WELCOME TO THE ANNUAL ICCVAM
PUBLIC FORUM.
I'M ANNA LOWIT WITH JOHN GORDON,
THE CHAIRS OF THE INTERAINGE SHY
COORDINATING COMMITTEE FOR
VALIDATION OF ALTERNATIVE
METHODS.
IT'S ACTUALLY -- THERE ARE A FEW
OF US IN THE ROOM, NICE TO SEE
ACTUAL FACES, GOOD TO HAVE SO
MANY PEOPLE ONLINE LISTENING.
IT'S GOING TO BE A FUN TWO DAYS.
, ONE OF MY FAVORITE ICCVAM
EVENTS ON THE CALENDAR TO LISTEN
TO ALL OF OUR COLLEAGUES AND THE
COOL THINGS THEY HAVE BEEN
DOING.
I ALWAYS COME OUT OF THE MEETING
INVIGORATED TO DO SOMETHING NEW
AND COOL, SO IT'S GOING TO BE A
FUN DAY AND A HALF, AND WITH
THAT GLAD YOU'RE HERE TO JOIN US
AND DAVE ALLEN IS GOING TO HELP,
WE'LL GO AROUND THE ROOM
PHYSICALLY AND HE WILL BE
CALLING OUT THE NAMES ONLINE.
>> DAVE ALLEN, SUPPORTING
NICEATM.
>> NICOLE KLEINSTREUER.
>> JOHN GORDON, CO-CHAIR OF
ICCVAM.
>> MONIQUE PERRON, EPA.
>> SUZANNE FITZPATRICK, FDA.
>> JESSICA LEET, RESEARCH
TOXICOLOGIST U.S.GS AND DOI.
>> (INDISCERNIBLE) PHYSICIAN
COMMITTEE FOR RESPONSIBLE
MEDICINE.
>> ANDERSON, COMMITTEE FOR
RESPONSIBLE MEDICINE.
>> EMILY BRANDON, TOX
DOLLINGIST.
>> SCIENCE CONSORTIUM
DR. JOHN GORDON WILL TALK ABOUT
U.S. CONSUMER PRODUCT COMMISSION
PROGRESS ON NAMs.
>> ALL RIGHT.
WELL, THANK YOU FOR COMING.
FOR THOSE ON THE WEBCAST, THANK
YOU AS WELL.
I AGREE WITH ANNA, THIS IS A
FANTASTIC DAY.
I'M GLAD I'M GOING TO GO FIRST
AND SIT BACK THE REST OF THE
TALKS AND LISTEN THE REST OF THE
TIME HERE.
I THANK DAVE ALLEN FOR BAILING
ME OUT OF PARKING JAIL THIS
MORNING.
WE HAD A SNAFU WITH THE ENTRY
LIST, DAVE HAD TO LET US IN.
ANYWAY, I WANT TO TALK ABOUT
WHAT WE'RE WORKING ON AT THE
CPSC, AND JUST WHAT WE'VE BEEN
WORKING ON THERE.
LET ME FIGURE OUT HOW TO MAKE
THIS WORK.
I DID, ALL RIGHT, GREAT.
TWO THINGS, SOME OF YOU HAVE
SEEN THE STUFF ON THE GUIDANCE
BEFORE, IT WILL BE DIFFERENT.
ALSO THE WEB PAGE UPDATE, THIS
IS GOING TO BE A NICE SURPRISE
BECAUSE WE DO HAVE A LIVE UPDATE
FOR THE SHOW.
ALL RIGHT.
BACKGROUND.
SUBSTANCE ACT REQUIRES
CAUTIONARY LABELING ON CONSUMER
PRODUCTS FOR POTENTIAL HAZARDS
TO CONSUMERS BUT DOES NOT
REQUIRE ANY SPECIFIC TESTING
BEING DONE WHICH MEANS YOU CAN
USE NAMs IN THESE SITUATIONS.
YOU DON'T HAVE TO USE IT.
FOR TOXICITY TESTING FOR
IRRITATION YOU DON'T NEED TO USE
THE ANIMAL TEST.
YOU CAN USE NAMs.
IN FACT, THE 2012 CPSC POLICY
STRONGLY ENCOURAGES USE OF
ALTERNATIVE METHODS TO ALLEVIATE
PAIN AND SUFFERING WHICH WE'RE
ALL AWARE OF.
POLICY ENCOURAGES EXISTING DATA,
HUMAN DATA, PRIOR ANIMAL
TESTING, EXPERT JUDGMENT,
NAMs, AND USING NEW ANIMAL
TESTING AS A LAST RESORT.
AND THIS IS THE TITLE FOR THE
GUIDANCE DOCUMENT.
IT'S FOR THE METHODS, AND FOR
THE DATA ASSOCIATED WITH THOSE
METHODS.
GUIDING PRINCIPLES OF THE
METHODS, WE WANT TO ENSURE THE
METHOD IS PROPERLY REVIEWED FOR
ACCURACY AND ROBUSTNESS.
SO WE HAVE CONFIDENCE IN THE
METHOD WE'RE BRINGING FORWARD,
SHOWING THE DATA PERTAINS TO THE
CPSC DOMAIN OF WHAT WE ACTUALLY
REGULATE.
SO IF SOMETHING'S BEEN ONLY
TESTED ON PESTICIDES MAY OR MAY
NOT BE EFFICIENTLY REVIEWED FOR
CPSC
CPSC SINCE WE DON'T LOOK AT
PESTICIDES.
WE LOOK AT COMPLEX MIXTURES AND
FINISHED PRODUCTS, WE DON'T
REGULATE INDIVIDUAL CHEMICALS.
THAT'S AN FDA, EPA, AND OTHER
AGENCIES.
GUIDANCE OVERVIEW, SIMILAR TO
THE VALIDATION WORK GUIDANCE,
WHICH WE'LL HEAR ABOUT LATER,
THE DOCUMENT IS NOT MANDATORY.
EVERYTHING WILL BE EVALUATED ON
CASE-BY-CASE BASIS REQUIRING
EXPERT PROFESSIONAL JUDGMENT.
IT'S NOT A CHECKLIST OR
BLUEPRINT FOR JUST OBTAINING
APPROVAL.
AND IF ACCEPTED, THE SUBMITTED
METHOD WILL BE VALID AND
ACCEPTABLE FOR A SPECIFIC
PURPOSE.
CONTAINS AN OPTIONAL NOMINATION
FORM SO YOU CAN NOMINATE THE
METHOD, ORGANIZE THE INFORMATION
FOR US SPEEDING UP THE PROCESS.
IF YOU WANT TO NOMINATE A METHOD
FOR CPSC TO REVIEW, PLEASE DO
SO.
THAT'S WHAT THIS GUIDANCE
DOCUMENT IS ALL ABOUT, SO
DEVELOPERS CAN NOMINATE THEIR
METHODS, GET THEM TO US, AND
SPEED THE PROCESS ALONG AND HELP
OUT WITH USING NAMs FOR CPSC
TO DO TOXICOLOGICAL EVALUATIONS.
THE GUIDANCE DOCUMENT ITSELF,
THE FR NOTICE WAS PUBLISHED IN
MARCH OF 2021, FIVE PUBLIC
COMMENTS, THANK YOU, THEY WERE
VERY HELPFUL.
FINAL VERSION WAS APPROVED IN
APRIL OF 2022, UNANIMOUS VOTE OF
COMMISSION, AND THEY WERE HAPPY
TO HAVE THIS OUT, AND FINAL
VERSION WAS PUBLISHED IN APRIL
OF 2022.
AND WE HAVE IT ON OUR WEBSITE
BUT WE ALSO RECOGNIZE
REGULATIONS.GOV IS GENERALLY THE
REPOSITORY FOR SUCH DOCUMENTS,
SO IT'S GOOD TO BOOKMARK THAT IF
YOU'RE INTERESTED IN HAVING THE
DOCUMENT.
AND NOW WE HAVE A WEB PAGE
UPDATE THAT I WOULD LIKE TO SHOW YOU
WE'VE REDESIGNED THE WEB PAGE,
FIVE SECTIONS, WE'LL MOVE THE
MICROPHONE.
FIRST SECTION IS ON THE ANIMAL
TESTING POLICY, THE SAME AS
NORMAL ANIMAL TESTING POLICY
WE'VE ALWAYS HAD.
