## SCIENTIFIC ISSUES CONCERNING HEAL TH EFFECTS OF CHLORPYRIFOS INTRODUCTION ANNA L OWIT , PH. D. SENIOR SCIENTIST USEP A, OFFICE OF PESTICIDE

PROGRAMS April 10, 2012 FIFRA SAP

# Introduction

 

## NRC Reports  

### Toxicity Testing in the 21st Century: A Vi sion and a Strategy (2007) :  

### Adverse outcome pathways **2**

 

### Integration across multiple lines of evidence

 

### Disruption of homeostasis leading to adverse outcomes  

### Science & Decisions (2009) :  

### Improved technical analysis (including mode of action)  

### Evaluation of alternative interpretations/approaches  

### Better align risk assessment & risk management  Use of improved problem formulation

# Regulatory Context: Chlorpyrifos
 

### Organophosphate pesticide first registered in 1965  

### In June 2000:  

### The technical registrants entered into an agreement with the Agency to eliminate and **3**



### phase out nearly all uses that result in residential exposures  

### Some mitigation on food (apples & tomatoes)  

### Some mitigation for workers (PPE & engineering controls for some uses)  

### Registration Eligibility Decision (RED) in 2006  

### September 2007 petition from NRDC & P ANNA to revoke all tolerances & cancel registrations

# Recent SAPReviews

**4**  

### 2008: New science on infants, children, & pregnant women from experimental laboratory toxicology & epidemiology studies  

### Evaluated both AChE & non - cholinergic modes of action
 

### 2009: Approach for risk assessment of semi -volatile pesticides  

### http://www.epa.gov/scipoly/sap/meetings/2009/12010 9meeting.html
 

### 2010: Development of the draft “Framework for Incorporating Human Epidemiologic & Incident Data in Health Risk Assessment”  

### http://www.epa.gov/scipoly/sap/meetings/2010/02021 0meeting.html

# Regulatory Context: Chlorpyrifos **5**  

### Registration review opened in March 2009 and is expected to conclude by the end of 2015  http://www.regulations.gov/#!docketDetail;D=EP A- HQOPP -2008 - 0850
 

### July 201 1 Preliminary Risk Assessment  http://www.regulations.gov/#!documentDetail;D=EP A- HQ OPP -2008 - 0850 - 0025  Focus on AChE - inhibiting potential  Most sensitive dose - response data  We ight of the evidence evaluation integrating data from epidemiology, biomonitoring, & experimental toxicology studies to be conducted

# 2008 FIFRA

SAPReview
 

# Preliminary review of scientific literature with focus on infants, children & pregnant women  

### Epidemiology **6**

 

### Age -dependant metabolism  

### Intra -species variability of paraoxonase (PON1)  

### AChE/ChE inhibition data  

### Va rious lifestages  

### Multiple routes, durations  

### In vivo rodent studies evaluating long -term ef fects  

### Biomonitoring studies

# 2008 FIFRA

SAPReview

**7**  

### Key recommendations from SAP

 

### AChE/ChE data remains the most appropriate data for deriving points of departure  Route specific & lifestage -specific AChE/ChE data appropriate  

### In vivo rodent studies on long -term ef fects from early In vivo rodent studies on long term ef fects from early life exposure  Limited dose - response data  Only doses of 1 mg/kg or greater demonstrate significant ef fects on behavior  

### Epidemiology studies:  “Chlorpyrifos likely played a role”  Only measuring biomarkers (3rd trimester maternal, cord blood, meconium) at one point in time  Cannot exclude possibility that the ef fects seen were due to chlorpyrifos in combination with other pesticides**8** 

# Draft Framework for Incorporating Epi

 

## Concepts based on peer- reviewed, robust principles & tools  

## Standard practice in epidemiology, toxicology & risk assessment  

## Consistent with recommendations from  

### NRC 2007: Toxicity T

esting in the 21st Century  

### NRC 2009: Science & Decisions: Advancing Risk Assessment  

## Flexibility to incorporate information from dif ferent sources based on AOPconcept  

## Transparent tool for organizing, reviewing & interpreting complex information

# Draft Framework for Incorporating Epi **9**  

### Mode of Action Framework (Modified Bradford Hill Criteria)  

### Postulated mode of action  Identify sequence of key events on the path to health outcome 

### Experimental support   Concordance of dose - response for key events  Te mporal relationships for key events  

### Biological plausibility & coherence  

### Strength, consistency & specificity  

### Other modes of action  

### Identify uncertainties  

### Conclusion

## Adverse Outcome Pathway

**10**

Chemicals Molecular Ta rget Cellular

Response Ti ssue/

Organ Individual Population Pharmacokinetics **In vitro studies**  **Biomonitoring &**  **Exposure data Structure**  **Activity Relationships** 

**To xicity**  **Pathways In vivo studies** 

**Exposure data Epidemiology**  **To xicity**  **Pathways**
**Human Incidents** 

**Molecular initiating event**  **Key ev ents or predicti**  **ve relationships spanning**  **levels of biological**  **organization** Adverse outcome relevant to risk assessment Greater Toxicological Understanding Greater Risk Relevance**Biologic inputs**  **“Normal” Biological**  **Function Adaptive**  **Re sponses**  **Early cellular**

