# Presentation: 273310

## Development, QA/QC and Status of Study Protocols 

**Development, QA/QC and Status**** of Study Protocols**

**David R. Mattie, PhD, DABT**
**Operational Toxicology Branch**
**AFRL/HEST**
**Perchlorate Stakeholders Forum**
**Sponsored by the IPSC**
**Henderson, NV**
**19-21 May 1998**

## Outline

**Development of Study Protocols **
**QA/QC Procedures**
**Status of Studies**

## Outline

**Development of Study Protocols**** **
**QA/QC Procedures **
**Status of Studies**

## May 1997 Perchlorate Study Protocol Review Meeting

**May 1997 Perchlorate Study Protocol Review Meeting**

**Expert Peer Review Panel:**
**Bring together the experts to determine what toxicology studies need to be conducted**
**Discuss protocols for 90-day and developmental neurotoxicity studies**
**Discuss additional studies needed**
**Prioritize all studies without regard to funding**

## May 1997 Perchlorate Study Protocol Review Meeting

**May 1997 Perchlorate Study Protocol Review Meeting**

**Dr. Joe Brown, California EPA, Office of Environmental Health Hazard Assessment **
**Dr. Dan Caldwell, Toxicologist, Belle Meade, NJ **
**Dr. Dorothy Canter, U.S. EPA, Office of Solid Waste and Emergency Response **
**Dr. Charles Capen, Ohio State University, Department of Veterinary Biomedicine **
**Dr. John Christopher, California EPA, Department of Toxic Substances Control **
**Dr. Marvin Friedman, Cytec Industries, Inc. **

## May 1997 Perchlorate Study Protocol Review Meeting

**May 1997 Perchlorate Study Protocol Review Meeting**

**Mr. Greg Harvey, U.S. Air Force, Wright-Patterson Air Force Base **
**Ms. Annie Jarabek, U.S. EPA, National Center for Environmental Assessment **
**Dr. David Morry, California EPA, Office of Environmental Health Hazard Assessment **
**Dr. Marilyn Underwood, California Department of Health Services **
**Dr. David R. Mattie, AFRL, USAF**

## May 1997 Perchlorate Study Protocol Review Meeting Outcomes

**May 1997 Perchlorate Study Protocol Review Meeting Outcomes**

**Prioritized list of 8 studies **
**Agreement to continue as reviewers to develop and refine study protocols**
**All final protocol information to be made available to the public through use of the world-wide-web on TERA’s site**
**Add reviewers and experts as needed**

## TOXICITY STUDIES Recommended List:

**TOXICITY STUDIES ****Recommended List:**

**1. 90-Day Subchronic Study**
**2. Developmental neurotoxicity Study**
**3. Genotoxicity assays**
**4. Mechanistic**
**5. ADME - Absorption, Distribution,        Metabolism and Elimination**
**6. Developmental Study**
**7. 2-Generation Reproductive Study**
**8. Immunotoxicity**

## Protocol Review Team (as of 12 Jan 98)

**Protocol Review Team (as of 12 Jan 98)**

**Dr. Joe Brown, California EPA, Office of Environmental Health Hazard Assessment (OEHHA)**
**Dr. Dan Caldwell, Toxicologist, Belle Meade, NJ**
**Dr. Dorthy Canter, US EPA (OSWER)**
**Dr. Charles Capen, Ohio State University**
**Dr. John Christopher, California EPA, DTSC**
**Dr. Eric Clegg, US EPA (NCEA)**
**Dr. Kevin Crofton, US EPA National Health and Environmental Effects Research Laboratory (NHEERL)**
**Dr. Vicki Dellarco, US EPA (OW)**

## Protocol Review Team (as of 12 Jan 98)

**Protocol Review Team (as of 12 Jan 98)**

**Dr. Marvin Friedman, Cytec Industries, Inc**
**Mr. Greg Harvey, USAF, Wright Patterson AFB**
**Ms. Annie Jarabek, US EPA (NCEA)**
**Mr. Kevin Mayer, US EPA (Region IX)**
**Dr. David Morry, California EPA (OEHHA)**
**MaryJane Selgrade, US EPA (NHEERL)**
**Dr. Marilyn Underwood, California Department of Health Services**
**Ms. Brenda Pohlmann, Nevada Division of Environmental Protection**

## Status of Study Protocols

**6 out of 8 are in progress**
**Mechanistic and kinetic protocols are still being developed**

## Outline

**Development of Study Protocols **
**QA/QC Procedures**
**Status of Studies**

## QA/QC ProceduresAir Force Sponsored Studies

**QA/QC Procedures****Air Force Sponsored Studies**

**Contract lab delivers draft report to AFRL for review by contract monitor and project director**
**Review includes:**
**QA/QC to confirm study conducted according to protocol requirements**
**Contractual review for form and contract requirements**

## QA/QC Procedures Air Force Sponsored Studies

**QA/QC Procedures ****Air Force Sponsored Studies**

**Comments returned to contract lab**
** ****Editorial, contractual, format**
**Contract lab addresses comments**
**Final draft to AFRL for technical review by Senior Scientist and associates with necessary expertise**
**Contractor addresses final comments**

## QA/QC Procedures Air Force Sponsored Studies

**QA/QC Procedures ****Air Force Sponsored Studies**

**Final report delivered to AFRL**
**Final report delivered to EPA/NCEA within 48 hours**
**Total review time:  45 days**