THE NEXT CLICKABLE SECTION IS
THE GUIDANCE DOCUMENT ITSELF.
IT'S WORKING NOW?
GREAT.
NOW YOU CAN SEE WHAT I'VE GOT
HERE.
THE SECOND SECTION, IF YOU COULD
PULL DOWN MENU, GUIDANCE
DOCUMENT ITSELF IS IN THERE, A
SUMMARY OF THE GUIDANCE
DOCUMENT, AND THE NEXT SECTION
DEFINITIONS HAS SOME REALLY GOOD
LINKS TO THE FHSA, CHRONIC
HAZARD GUIDELINE, SEVERAL
DEFINITIONS WITHIN THE FHSA
ITSELF ON TOXICITY.
THE NEXT SECTION, CPSC-APPROVED
METHODS, HARD TO READ, THAT
CONTAINS THE LIST OF ALL THE
METHODS THAT CPSC REVIEWED, AND
IN THAT SECTION YOU CAN SEE A
BRIEF DESCRIPTION OF THE METHOD,
ON THE NEXT SLIDE.
YEAH, THIS SECTION HERE HAS A
TITLE OF COURSE, CONTACT
INFORMATION, BRIEF DESCRIPTION,
THE STAFF RECOMMENDATIONS ON USE
FOR THIS METHOD, AND THE
DOCUMENT ITSELF IS CLICKABLE.
YOU CAN DOWNLOAD A PDF OF
BRIEFING PACKAGES ON EACH OF THE
METHODS, SO YOU CAN SEE WHAT
CPSC HAS DONE AND WHAT WE
RECOMMEND AND FIND THESE IN THE
FOIA PAGE OF OUR CPSC WEBSITE
WHICH I WAS GOING TO SHOW YOU AS
WELL BUT WE CAN'T GET THERE.
SO ESSENTIALLY WHAT WE HAVE HERE
IS THE FREQUENTLY ASKED
QUESTIONS, GOOD IF YOU HAVE
QUESTIONS, ALSO IF YOU NEWED TO
GET HOLD OF US, SIMPLY THE WEB
ADDRESS UP HERE AT THE TOP
ALTERNATIVE METHODS, DIRECTLY TO
MYSELF AND OTHER PEOPLE IN THE
HEALTH SCIENCES DEPARTMENT.
THIS EFFORT IS GOOD FOR FEDERAL
AGENCIES TO TAKE OVER AND MAKE
SURE WE HAVE CLARITY.
WE DO NEED CONFIDENCE, IT'S VERY
IMPORTANT TO HAVE CONFIDENCE IN
THESE METHODS AND IMPORTANT TO
BE CLEAR HOW WE'RE GOING TO USE
THESE METHODS AND HOW THE PUBLIC
CAN USE THESE METHODS WITH
FEDERAL AGENCIES.
HAVE CONFIDENCE AND CLARITY,
DREAMILY IMPORTANT.
WE CAN'T EXPECT THE DEVELOPERS
OR TESTING LABS TO PUT TWO AND
TWO TOGETHER AND SAY, OH, THIS
IS HOW THIS IS DONE.
WE NEED TO BE VERY CLEAR ABOUT
WHAT WE'RE -- HOW WE'RE GOING TO
USE METHODS AND WHAT WE USE THEM
FOR.
DOESN'T MEAN THEY CAN'T BE USED
FOR OTHER THINGS BUT WHAT WE DO
KNOW AND ESTABLISH WE NEED TO BE
CLEAR ON.
I THINK NICOLE AND SOME OTHERS
ARE WORKING ON A PLAN TO LOOK AT
TOXICITY ENDPOINT, MARRYING THAT
WITH THE NAM AND PATHWAY AND KEY
EVENTS, OECD METHODS THAT MAP TO
THAT AND I THINK THAT'S GOING TO
BE VERY GOOD AT ADDING CLARITY
TO HOW YOU GO ABOUT DOING
TOXICITY, SOMETHING AS SIMPLE AS
A FLOWCHART SHOWING OECD METHOD
123 TO THIS EVENT OR PATHWAY,
AND GOES TO THIS TOXICITY
ENDPOINT.
VERY GOOD TO HAVE THOSE FOR
CLARITY.
WE CAN'T EXPECT THE REGULATORY
AFFAIRS OFFICIALS OR WHOEVER IS
MAKING THE DECISIONS TO DO THIS
WORK.
THEY HAVE THE CLEAR PATH ON HOW
THEY KNOW HOW TO DO STUFF, WITH
THEIR ANIMAL STUDIES.
THEY AREN'T GOING TO GO ON THIS
OTHER PATH UNLESS WE MAKE IT
VERY CLEAR TO THEM HOW TO USE
THESE METHODS IN THEIR
REGULATORY ACCEPTANCE.
SO I THINK THAT'S IT FOR ME.
[APPLAUSE]
THANK YOU.
WHO IS OUR NEXT SPEAKER?
OKAY.
>> SO WE DO HAVE A MINUTE FOR A
BRIEF CLARIFYING QUESTION IN THE
ROOM.
OR ONLINE.
>> GREAT PRESENTATION, JOHN.
APPRECIATE IT.
CPSC OBVIOUSLY COVERS PRODUCT
CATEGORIES, FORMULATIONS,
COMPLEX MATERIALS, AND CLEARLY
ALL THE VALIDATED TEST METHODS
HAVE GONE TO VALIDATION OF
INDIVIDUAL DISCRETE CHEMICALS
AND INGREDIENTS.
SO A LOT OF LITERATURE TALKS
ABOUT LIMITATIONS, APPLICATIONS
FOR CHEMICAL INGREDIENTS, AND
SOME LIMITATIONS ARE NOT
RELEVANT TO TESTING COMPLEX
FORMULATIONS.
MY QUESTION WOULD BE WITH THE
GUIDANCE AND GUIDANCE DOCUMENT
HERE, FOCUSING ON VALIDATED
METHODS USING INGREDIENTS ALONE,
IS THERE A MECHANISM TO UPDATE
THE GUIDANCE TO INTERPRET DATA
FROM TEST METHODS ON COMPLEX
FORMULATIONS RECOGNIZING THERE'S
COMPLEX FORMULATIONS TESTED BY
INDUSTRY IN A NON-REGULATORY
SETTING FOR MANY YEARS AND HAVE
BEEN ABLE TO WIDEN THE SCOPE,
WHICH IS LIMITED BY LIMITATIONS
OF INGREDIENTS TESTING
APPROACHES.
>> OKAY.
YEAH, WE DEFINITELY LIKE THE
IDEA OF TEST ED ON COMPLEX
MATERIALS BUT MOST HAVE NOT BEEN
OR CANNOT BE SO WE DO LOOK AT
INDIVIDUAL COMPONENTS OF A
COMPLEX MIXTURE DURING TOXICITY
ASSESSMENT FOR COMPLEX MIXTURES.
WE ALSO LOOK AT EXPOSURE
SCENARIOS AS WELL, SOMETHING
THAT THE PAINT ON THE INSIDE OF
A MARBLE MAY BE TOXIC BUT NOT
ACCESSIBLE.
>> I MIGHT ADD BRIEFLY A LOT OF
END USERS, CROs HAVE QUITE A
BUILT OF EXPERIENCE IN TESTING
COMPLEX FORMULATIONS WITH THESE
NAMs, WHICH OFFER THE
OPPORTUNITY TO SHARE IN OUR
KNOWLEDGE BASE AND HELP
UNDERSTAND HOW THESE METHODS CAN
BE USED OUTSIDE THE SCOPE OF
SIMPLY INGREDIENT TESTING, FROM
OUR ORGANIZATION AS WELL.
>> ANY ABILITY TO HELP US
UNDERSTAND HOW TO USE NAMs
BETTER AND MAKE IT CLEARER FOR
FOLKS, THERE'S ANOTHER C,
CLARITY, WE NEED TO SPEND TIME
ON.
COOPERATING BETWEEN BUSINESSES
OUT THERE WHO HAVE A GOOD IDEA
WHAT WE ACTUALLY NEED IS A
REALLY GOOD IDEA.
AND SETTING UP WEBINAR OR
WHATEVER WE NEED TO DO TO
PROVIDE THAT INFORMATION WOULD
BE FANTASTIC, AND ALLOWING CPSC
SPECIFICALLY TO UNDERSTAND
MIXTURES.