**changes Exposure**  **Uptak e** **- Delivery**  **to T**

**arget Tissues**  **Pe rturbation**  Cellular re sponse pathway **II. Ad**  **verse Outcome Pathw** **ays –**  **definition and example** 

Adverse Outcomes (e.g., mortality

, Re productive Impairment) **Cell inury, Inability to**  **regulate Re**  **sponses**

Molecular initiating event Pe rturbed cellular

response pathway Adverse outcome relevant to risk assessment Toxicity Pathway

Adverse Outcome Pathway Modify From NRC 2007

# July 201 1 Preliminary Risk Assessment **12**  

## AChE/ChE inhibiting potential of chlorpyrifos  

### Most sensitive dose - response data available  

### Route specific studies (oral, dermal, inhalation)  

### Lifestage sensitivity  

## Process for deriving points of departure  

### In 2008, the Agency performed a comprehensive review of the literature for AChE inhibition.  

### 2012 review has been supplemented with the newest data  

### Benchmark dose approach

# July 201 1 Preliminary Risk Assessment **13**  

### AChE/ChE inhibiting potential of chlorpyrifos  

### Acute, oral: BMDL 10 

### 0.36 mg/kg for RBC AChE inhibition  PND1 1 rat pups provide the most sensitive cholinesterase inhibition data  Consistent with the concept that younger juvenile animals are more sensitive due to immature metabolic systems  

### Chronic, oral: BMDL 10 

### 0.03 mg/kg/day for RBC AChE inhibition  As the metabolic systems mature at or near adult levels, sensitivity disappears  In repeated dosing studies, pups exhibit similar sensitivity to adult rats  Pregnant dams provide the most sensitive data

# April 2012

**14**  

# Key scientific questions 1. 

## Lines of evidence that suggest chlorpyrifos exposure results in long -term neurodevelopmental ef fects from early life exposure 2. 

## Lines of evidence that adverse ef fects may be attributed to doses lower than those which elicit 10% inhibition of AChE, i.e. , the dose levels previously used for regulatory decision making

# April 2012

**15**  

### Compared to 2008, 2012 analysis incorporates new data available and/or provides more in -depth analysis  

### AChE/ChE inhibition  

### Other mechanistic data ---- Evaluation of plausible mechanistic Evaluation of plausible hypotheses on modes of action/adverse outcome pathways (MOA/AOP) leading to neurodevelopmental outcomes  

### Adverse outcomes in rodents, including neurodevelopmental studies on behavior and cognition ef

fects.  

### Epidemiologic studies from three major children’ s health cohorts in the U.S.  

### Biomonitoring and physiologically- based pharmacokinetic/pharmacodynamic (PBPK/PD)

## 2007 NRC T

ox icity T esting in the 21 st 

## Cen tury

Compounds Affected Pathway Dose Response

Analysis for Perturbations Calibrating

in vitro and human Population Based Studies
Exposure Guideline **Mode of Action**  Chemical Characterization Dose Response Assessment

Assess Biological Perturbation Measures of

dose in vitro Perturbations

of Toxicity Pathways in vitro and human Dosimetry
Human Exposure Data Exposure Guideline

Hazard Characterization

Risk Characterization

Exposure Assessment NRC, 2007. Fig 3 - 7 Risk Assessment Components Metabolite(s)**MOA /AOP**  **Critical**

**Duration Pathw** **ay of**  **Exposure Lifestage** 

Infants & Toddlers Direct exposure in food, water, air from volatization/spray drift, AChE inhibition Critical duration: from 1 day to time of metabolic maturation Cholinergic toxicity

MOA: Unknown; Multiple Hypotheses Critical duration: Unknown. Neurodevelopment al outcomes in children (learning & motor deficits)

Mother Direct exposure in

food, water, air from volatization/spray drift, worker (applicator, post AChE inhibition Critical duration: from 1 day up to steady state (approx 2 - 3 weeks) with a max exposure of 9 mos Cholinergic toxicity

Pregnant Female (applicator, post app) max exposure of 9 mos

Fetus Cross - placental exposure AChE inhibition Critical duration: from 1 day up to 9 months Equal or less sensitive to mother; protect for mother’s AChE inhibition
— protect for fetus

MOA: Unknown; Multiple Hypotheses Critical duration: Unknown. Neurodevelopm e ntal outcomes in children (learning & m otor deficits)

# Outline of Presentations

**18**  

## Introduction (Anna Lowit)  

## Adverse Outcome Pathways: Data for Chlorpyrifos at V

arying Levels of Biological Organization (William Mundy) Chlorpyrifos Ef

fects on the Developing Brain:  

## Animal Studies (Virginia Moser)  

## Review of Children’ s Health Epidemiology Cohort Studies (Carol Christensen)  

## Review of Chlorpyrifos Biomonitoring Research and Interpretive Approaches (Aaron Niman )  

## Summary & Next Steps (Anna Lowit)

# Questions? **19**