## QA/QC ProceduresPSG Sponsored Studies

**QA/QC Procedures****PSG Sponsored Studies**

**Contract lab delivers draft report to TERA/PSG for review by contract monitor**
**Review includes:**
**QA/QC to confirm study conducted according to protocol requirements**
**Contractual review for form and contract requirements**
**Editorial, contractual, format**

## QA/QC ProceduresPSG Sponsored Studies

**QA/QC Procedures****PSG Sponsored Studies**

**Draft report undergoes technical review by AFRL**
**Contractor addresses all comments**
**Final report delivered to TERA/PSG**
**Final report delivered to EPA/NCEA within 48 hours**
**Total review time:  32 days**

## QA/QC Procedures Summary

**QA/QC Procedures Summary**

**Standardized review process for all studies**
**Technical review by AF Senior Scientist team**
**Commitment to expedited review process to accommodate assessment schedule**

## Outline

**Development of Study Protocols **
**QA/QC Procedures **
**Status of Studies**

## TOXICITY STUDIES Recommended List:

**TOXICITY STUDIES ****Recommended List:**

**1. 90-Day Subchronic Study**
**2. Developmental neurotoxicity Study**
**3. Genotoxicity assays**
**4. Mechanistic**
**5. ADME - Absorption, Distribution,        Metabolism and Elimination**
**6. Developmental Study**
**7. 2-Generation Reproductive Study**
**8. Immunotoxicity**

## 1. 90-day subchronic study

**1. 90-day subchronic study**

**Guideline study:  OPPTS 870.3100**
**Added additional tests for:**
**Reproductive parameters**
**Mutagenic effects in bone marrow**
**Thyroid hormone levels**
**Contract lab with necessary expertise**
**Air Force collaboration**
**Stability study and dose verification**
**Hormone analysis**

## 2. DevelopmentalNeurotoxicity Study

**2. Developmental****Neurotoxicity Study**

**Guideline study:  OPPTS 870.6300**
**Added thyroid histopathology of pups at day five**
**Contract lab with demonstrated proficiency in this specialized study**
**Air Force collaboration**
**Stability study and dose verification**
**Thyroid histopathology**
**Hormone analysis**

## 3. Genotoxicity Assays

**3. Genotoxicity Assays**

**Tests:**
**Ames Bacterial Mutation Assay (40 CFR 798.5265)**
**Mouse Lymphoma Assay (40 CFR 798.5300)**
**In vivo mouse bone marrow micronucleus test (40 CFR 798.5395)**
**Contract lab with necessary expertise**

## 4. Mechanistic

**4. Mechanistic**

**Literature search for perchlorate discharge test by AFRL**
**Studies proposed:**
**Effects of perchlorate in the developing animal**
** ****Iodine uptake**
**Biomarkers of Perchlorate Neurotoxicity**
**By Neurotoxicity Division of USEPA NHEERL**

## 5. ADME - Absorption, Distribution, Metabolism and Elimination

**5. ADME - Absorption, Distribution, Metabolism and Elimination**

**Study protocols under development**
**Perchorate kinetics**
**Iodine inhibition kinetics **
** ****By Air Force toxicology lab**

## 6. Developmental Study

**6. Developmental Study**

**Guideline study:  OPPTS 870.3700**
**Additional groups added to study**
**Added hormone analysis and thyroid histopathology**
**Contract lab with expertise**

## 7. 2-Generation Reproductive Study

**7. 2-Generation Reproductive Study**

**Guideline study:  OPPTS 870.3800**
**Added analysis of thyroid hormones and histopathology of thyroids at additional timepoints**
**Contract lab with necessary expertise**

## 8. Immunotoxicity

**8. Immunotoxicity**

**Incorporated aspects of guideline study (OPPTS 870.7800) to address concerns for perchlorate**
**Proposed by Air Force Post Doc**
**At Medical University of South Carolina**
**Air Force collaboration**

## TOXICITY STUDIES Recommended List:

**TOXICITY STUDIES ****Recommended List:**

**1. 90-Day Subchronic Study**
**2. Developmental neurotoxicity Study**
**3. Genotoxicity assays**
**4. Mechanistic**
**5. ADME - Absorption, Distribution,        Metabolism and Elimination**
**6. Developmental Study**
**7. 2-Generation Reproductive Study**
**8. Immunotoxicity**

## Report Status

**Report Status**

**Final and interim reports will be sent to NCEA/EPA for assessment and the setting of the revised RfD **

## Report Status

**Report Status**

**Final Reports available for EPA assessment:**
**1. 90-Day (Spring 98)**
**2. Developmental neurotoxicity study (Spring 98)**
**3. Genotoxicity assays (Summer 98)**
**6. Developmental study (Summer 98)**

## Report Status

**Report Status**

**Interim reports available for EPA assessment:**
**5. ADME - Absorption, Distribution, Metabolism and Elimination (Summer 98)**
**7. 2 Generation reproductive (Summer 98)**
**8. Immunotoxicity (Summer 98)**

**David R. Mattie PhD, DABT****Director of R&D Business Development****Operational Toxicology Branch****Air Force Research Laboratory****DSN 785-3423, Ext. 3105****Commercial (937) 255-3423, Ext. 3105**

**E-Mail:**
**MATTIED@FALCON.AL.WPAFB.AF.MIL**
**FAX:**
**513-255-1474**
**WEB SITE:**
**VOYAGER.WPAFB.AF.MIL**

**Bldg 79**
**2856 G Street**
**Wright-Patterson AFB, OH**
**45433-7400**