THE FDA AND EPA OBVIOUSLY HAVE
NEED FOR THAT TOO.
FDA WITH THEIR MEDICAL DEVICES,
ON A PRACTICAL LEVEL, MEDICAL
DEVICES AND CONSUMER PRODUCTS
ARE VERY SIMILAR.
THEY ARE METAL, PLASTIC, RUBBER.
THEY NEED TO BE TESTED.
SO FROM THAT POINT OF VIEW, I
THINK FDA AND CPSC WOULD BENEFIT
GREATLY FROM KNOWLEDGE FROM ANY
GROUP ON MIXTURES TESTING THAT
WE COULD GET ANY INFORMATION
WOULD BE GREAT.
>> ONE QUESTION IF THERE'S
TIME.
>> VERY QUICKLY.
>> OECD TEST GUIDELINES ARE NOT
AUTOMATICALLY ADDED TO THE LIST,
FOR SKIN SENSITIZATION I SEE
NNLA BUT NOT THE NEWER IN VITRO
TESTING APPROACHES.
>> YEAH, ANY METHOD IS ALLOWED
TO BE USED.
WHAT WE DO IS REVIEW THEM TO
MAKE THEM EASIER AND MORE
OBVIOUS, MORE CLARITY, BECAUSE
IF I DON'T REVIEW IT OR SOMEBODY
AT CPSC DOESN'T REVIEW THIS
METHOD I DOUBT ANYBODY'S GOING
TO USE IT BECAUSE THEY ARE NOT
GOING TO KNOW, OKAY, THIS NO
METHOD, HOW IS CPSC GOING TO
ACCEPT THIS?
I DON'T KNOW SO I'M NOT GOING TO
USE IT.
THAT'S WHY I LIKE REVIEWING
THEM, PUTTING THEM ON THE
WEBSITE FOR CLARITY, WE'VE
REVIEWED THIS, THIS IS GOOD.
BECAUSE IF WE DON'T LET THE
DEVELOPERS OR TESTING LABS KNOW
WHAT WE DO, A LOT OF TIMES THEY
WILL MOVE TO SOMETHING ELSE.
>> SOMEONE NEEDS TO SUBMIT A
NOMINATION FOR THOSE METHODS OR
--
>>ANYBODY CAN NOMINATE A
METHOD.
IF YOU SEE A METHOD THAT YOU
THINK WOULD BE HELPFUL, USED BY
INDUSTRY, PLEASE NOMINATE IT.
>> GREAT.
THANK YOU SO MUCH, JOHN.
OKAY.
IT'S MY PLEASURE TO INTRODUCE
MONIQUE PERRON TO GIVE AN UPDATE
FROM EPA OFFICE OF PESTICIDE
PROGRAMS, ALSO FOR THE FOLKS
WATCHING ON THE WEBCAST WE DO
HAVE AN E-MAIL ADDRESS YOU CAN
SEND QUESTIONS IN TO, AND WE'LL
HAVE TIME LATER IN THE DAY AND
TOMORROW TO COME BACK TO ANY OF
THOSE QUESTIONS.
ICCVAMQUESTIONSNIEHS AT NIH.GOV,
WE'LL MAKE SURE TO PUT THAT ON
THE SLIDE THAT'S SHOWING DURING
THE BREAK WHEN WE BREAK AFTER
THE NEXT TALK.
MONIQUE, OVER TO YOU.
>> THANK YOU, NICOLE.
THANK YOU, EVERYONE, FOR
JOINING.
I'M GOING TO GIVE -- PROVIDE AN
UPDATE ON ACTIVITIES THAT ARE
ONGOING AT THE OFFICE OF
PESTICIDE PROGRAMS AT THE UNITED
STATES ENVIRONMENTAL PROTECTION
AGENCY.
AS ALWAYS, WE LIKE TO INCLUDE
OUR DISCLAIMER THAT THE VIEWS I
EXPRESS MAY NOT NECESSARILY
REPRESENT THOSE OF THE AGENCY.
I WANTED TO START OFF WITH WE
PROVIDED A FEW UPDATES ON OUR
NAM WORK PLAN, IN THE PAST FEW
YEARS.
WE PUT OUT ORIGINAL WORKPLAN,
THEN UPDATED IT SOON AFTER THAT
IN 2021, BUT THE OBJECTIVES OF
THAT WERE ESSENTIALLY UNTOUCHED.
AND ONE OF OF THE ONES I WANTED
TO FOCUS ON IS ONE OF THE
OBJECTIVES OR GOALS TO ESTABLISH
SCIENTIFIC CONFIDENCE, AND AS
PART OF THAT THE AGENCY IS
WORKING ON A CONFIDENCE
FRAMEWORK, SCIENCE CONFIDENCE
FRAMEWORK, AND LUCKILY FOR US
THIS ISN'T STARTING FROM
SCRATCH.
THERE'S A LOT OF DIFFERENT
FRAMEWORKS, AND DOCUMENTS OUT
THERE, THAT WE'RE TRYING TO
BUILD OFF OF AND CONSIDER.
ONE OF THE MOST RECENT ONES WAS
PUBLISHED IN 2022, WHICH IS IN
THE BOTTOM RIGHT-HAND CORNER
HERE.
AND WHAT YOU SEE ACROSS A LOT OF
THESE FRAMEWORKS IS VERY
CONSISTENT COMPONENTS OF A
FRAMEWORK AND SO FOR EPA WE'RE
WORKING TO DO A SCIENTIFIC
CONFIDENCE FRAMEWORK MORE
GENERALIZABLE APPLICABLE TO A
BROAD RANGE OF NAMs.
DECISIONS I MAKE IN THE OFFICE
OF PESTICIDE PROGRAMS ARE
ACCORDING TO STATUTES WE NEED TO
FOLLOW WHILE OUR COLLUSION IN
POLLUTION PREVENTION AND TOXICS
LOOKING AT INDUSTRIAL CHEMICALS
HAVE TO CONSIDER OTHER
REGULATORY CONTEXT.
SO IT'S TRYING TO KEEP THIS MUCH
MORE BROAD SO WE CAN UTILIZE
THIS FRAMEWORK ACROSS DIFFERENT
PARTS OF THE AGENCY.
THERE'S A LOT OF DIFFERENT
ONGOING ACTIVITIES RELATED TO
THAT AS WELL.
JUST LAST FALL WE HAD OUR THIRD
CONFERENCE FOR STATE OF THE
SCIENCE ON THE DEVELOPMENT AND
USE OF NEW APPROACH METHODS FOR
CHEMICAL SAFETY.
THAT WAS IN OCTOBER, 2022.
AND RECENTLY THE REPORT CAME OUT
SO YOU CAN SEE ALL OF THE
PRESENTATIONS AND DISCUSSIONS,
WE HAD BREAKOUT GROUPS TO TALK
ABOUT THE FRAMEWORK IN
PARTICULAR, AND IN THE
COMPONENTS THAT WOULD GO INTO
THAT.
ADDITIONAL WHICH YOU'LL HEAR
WILL LATER IN THE MEETING WE'VE
BEEN ACTIVE IN THE VALIDATION
WORK GROUP FOR ICCVAM, THAT'S
TASKED WITH UPDATING VALIDATION
GUIDANCE AND ADDITIONAL HAVE A
PANEL CONVENED AT THE NATIONAL
ACADEMY OF SCIENCES TO LOOK AT
THE VARIABILITY AND RELEVANCE OF
CURRENT MAMMALIAN TOXICITY
STUDIES AND ALSO DIFFERENT
CONFIDENCE FRAMEWORKS AND,
AGAIN, TO INFORM WHAT COMPONENTS
WE SHOULD BE CONSIDERING TO
INCORPORATE INTO OUR SCIENTIFIC
CONFIDENCE FRAMEWORK.
A LOT OF WORK GOING ON THERE.
HOPEFULLY THAT WILL GIVE
GUIDANCE TO STAKEHOLDERS TO KNOW
WHAT WE'RE LOOKING FOR WHEN WE
NEED TO -- BECAUSE WE'RE TRYING
TO MAKE REGULATORY DECISIONS AND
NEED TO BE CONFIDENT IN THE
UNDERLYING SCIENCE.
