pesticides, 

DNTs do not provide sensitive endpoints for risk 

assessment or provide sufficient information related to the 

susceptibility of infants and children; furthermore, the 

effects they do show can be found in other guideline 

studies.”

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 12
Background

• EPA Request for proposals

– “For study design/protocols to evaluate potential 

differential sensitivity between juvenile and adult 

rats.”

– “It is unknown whether such sensitivity would 

occur at lower doses more relevant for human 

health risk assessment” 

– 1-day FIFRA SAP meeting in July 2010

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 13
Background – Industry Response

• April 2010 - Pyrethroid/pyrethrins Technical Working 

Group (PPTWG) 

– Took a big picture view to address rats and humans

– Need to embrace state-of-the art approaches consistent 

with the NAS Toxicity Testing in the 21st Century (Tox21)

• May 2010 - PPTWG submits proposal to EPA followed 

by meeting to discuss content and next steps

• June 2010 - Revised PPTWG proposal submitted to 

EPA – transmitted to SAP

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 14
Background

• July 2010 – One day SAP focused on proposal

• October 2010 – SAP report issued

• Since October 2010

– Identification and establishment of collaborators

– Adoption, development, refinement of scientific methods

– Over 12 presentations at national and international 

toxicology meetings

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 15
Collaborators - Pharmacokinetics

• LFR Molecular Sciences, Surrey, UK. 

– Prof. Brian G. Lake

• The University of Georgia, Athens, GA. 

– Drs. Catherine White and James Bruckner

• Medical College of Wisconsin, Milwaukee, WI.*

– Drs. Ron Hines* and Gail McCarver. *Currently Deputy 

Director for Human Health Research with US EPA Office of 

Research and Development.

• The Hamner Institutes for Health Sciences, 

Research Triangle Park, NC. 

– Drs. Harvey Clewell and Miyoung Yoon.

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 16
Collaborators - Pharmacodynamics

• University of Cincinnati, Cincinnati, OH.

– Drs. Charles Voorhees and Michael Williams

• Salve Regina University, Newport, RI. 

– Dr. Steve Symington

• University of Massachusetts, Amherst, MA. 

– Dr. John Clarke

• ChanTest Corporation, Cleveland, OH

– Dr. Glenn Kirsch

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 17
The Question

Are Children More Sensitive than Adults to 

Possible Neurological Effects following 

Pyrethroid Exposure?

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 18
CAPHRA Program Working Hypotheses 

1 - Age-related Sensitivity in rats is due to pharmacokinetic 

(PK), not Pharmacodynamic (PD) differences

Sensitivity is limited to high doses 

2 - PBPK models can be used to predict target tissue levels 

in adults and children 

Do age-related differences exist?

3 - Data can support read-across from a limited number of 

pyrethroids to the entire class

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 19
CAPHRA in the Context of Risk Assessment

• Traditional 

– Risk Assessment in the Federal Government – Managing 

the Process – US National Research Council 1983

• New and forward thinking

– Toxicity Testing in the 21st Century: A Vision and a Strategy 

– US National Research Council 2007

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 20
Risk Assessment

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 21

Hazard Identification

What are the toxic effects of 

interest? Exposure Assessment

How much of the pesticide 

reaches the body? 

How much reaches the tissue 

of interest ? 

Dose-response Assessment

At what doses is the toxicity manifest?

(external vs. internal )

Risk Characterization

Application of safety factors

Calculation of Margins of Exposure
Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 

22

CAPHRA Conceptual Framework

Based on NAS – Toxicology Testing in the 21st Century

CAPHRA Focus
23

Representative pyrethroids to

support read across

Short term responses < 

24 hrs

Measurement of parent PYR 

in plasma and brain in rats

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 

23

Use of Human Tissue

Adverse Outcome 

Pathway
PBPK modeling to 

predict parent PYY 

in plasma and brain

in juvenile humans

Collection of 

age and species-related 

parameterization data

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 24
Targeted Testing – Representative 

