## 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

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# Pyrethroids : Vital tools for agricultural and residential pest control and for public health protection

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# 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 methyl carbamate 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
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# 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 21 st 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
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# 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?

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## 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

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# 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 ExposureExclusive 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 21 st Century

CAPHRA Focus23 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 PathwayPBPK modeling to predict parent PYY in plasma and brain in juvenile humans Collection of age and species- related parameterization data

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## 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
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# 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.

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## 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

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