SO FOR QUITE A LONG TIME, OUR
COLLEAGUES IN THE OFFICE OF
RESEARCH AND DEVELOPMENT HAVE
BEEN TAKING PART IN
INTERNATIONAL EFFORT TO DEVELOP
IN VITRO ASSAYS THAT ARE PART OF
A BATTERY TO EVALUATE
DEVELOPMENTAL NEUROTOXICITY
POTENTIAL.
THIS BATTERY, A LARGE PORTION OF
IT, WAS DEVELOPED BY RESEARCH IN
ORD, AND THE BATTERY WAS ALSO
BROUGHT TO OUR FIFRA PANEL IN
2020.
RECENTLY IN MARCH 2023 WE PUT A
RESPONSE TO THE SAP
RECOMMENDATIONS AND COMMENTS
INTO THE DOCKET, ON THE SLIDE
YOU CAN SEE A DOCKET LINK IF YOU
WANT TO GO TO THE DOCUMENT.
ULTIMATELY RESPONDING TO SOME
RECOMMENDATIONS, PROVIDING
CLARIFYING INFORMATION AND
ADDITIONAL INFORMATION TO
IDENTIFY COMMENTS IN THE SAP
REPORT.
AND THE WORK DOESN'T STOP THERE.
THERE'S BEEN ONGOING WORK AT
OECD LEVEL WITH THIS BATTERY AS
WELL, AND WE'RE HAPPY TO SEE
THAT AT THE RECENT WNT MEETING
IN APRIL 2023 THE GUIDANCE ON
EVALUATION OF DATA FROM THE
BATTERY WAS ACCEPTED, SO THAT
WAS WONDERFUL NEWS, SO WE HOPE
TO SEE ADDITIONAL ORGANIZATIONS
LOOKING TO UTILIZE THIS
INFORMATION AS PART OF THEIR
WEIGHT OF EVIDENCE FOR DNT
POTENTIAL.
OPP AS WELL AS COLLEAGUES IN
OFFICE OF POLLUTION AND
PREVENTION, OPT PROVIDED
CHEMICAL NOMINATIONS IN THE
FIRST ROUND AS WELL AS SECOND
ROUND STARTING TO GET PULLED
TOGETHER.
AND THEN LASTLY I JUST ALSO
WANTED TO NOTE THAT DATA FROM
THE IN VITRO DNT TESTING HAS
BEEN USED IN A WEIGHT OF
EVIDENCE ANALYSIS TO SUPPORT THE
NEED FOR ADDITIONAL DNT DATA.
SO I THINK AT A PREVIOUS MEETING
WE'VE PROVIDED UPDATES FOR
PUBLICATION AND WHERE WE UTILIZE
DATA TO WAIVE THE NEED FOR
ADDITIONAL DNT INFORMATION, WE
HAVE SORT OF THE OPPOSITE HERE
WHERE THE INFORMATION SUPPORTED
A CONTINUED NEED TO SEARCH FOR
MORE INFORMATION TO INFORM OUR
DECISION MAKING.
WE ALSO HAVE A LOT OF WORK GOING
ON IN THE NAMs SPACE IN TERMS
OF THE ENDOCRINE DISRUPTION.
JANUARY 2023 RELEASED A WHITE
PAPER EDSP.
TWO MODELS, E.R. MODEL IS 18
ASSAYS, AND A.R. MODEL MADE UP
OF 11 ASSAYS, THESE ARE
BASICALLY WE'RE SAYING THAT
THESE HAVE THE POTENTIAL TO BE
USED AS ALTERNATIVES FOR ASSAYS
IN THE TIER 1 BATTERY.
THERE'S ADDITIONAL MODELS NOTED
IN THE DOCUMENT FOR PRIORITY
SETTING, OR THAT COULD BE
UTILIZED AS OTHER SCIENTIFICALLY
RELEVANT INFORMATION FOR WEIGHT
OF EVIDENCE.
AND THEN I DON'T THINK -- I
WOULD NEED ANOTHER PRESENTATION
TO TALK ABOUT ONGOING RESEARCH
OUR COLLEAGUES IN ORD ARE ALSO
TAKING PART IN.
IF YOU FOLLOWED THE STRAP
PLANNING AT ORD ENDOCRINE
DISRUPTION IS ONE OF THE BIGGEST
PIECES AS WELL AS NAMs,
TOGETHER THERE'S A LOT OF WORK
INNING THERE.
ANOTHER INITIATIVE THAT WE'RE
SEEING KIND OF GET OFF THE
GROUND IN OPP IS THE REDUCTION
OF DOG STUDIES, TRYING TO LOOK
AT POTENTIAL TO REDUCE OUR
POSSIBLY ELIMINATE USE OF DOG
STUDIES TO SUPPORT REGULATORY
DECISIONS.
IN 2021 TOOK PART IN
COORDINATING WITH THE CENTER FOR
ALTERNATIVE TO ANIMAL TESTING,
WITH WORKSHOP ON CHALLENGES AND
OPPORTUNITIES FOR OVERCOMING DOG
USE FOR PESTICIDE EVALUATION AND
REGISTRATION.
THAT HAS LED TO OUR COORDINATING
EFFORTS THROUGH THE HEALTH AND
ENVIRONMENTAL SCIENCES
INSTITUTE.
WE SET UP A WORK THROUGH TO WORK
THROUGH RETROSPECTIVE ANALYSES
TO SEE ARE THERE PARTICULAR
CHEMICAL GROUPS THAT RELY WHERE
THE DOG IS THE MOST SENSITIVE
AND WE STILL REALLY NEED DOG
STUDIES TO INFORM THERE UNTIL WE
CAN DEVELOP ALTERNATIVE METHODS,
ARE WE ESSENTIALLY BARELY USING
THE DOG STUDY, SO TRYING TO GET
A GOOD GRASP ON THE IMPACT OF
THE DOG STUDIES FOR OUR
EVALUATIONS, AND THEN WORKING
THROUGH THAT, YOU KNOW, THROUGH
THE RESULTS OF THOSE ANALYSES TO
FIGURE OUT WHAT OUR NEXT STEPS
WILL BE.
BUT THAT DOESN'T MEAN WE'RE ONLY
FOCUSED ON THAT.
WE'RE ALSO LOOKING AT POTENTIAL
TO USE KINETIC DATA AND
COMPARATIVE METABOLISM DATA AND
OTHER IN VITRO DATA TO TRY TO --
COULD WE DEVELOP A FRAMEWORK OR
FLOWCHART HOW YOU GET TO THE
POINT WHERE YOU DO OR DO NOT
NEED TO UTILIZE THE DOG STUDIES
IN OUR DECISION MAKING.
THROUGHOUT THE YEARS WE'VE GIVEN
UPDATES ON WORK ON EYE
IRRITATION FOR OUR COLLEAGUES IN
ANTIMICROBIAL DIVISION, WE HAVE
A POLICY FOR ACCEPTING EYE
IRRITATION ASSAYS FOR
ANTIMICROBIAL CLEANING PRODUCTS.
WE'VE DONE PERSPECTIVE AND
RETROSPECTIVE EVALUATIONS WITH
NIH.
THERE'S A PRETTY RECENT
MANUSCRIPT THAT WAS A
COLLABORATION WITH PETA AND
OTHERS TO LOOK AT HUMAN
RELEVANCE AND STRENGTHS AND
UNCERTAINTIES OF THE DIFFERENT
EYE IRRITATION ASSAYS THAT ARE
OUT THERE.
AND MORE RECENT TIME WE HAVE
STAFF THAT HAVE BEEN WORKING
WITH NICEATM AND PETA AND IIVS,
AND THAT MANUSCRIPT IS ALMOST TO
THE FINISH LINE SO HOPEFULLY
LATER THIS YEAR IT WILL BE OUT
IN THE PUBLIC AND YOU GUYS WILL
BE SEEING THAT AS WELL.
AND I ALSO WANTED TO MENTION ONE
ADDITIONAL PUBLICATION THAT I
FEEL LIKE WENT UNDER THE RADAR
LAST YEAR BUT I THINK THIS IS A
GREAT RESOURCE.
THIS DOCUMENT -- THIS
PUBLICATION WAS A COLLABORATION
ACROSS DIFFERENT JURISDICTIONS
TO TALK ABOUT HOW CAN NAMs BE
USED, WHAT'S THE REGULATORY
FLEXIBILITY, WHAT ARE SOME
EXAMPLES OF THAT.