Molecules

• Seven Core Pyrethroids

– Based on potential for exposure to children

– Type I 

• Bifenthrin, Permethrin, Pyrethrum, Prallethrin

– Type II 

• Cypermethrin, Deltamethrin

– Mixed 

• Esfenvalerate

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 25
26 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
27 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Science Program – Conceptual 

Framework

28 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Pathway from Exposure to Effect

29 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Factors Potentially Leading to AgeRelated Sensitivity

• Pharmacokinetic

– Absorption, metabolism, distribution, elimination 

(ADME)

• Pharmacodynamic

– Outlined in the Adverse Outcome Pathway (AOP)

• Important considerations

– Species (human vs. rat)

– Age (adult vs. Juvenile)

– Dose (high – saturates metabolism vs. low)

30 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Factors Potentially Leading to Age-Related 

Sensitivity – Pharmacokinetics

31 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Pharmacokinetics – Targeted Testing

32 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
33 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Age-Related Sensitivity – Pharmacokinetics

Criterion for Assessment

• Is the target tissue concentration following an 

environmentally relevant dose of deltamethrin 

similar or lower in a 1-2 year old child 

compared to an adult human? 

– If yes, children are not more sensitive than adults 

due to PK differences

34 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Factors Potentially Leading to Age-Related 

Sensitivity – Pharmacodynamics

The Adverse Outcome Pathway

35 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Pharmacodynamics – Targeted Testing

36 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
37 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Age-Related Sensitivity – Pharmacodynamics

Criteria for Assessment

• Rat In Vivo Studies

– Have we reproduced studies demonstrating agerelated sensitivity based on external dose? 

• If so, what is the basis for this? 

– Are target* tissue concentrations associated with 

NOAELs for neurotoxicity comparable for PND15 

and adult rats? 

• If yes, then age-dependent PD differences are not likely

*brain

38 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Age-Related Sensitivity – Pharmacodynamics

Criterion for Assessment

• Human VSSC Channels

– Are the channel most associated with early postnatal life more sensitive to effects from 

pyrethroids than a channel that becomes 

predominant later in life?

• If not, then age-dependent PD differences are not likely

39 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Age-Related Sensitivity – Pharmacodynamics

Criteria for Assessment

• Neurolemma from Rat Brains

– Do the responses to deltamethrin differ between 

rat neurolemma preparations derived from PND15 

and adult rats?

• If not, then age related pharmacodynamic differences 

are not likely to render juvenile more sensitive than 

adults

40 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)
Preview of Results - Pharmacokinetics

• The developing human PBPK model predicts that 

juvenile humans will have lower plasma and brain 

concentrations of deltamethrin than adults following 

an identical administered dose.

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 41
Preview of Results - Pharmacodynamics

• Predicted brain Cmax levels in PND15 and adult rats at the 

common NOAEL for neurotoxicity (1 mg/kg/day) indicate that 

the brain Cmax would be ~4x higher in PND15 than in adults. 

This suggests that, if anything, the PND15 animals are less 

sensitive to pyrethroids than adults. 

• The isolated human channel most prevalent in juveniles aged 

1-2 years (and most likely, adults) is less sensitive than the 

isoform more prevalent at birth. 

• Rat neurolemma studies conducted with deltamethrin and 

permethrin show no age-related differences in sensitivity 

(relative potency). Both pyrethroids appeared to be more 

efficacious on adult vs, juvenile neurolemma-injected oocytes

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 42
Preview – Conclusions

• Age-related pharmacodynamic differences are unlikely to 

play a role in juvenile sensitivity. Further, there are key 

species-specific pharmacokinetic differences between rats 

and humans making human significantly more adept at 

pyrethroid detoxification.

• Based on existing and new data developed by CAPHRA and 

the application of In Vitro to In Vivo Extrapolation (IVIVE), 

the developing human model predicts that age-related 

pharmacokinetic differences lead to lower (not higher, as 

with the developing rat model) plasma and brain 

concentrations. 

• All things considered, juveniles are not likely to be more 

sensitive to pyrethroid neurotoxicity than adults. 

Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA) 43
Pharmacodynamics

44 Exclusive Property of the Council for the Advancement of 

Pyrethroid Human Risk Assessment, LLC (CAPHRA)