SO IT'S LOOKING AT CANADA AND
EUROPE AND THE U.S., LOOKING AT
INDUSTRIAL CHEMICALS AND
PESTICIDES, SO I THINK I JUST
WANTED TO REALLY HIGHLIGHT THAT
I THINK THIS DOCUMENT IS A GREAT
RESOURCE FOR SOMEBODY TRYING TO
GET A HANDLE ON HOW NAMs ARE
BEING USED IN A REGULATORY
CONTEXT ACROSS DIFFERENT
JURISDICTIONS.
AND TYPICALLY MOST OF WHAT WE
DISCUSS WITH OPP IS HUMAN HEALTH
BUT WE DID HAVE SOME PROJECTS
ONGOING IN THE ECO-TOX REALM.
THE RETROSPECTIVE ANALYSES OF
CONTINUED, FISH ACUTE
RETROSPECTIVE I TALKED ABOUT
BEFORE WHERE WE REQUIRE THREE
DIFFERENT FISH STUDIES BUT COULD
WE REDUCE THAT DOWN TO TWO OR
POSSIBLY ONE, AND ACTUALLY
RECENTLY WE PUBLISHED A
MANUSCRIPT OF THE RETROSPECTIVE
ANALYSIS, THERE'S PROMISE TO
REDUCE THE NUMBER OF ANIMALS AND
INTERNALLY TRYING TO FIGURE OUT,
YOU KNOW, WILL THIS TURN INTO A
GUIDANCE TOWARDS -- WILL THIS
INFORMATION BE USED TO
ULTIMATELY PROVIDE GUIDANCE HOW
WE CAN REDUCE THOSE STUDIES
BEFORE REGISTRANTS GO OUT AND
CONDUCT THEM.
AND ADDITIONALLY WE'RE
CONTINUING OUR WORK ON THE AVIAN
REPRODUCTIVE RETROSPECTIVE, WE
CURRENTLY REQUIRE TWO BUT ARE
TWO SPECIES NEED AND WE'RE STILL
IN THE DATA CURATION AND
EXPLANATION, STILL CHUGGING
ALONG.
AND THEN JUST BRIEFLY, WE'RE
CONTINUING OUR WORK WITH NICEM
AND OTHERS.
WE HAVE MODELING WORK FOR
ECOSAR, YOU'LL HEAR ABOUT THAT
IN THE NEXT PRESENTATION, A LOT
OF WORK IN THE ECO-TOX BASE, A
LOT OF DIFFERENT EFFORTS GOING.
AND LASTLY, JUST WANTED TO
MENTION OUR WEBSITE.
I DIDN'T INCLUDE A LINK TO CLICK
ON, DON'T WORRY.
BUT WE CONTINUE TO UPDATE THIS.
WE'RE IN THE PROCESS RIGHT NOW
OF LOOKING AT WHAT NEEDS TO GET
UPDATED FOR THIS YEAR, ADDING
OUR METRICS, SO ON THE
RIGHT-HAND SIDE YOU CAN SEE WE
HAVE A METRICS PAGE, STRATEGIES
TO REDUCE ANIMAL TESTING AND
STRATEGIES TO REPLACE ANIMAL
TESTING, SO WE'RE TRYING OUR
BEST TO KEEP THAT UP TO DATE.
WE'RE LATER THAN USUAL THIS YEAR
BUT WE SHOULD BE SEEING SOME
UPDATES FOR LATER THIS YEAR.
I THINK THAT'S IT.
[APPLAUSE]
>> DO WE HAVE ANY QUESTIONS IN
THE ROOM FOR MONIQUE?
OKAY.
ONE QUESTION.
>> QUICK QUESTION.
SO THANKS, MONIQUE, ALWAYS LOTS
OF EXCITING THINGS IN YOUR
PRESENTATIONS.
YOU MENTIONED ACUTE FISH
TOXICITY DECIDING WHAT TO DO
AND
WHERE THAT GOES TOWARDS
GUIDANCE, A COUPLE THINGS OPP
HAS MADE GREAT ACTIVITY ON,
DERMAL PENETRATION, ET CETERA.
ARE THERE PLANS TO MOVE THOSE
AND THINGS COMING IN THE FUTURE
LIKE EYE TESTING TOWARDS
GUIDANCE POLICIES, ET CETERA?
>> YEAH, WE'VE BEEN HAVING
INTERNAL CONVERSATIONS ON THAT
BECAUSE THERE'S BEEN
DIFFICULTIES IN THE AGENCY OF
MOVING GUIDANCE AND POLICY
DOCUMENTS ALONG, AND SO WE
WANTED TO MAKE SURE WE'RE
UTILIZING RESOURCES IN A SMART
WAY, ALSO BEING SUCCESSFUL IN
GETTING GUIDANCE DOCUMENTS OR
POLICY DOCUMENTS OUT THERE SO
THERE HAVE BEEN INTERNAL
CONVERSATIONS WHAT TO FOCUS ON
AND HOW TO IMPROVE THAT PROCESS
BUT THERE'S STILL WORK THAT
NEEDS TO GET DONE THERE TO GET
THERE.
BUT, YEAH, I THINK IT IS
IMPORTANT TO HAVE THOSE
DOCUMENTS SO THAT STAKEHOLDERS,
YOU KNOW, ARE MORE -- THERE'S
MORE CLARITY TO STAKE HOLDERS
WHAT WE'RE WILLING TO DO AND HOW
WE'RE DOING IT BUT ALSO
INTERNALLY FOR OUR STAFF, ALSO
HELPS, YOU KNOW, FOR THEM TO
KNOW WHAT WE'RE DOING AND WHAT
WE ACCEPT AND ALL OF THAT STUFF.
SO I THINK IT'S SOMETHING THAT
WE NEED TO WORK ON THOUGH.
THANKS.
>> OKAY.
GREAT.
AND NEXT PRESENTER, LAST
PRESENTER OF THE MORNING SESSION
BEFORE A BREAK IS ANNA LOWIT,
UPDATE FROM OPPT.
>> HI, EVERYBODY.
SO I'M GOING TO WATCH MY CLOCK
BECAUSE SOME OF YOU KNOW ONCE I
GET STARTED SOMETIMES I TEND TO
RUN OVER.
HOPEFULLY I CAN GET US CLOSE TO
BACK TO WHERE WE ARE SUPPOSED TO
BE.
I GUESS I USE THIS TO FOR WASHED
THE SLIDES.
GOT IT.
OKAY.
SO I'M GOING TO SHOW THE
DISCLAIMER BECAUSE OUR VIEWS ARE
THOSE OF MY OWN AND NOT OF MY
AGENCY.
OKAY.
SO, A FEW UPDATES, I'M GOING TO
DO A WHIRLWIND LIKE MONIQUE HAS.
I'VE BEEN WITH THE PROGRAM A
LITTLE BIT OVER A YEAR, YOU'LL
SEE THAT ONE OF MY FIRST
ACTIVITIES, ONE OF MY PRIORITIES
WHEN I MOVED OVER IN THE NAMs
SPACE WAS TO BEGIN TO BUILD
THOSE COLLABORATIONS AND THOSE
IMPORTANT CONNECTIONS NOT ONLY
WITH THE OFFICE OF RESEARCH AND
DEVELOPMENT BUT WITH OUR
EXTERNAL COLLABORATORS, SOME OF
WHOM ARE HERE IN THE ROOM, MANY
ONLINE.
AND AS WE KNOW, IT'S BEEN THOSE
COLLABORATIONS AND THOSE
ENGAGEMENTS THAT HAVE REALLY
ADVANCED THE PESTICIDE PROGRAM
RAPIDLY.
A LOT OF THAT YOU SAW IN
MONIQUE'S PRESENTATION, THAT
WE'VE BEEN TALKING ABOUT FOR A
LONG TIME, AND OTHER THINGS THAT
AREN'T TALKED ABOUT TODAY.
AND SO WE'RE STARTING TO SEE
REALLY THE FRUITS OF THOSE
ENGAGEMENTS, AND REALLY STARTING
TO SEE SOME ACCELERATION IN THE
TOXICS PROGRAM.
THAT'S EXCITING.
ONE OF THOSE IS REALLY ONGOING
RESEARCH PROGRAM TO SUPPORT THE
NEW CHEMICALS PROGRAM, UNDER
TSCA.
TSCA IS SPLIT BETWEEN EXISTING
CHEMICALS AND NEW CHEMICALS, SO
OPPT IS THE GATE KEEPER TO NEW
CHEMICALS IN THE MARKET FOR
INNOVATION SO THINGS IN YOUR --
YOU KNOW, THINGS YOU CARRY
AROUND IN YOUR CAR, YOUR PHONE,
ET CETERA.
ALL THOSE CHEMISTRIES GO THROUGH
THE NEW CHEMICALS PROGRAM.
A LOT OF METHODS HAVE BEEN USING
FOR A VERY LONG TIME, UNIQUE
PROGRAM BECAUSE THEY ONLY HAVE
EITHER 30 OR 90 DAYS TO EVALUATE
NEW CHEMICALS BEFORE THEY ARE
APPROVED FOR MARKET.
SO A LOT OF METHODS THEY HAVE
BEEN USING ARE THE SAME AS THEY
HAVE BEEN DOING FOR A LONG TIME.
LAST YEAR WE INITIATED A
COLLABORATIVE RESEARCH ACTIVITY,
OFTEN CALLED NCCRP, NEW
CHEMICALS COLLABORATIVE RESEARCH
PROGRAM.
SO FAR WE'VE BEEN WORKING WITH
OFFICE OF RESEARCH AND
DEVELOPMENT, UPDATED LAST YEAR.
THE COMING YEAR WILL BE ACTIVELY
WORKING WITH EXTERNAL
STAKEHOLDERS AND OTHER FEDERAL
PARTNERS TO HELP ADD TO THAT
PROGRAM AND FILL IN SOME OF THE
RESEARCH GAPS.
THIS YEAR'S UPDATE IS REALLY
ABOUT THE FINALIZATION OF THAT
PROPOSAL, AND SO YOU CAN SEE
OCTOBER OF 22 THAT DOCUMENT WAS
FINALIZED, REVISED BY FEDERAL
COMMITTEE, BOSC, ALSO NOW
AVAILABLE.
THE BOSC PROVIDED IMPORTANT
RECOMMENDATIONS BUT REALLY
DIDN'T FOUNDATIONALLY CHANGE THE
DIRECTION OF THE PROGRAM.
ONE OF THE NEW THINGS IN THE
TSCA PROGRAM IN THE LAST YEAR IS
A COLLABORATIVE EFFORT TO BRING
IN THE GUIDELINES, I DON'T
EXPECT ANYBODY TO READ THE TINY
PRINT BUT SAFE TO SAY THERE'S A
DECISION FRAMEWORK DEVELOPED
WITH COLLABORATORS AND OUR STAFF
AT THE NEW CHEMICALS PROGRAM, TO
BEGIN TO BRING IN MORE FULLY EYE
IRRITATION ASSAYS IN HAZARD
CALLS FOR NEW CHEMICALS.
THIS IS EXTRACTED FROM A POSTER
PRESENTED IN MARCH ARE FOR SOT
MEMBERS YOU CAN STILL FIND THAT
I BELIEVE ON THE WEBSITE AND GET
THE DETAILS.
BUT WE'RE ALSO WORKING ON
SIMILAR FOR EYE IRRITATION AND
SKIN SENSITIZATION FOR HAZARD
CALLS AND QUANTITATIVE
ASSESSMENT FOR SKIN SENSITIZERS.
WHAT'S IMPORTANT HERE, AND WHAT
MAKES IT UNIQUE I THINK IS THIS
FRAMEWORK PRIORITIZES THE USE OF
IN VITRO STUDIES FROM HUMAN DATA
OVER THAT OF ANIMAL MODELS.
ANOTHER BRAND NEW ACTIVITY
THAT'S A COLLABORATION BETWEEN
OPPT AND MANY OTHER STAKEHOLDERS
WORLDWIDE IS THE WORK IN
SENSITIZATION, PROPOSAL OF
PROJECT FOR DETAILED -- TRYING
TO NOT USE ACRONYMS, DETAILED
REVIEW PAPER APPROVED LAST MONTH
AT THE OECD.
TOXIC SPACE, RESPIRATORY
SENSITIZATION IS REALLY
IMPORTANT ENDPOINT IN TERMS OF
DETERMINING HAZARD AND NO
HAZARD, KNOCK APPROVED, ENTIRELY
BASED ON STRUCTURE.
IT'S AN IMPORTANT AND REALLY
POTENTIALLY FATAL ENDPOINT AND
SERIOUS POISONING IMPACT SO
WE'RE EXCITED ABOUT THE
POTENTIAL IN THE NEXT FEW YEARS
TO HAVE A NAMs-BASED APPROACH
FOR RESPIRATORY SENSITIZATION.
ONE OF THE AREAS THAT WE'VE BEEN
WORKING CLOSELY WITH ORD ON, AS
YOU HEARD FROM MONIQUE A FEW
MINUTES AGO, THE OFFICE OF
CHEMICAL SAFETY AND POLLUTION
PREVENTION HAS BEEN EXCITED
ABOUT THE DNT NAMs BATTERY FOR
A LONG TIME, ACTIVELY ENGAGED IN
ITS -- SINCE ITS BEGINNING
ALMOST TEN YEARS AGO, AND WE'RE
STARTING TO REALLY SEE THE
FRUITS OF THAT NOT ONLY AT THE
OECD, AT THE APPROVAL OF THAT
GUIDANCE DOCUMENT, BUT ALSO THE
ACCELERATION OF AVAILABLE DATA
IN NAMs SPACE, A BRAND-NEW
PUBLICATION OUT OF ORD LOOKING
AT 16 PFAS FOR SCREENING IN THE
DNT SPACE AND WE'VE ALSO
PROPOSED A NUMBER OF CHEMICALS
TO BE TESTED BY THE NTP,
ADDITIONAL PFAS, ALSO SOME FIRE
RETARDANDS, EXCITED ABOUT
ACCELERATION OF AVAILABLE PFAS
INFORMATION TO HELP WITH
SCREENING AND NATIONAL
TESTING STRATEGY.
OPPT HAS BEEN A LEADER, AND ONE
THING WE'RE DOING IS UPDATING
THOSE AND BUILDING NEW TOOLS BUT
THERE ARE LONGSTANDING TOOLS
USED EVERY DAY, MANY PARTS OF
EPA USE ECOSAR FOR A VARIETY OF
THINGS, INCLUDING ACUTE
TOXICITY, IN PARTICULAR, AND
CHRONIC TOXICITY PARTICULARLY
FOR FISH AND DAPHNIDs, USING
ECOSAR FOR LOOKING EXPLICITLY AT
AQUATIC TOXICITY FOR NEW
CHEMICALS AND WEIGHT OF EVIDENCE
AND ANALOG SELECTION IN THE
EXISTING CHEMICALS PROCESS
LOOKING FORWARD TO UPDATES OVER
THE NEXT YEAR OR SO.
NOT ONLY FOR ECOSAR BUT MANY
QSARs BEING UPDATED.
NEW CHEMICALS PROGRAM IS A HEAVY
USER OF THE TOOLBOX, ACTIVELY
ENGAGED IN THE DEVELOPMENT IN
THE IMPROVEMENT OF TOOLBOX OVER
THE YEARS, ONCOLOGIC FOR EXAMPLE
WAS ORIGINALLY OPPT TOOL TAKEN
IN A FLUB OF YEARS AGO AND STAFF
PLAY A ROLE IN THE UPDATING
THAT.
OPPT HAS BECOME A LEADER IN THE
APPLICATION OF O.R. D TOOL
CALLED WEB-ICE.
ONE OF THE DIFFERENCES IS THE
PESTICIDE PROGRAM UNDER FIFRA
HAS SUBSTANTIAL CAPACITY, COMING
IN WITH EXTENSIVE DATABASES OF
TOXICITY INFORMATION, TENS OR
HUNDREDS OF MILLIONS OF ANIMAL
TESTING.
NO SUCH DATA EXISTS IN THE TOX
PROGRAM, THEY HAVE TO BE
CREATIVE HOW THEY USE AND
COLLECT INFORMATION.
INCREASING USING WEB-ICE TO
CORRELATE ACROSS SPECIES TO TAKE
THE LIMITED ECO-DATA THEY HAVE
AND EXPAND IT ACROSS THE FULL
ECOLOGICAL DATASET FOR DIFFERENT
SPECIES.
AND SEVERAL RISK EVALUATIONS
HAVE ACTUALLY ALREADY USED THE
WEB-ICE TOOL AND RISK
EVALUATIONS REVIEWED IN COMING
YEAR BY THE FACAs WILL EXPAND
THE USE OF THIS.
WITH THAT, I'LL STOP AND ASK IF
THERE ARE ANY QUESTIONS.
I THINK I GOT US BACK ON TIME.
[APPLAUSE]
>> ARE THERE ANY QUESTIONS IN
THE ROOM?
ANNA GOT US AHEAD OF SCHEDULE.
WE HAVE FIVE MINUTES.
SOME QUESTIONS HAVE COME IN
THROUGH THE ICCVAM QUESTIONS
E-MAIL ADDRESS FOR PREVIOUS
PRESENTERS SO WE CAN ADDRESS
THOSE BEFORE THE BREAK AS WELL
BUT FIRST ARE THERE ANY
QUESTIONS FOR ANNA?
VERY CLEAR, OKAY.
WE HAD A QUESTION COME IN ONLINE
FOR DR. GORDON, IF YOU WANT TO
COME BACK UP HERE.
DAVE, READ THE QUESTION PLEASE.
>> SURE.
FROM VICKIE FROM HSUS, CPSC
RECEIVED ANY SUBMISSIONS FROM
NAMs DEVELOPERS THROUGH THE
NEW PROCESS IN THE 2022
GUIDANCE, IF SO HOW LONG DO YOU
ANTICIPATE THE REVIEW PROCESS
TAKING?
>> WE HAVE ACCEPTED, GOTTEN A
COUPLE NOMINATIONS FOR METHODS
IN.
THOSE TOOK A LITTLE WHILE BUT
WE'RE MOSTLY WORKING ON THE WEB
PAGE TO UPDATE BEFORE WE STARTED
PUTTING MORE METHODS ON THE WEB
PAGE BECAUSE THE WAY IT WAS
BEFORE, IT WOULDN'T HAVE MADE
SENSE TO ADD INTO THE FORMAT WE
HAD BEFORE.
SO WE UPDATED, WE'VE UPDATED THE
WEBSITE, AND BOTH OF THOSE
METHODS, ONE IS ALREADY UP
THERE, THE OTHER WILL BE UP VERY
SOON.
IT'S IN CLEARANCE RIGHT NOW.
AND WILL BE IN FINAL CLEARANCE
NEXT WEEK.
IT WILL BE CLEARED WHEN WE CAN
PUT IT ON THE WEBSITE, A MATTER
OF DEALING WITH I.T. AND THEN
HOW EXACTLY WE'RE WE'RE GOING E
UPDATING AS WE MOVE FORWARD WILL
BE THE NEXT STEP.
>> OKAY, GREAT.
THANKS VERY MUCH, JOHN.
AND SO WE WILL TAKE A BREAK IN
JUST A MOMENT.
A REMINDER, TO THE FOLKS THAT
ARE VIEWING VIA THE WEBCAST
WHEN YOU GOT A REMINDER E-MAIL
ABOUT YOUR WEBCAST REGISTRATION
IT CAME FROM KATHERINE SPRINKLE
WITH THE THE E-MAIL ADDRESS IN
THE BODY OF THE E-MAIL, SO I'M
GOING TO PUT IT ON THE SLIDE AS
A PLACEHOLDER DURING THE BREAK,
SO YOU CAN SEE IT.
PROBABLY EASIEST TO JUST GO INTO
YOUR E-MAIL, SEARCH FOR
KATHERINE SPRINKLE OR PUBLIC
FORUM, WEBCAST AS KEY WORD AND
YOU'LL SEE THE CLICKABLE LINK
FOR THAT ARE ICCVAM QUESTIONS
E-MAIL ADDRESS, FEEL FREE TO
CONTINUE TO SEND QUESTIONS
DURING THE BREAK.
INDICATE WHICH SPEAKER AND WE
HAVE TIME BUILT INTO THE AGENDA
TO CEASE -- TO TAKE QUESTIONS.
WE'LL COME BACK AT 10:15.
>> WE'RE GOING TO RESUME THE
MEETING.
SO, FOLKS IN THE ROOM LOVE THAT
YOU'RE HAVING PRODUCTIVE
CONVERSATIONS BUT DON'T MAKE ME
START CALLING NAMES, ANNA.
[LAUGHTER]
OKAY.
SO WE DO HAVE ONE QUESTION THAT
CAME IN DURING THE BREAK FOR
ANNA.
DAVE?
OKAY.
>> THIS QUESTION IS FROM
MATTHEW.
IS THERE POSSIBILITY OF ADDING
NOEC POSITION TO ECOSAR TOOLS
CHRONIC ENDPOINT?
>> THANK YOU FOR THE QUESTION.
HOWEVER, IF IT'S POSSIBLE TO
RESPOND IN WRITING, AT A LATER
DATE, BECAUSE THAT'S REALLY A
QUESTION FOR OUR ORD COLLEAGUES
AT THE DULUTH LAB, MORE THAN IT
IS A PROGRAM OFFICE.
WE CAN HAPPILY GET BACK TO ON
YOU THE ANSWER TO THAT BUT I
DON'T THINK THERE'S ANYONE
ONLINE OR IN THE AUDIENCE TODAY
WHO KNOWS THE ANSWER TO THAT.
>> OKAY.
SO, KEEP THE QUESTIONS COMING.
WE'LL CONTINUE TO ADDRESS THEM
AS WE GET THEM.
SO OUR NEXT PRESENTER IS DR.
SUZIE FITZPATRICK, NEW
METHODOLOGIES IN FDA FOOD
SAFETY.
>> THANK YOU VERY MUCH FOR
ASKING ME TO TALK HERE TODAY.
I MADE A LITTLE BIT OF A MISTAKE
ON THE DATE.
I HOPE WE'RE STILL NOT TALKING
ABOUT THIS 300 YEARS FROM NOW,
SOMETIMES IT SEEMS LIKE WE MIGHT
BE.
I'M GOING TO PRESENT NEW
APPROACH METHODS FOR USE IN FDA
FOODS PROGRAM.
TOMORROW YOU'LL SEE WHAT WE'RE
DOING IN TOBACCO.
FAULD, IF YOU D. -- FDA HAS SIX
MEDICAL PERHAPS, THREE MEDICAL
CENTERS, DEVICE, BIOLOGICS,
DRUGS, TOBACCO AND FOOD.
AND WE ALL RECOGNIZE AND HAVE
BEEN TOLD BY THE OFFICE OF CHIEF
SCIENTIST THAT WE NEED TO BRING
PRODUCTS TO THE MARKET FASTER,
WE NEED TO INCORPORATE NEW TOOS
FOR OUR METHODS
EACH OF OUR SIX PRODUCT CENTERS
ARE UNIQUE AND WE'VE BEEN ASKED
TO CONCENTRATE ON DEVELOPING, IF
WE HAVEN'T ALREADY,
QUALIFICATION PROGRAMS.
YOU HEARD ABOUT THE MEDICAL
DEVICE PROGRAM FROM DR. GORDON.
WE ALSO HAVE I-STAND AND DDD
BIOMARKER PROGRAM AT CDER.
THIS IS A REPORT DONNA AND I PUT
TOGETHER, CHAIR THE ALTERNATIVE
METHODS WORK GROUP, A
CROSS-AGENCY WORK GROUP OF
SENIOR SCIENTISTS, WORKING
ACROSS THE AGENCY ON THINGS
WE'RE DOING UNIQUELY IN OUR
AGENCY AND SHARE WITH OTHERS.
THIS IS ON OUR WEBSITE.
IF YOU TYPE IN ALTERNATIVES AT
FDA.GOV, IT'S BEING UPDATED BUT
I THINK YOU CAN GET ONTO IT.
IF I HAD TO WRITE ANOTHER ONE OF
THESE, I WOULD ADD THE CONTEXT
OF USE.
WE GAVE IT A SNAPSHOT OF WE
SEARCH BUT WE DIDN'T SAY WHY WE
WERE DOING IT.
THAT'S REALLY IMPORTANT I THINK,
FOR FDA.
START WITH REGULATORY QUESTION,
AND DO THE RESEARCH TO ANSWER IT
AND FILL THE GAPS WE NEED TO
REGULATE OUR PRODUCTS.
I WENT THE WRONG WAY.
I WORK AT CFSAN.
OUR PRODUCTS LACK PRE-APPROVAL
AUTHORITY THAT.
MEANS WE HAVE TO SHOW -- SO FOR
EXCEPT FOR FOOD OF DIRECT FOOD
ADDITIVE AND PACKAGES, WE HAVE
TO DEMONSTRATE HARM ACCORDING TO
LABEL USE BEFORE WE CAN DO
ANYTHING ABOUT IT.
IT'S VERY IMPORTANT FOR US TO
DEVELOP THESE NEW METHODS TO
HELP US IDENTIFY TOXICITY IN
THESE DIFFERENT PRODUCTS IN THE
MARKET, AND ARE BEING USED BY
YOUR FAMILY.
INCLUDING DIETARY SUPPLEMENT,
COSMETICS, GRAS, METALS IN BABY
FOOD, CONSTITUENTS DEVELOPED
WHEN YOU HEAT FOOD, THERE'S A
PROCESS THAT OF THAT ENDS UP IN
FOOD, ABOUT A THOUSAND OF THEM.
IT'S NOT ACCEPTABLE TO OUR
CONSUMERS AND STAKEHOLDERS TO
SAY LET ME DO AN ANIMAL STUDY
AND I'LL BE BACK IN TWO YEARS TO
TELL YOU IF THAT'S A PROBLEM OR
NOT.
IT'S ESSENTIAL FOR US TO DEVELOP
NEW APPROACH METHODS.
WE HAVE A PROGRAM TO MOVE AWAY
FROM ANIMAL STUDIES.
WE'VE GOTTEN RID OF ALL THE
ANIMALS IN OUR LAB, IF WE DO
ANIMAL STUDIES WE MIGHT LEAN ON
NCTR, BUT ALSO HAVING LESS RELY
ANSWER ON ANIMAL STUDIES, TRYING
DO TAILORED DATA STUDIES BASED
ON GENERATION, I'LL TALK ABOUT
WHAT WE'RE DOING.
SO LET'S SEE IF I CAN GET THIS
TO THE NEXT ONE.
OKAY.
SO, IN 2017, REALLY IN ANSWER TO
THE FACT THAT EPA WAS PUTTING
OUT THESE GUIDANCES, AND WE HAVE
INTERAGENCY COMPETITION.
WE DECIDED WE WOULD PUT TOGETHER
OUR FDA PREDICTIVE TOXICOLOGY
ROADMAP.
I CHAIRED THIS COMMITTEE.
THIS GAVE A STRATEGY, IF YOU GO
TO THE NEXT ONE, GAVE US A
SIX-PART FRAMEWORK FOR HOW WE'RE
GOING TO ENHANCE FDA ENGAGEMENT
IN THE SCIENCE OF TOXICOLOGY.
WE WANTED TO DEMONSTRATE TO OUR
STAKEHOLDERS WE WERE INTERESTED
AND COMMITTED TO THE DEVELOPMENT
OF NEW TECHNOLOGIES, AND WE HAD
SIX PRINCIPLES TO WORK ON.
AND WE ARE ASKED BY CONGRESS,
I'M SURPRISED I'M STILL ASKED
ABOUT THIS AFTER WORKING ON A
DOCUMENT FIVE YEARS, WHAT ARE WE
DOING TO FOLLOW THESE SIX
PRINCIPLES.
FOR THE FOODS PROGRAM I'LL SHOW
YOU HOW WE'RE INCORPORATING THIS
INTO OUR WORK.
AM I GOING THE RIGHT DIRECTION?
THESE ARE THE PRINCIPLES.
I'LL GO THROUGH EACH SEPARATELY,
SIX PRINCIPLES THAT ALL OF THE
CENTERS ARE DOING, A LOT HAVE
DIFFERENT QUALIFICATION
PROGRAMS, LIKE I SAID WE HAVE
DIFFERENT PRODUCTS.
YOU'LL SEE WHAT WE'RE DOING IN
TOBACCO.
SO THE FIRST THING IS IT WAS TO
PUT TOGETHER A SENIOR LEVEL
TOXICOLOGY WORKING GROUP.
THAT'S WHAT WE'VE DONE HERE
UNDER THE OFFICE OF THE CENTER
DIRECTOR, WE PUT TOGETHER A
GROUP THAT CONTAINS NOT ONLY
SENIOR PEOPLE, NOT ONLY PEOPLE
IN THE REGULATORY PART OF FDA
BUT IN RESEARCH LABS AND JUNIOR
SCIENTISTS TOO, SO WE CAN MAKE
SURE WE HAVE -- HE SAID DON'T BE
OFFENDED THAT WE NEED SUCCESSION
SO WHEN WE'RE GONE PEOPLE ARE
WORKING ON THIS.
WE'VE DONE A LOT OF THAT.
ONE OF THE THINGS THAT I DO IS
MAKE SURE, I'LL TALK ABOUT IT
LATER, IF I CAN GIVE A TALK AND
HAVE JUNIOR PERSON DO IT FOR ME
INSTEAD, NOT THAT I'M TRYING TO
GET OUT OF WORK BUT I WANT TO
GIVE THEM THE EXPERIENCE, THE
NETWORKING, SO THEY CAN CONTINUE
ANYTHING WE DO.
YOU'LL SEE THEM AS WE WORK ON
OUR PROJECTS.
WE ARE ACTUALLY PART OF WHAT'S
CALLED THIS KICK PROGRAM FOR
CHEMICALS, DEADLINES TO MEET TO
ACCOMPLISH ALL THESE GOALS.
DEADLINES TO THE OFFICE OF
CENTER DIRECTOR AND
COMMISSIONER.
WE'VE DEVELOPED A CHARTER FOR
NAMs WORKING GROUP, TO
IDENTIFY WHAT'S BEING CURRENTLY
USED IN THE FOOD INDUSTRY,
ACADEMIC AND OTHER GOVERNMENT
AGENCIES, NATIONALLY AND
INTERNATIONALLY, DEVELOP A PLAN
TO EVALUATE THE APPLICABILITY.
WE'RE WORKING ON POSSIBLE
QUESTIONS THAT WE WOULD ASK ANY
COMPOUND IN VALIDATION, MIGHT
NEED DIFFERENT TYPE OF GUIDANCE
FOR MICROPHYSIOLOGICAL SYSTEMS
VERSUS IN SILICO VERSUS BIOLOGIC
OR BIOMARKERS, STAKEHOLDER
WORKSHOPS ON CRITERIA, NAMs,
STATUS, GAPS, IT'S VERY
IMPORTANT TO WORK WITH ALL OF
OUR STAKEHOLDERS ACROSS THE
FEDERAL AGENCY, FEDERAL FAMILY,
AND ALL OF YOU HERE TO PUT THESE
IN PLACE BECAUSE WE ALL WANT A
SAFE FOOD SUPPLY.
AS I TALKED WITH TRAINING OF OUR
CFSAN REGULATORS AND RESEARCHES,
MAKING SURE THERE'S EDUCATION.
WE'RE PUTTING UP A WEBSITE SO
THEY CAN SEE WHERE ANY PAPERS
THAT ARE ESSENTIAL TO THEM, ANY
WORKSHOPS, ANYTHING THAT'S
AVAILABLE TO THEM.
WE ARE DOING TRAINING BY DOING,
AS I CALL IT.
WE HAVE, FOR EXAMPLE, TALKING TO
THE U.K. ABOUT THEIR ROADMAP FOR
FOOD SAFETY, AND INSTEAD OF ME
LEADING THAT WE HAVE TWO OF OUR
PROMISENING I HATE TO SAY JUNIOR
SCIENTISTS BUT YOUNGER THAN ME
THAT WILL TAKE THE LEAN ON SOME
OF THESE THINGS AS WELL AS GO
SOME INTERNATIONAL ACTIVITIES.
SO THAT WE MAKE SURE THAT IT'S
NOT JUST A COUPLE PEOPLE WHEN WE
LEAVE, IF WE CAN LEAVE, THEY
CAN -- IT STILL CONTINUES.
THAT'S WHAT WE CALL CONTINUE BY
DOING.
THIS LOOKS LIKE IT'S GOING ON
ITS OWN.
TRAINING, OKAY.
I DON'T KNOW WHAT I PUSHED.
I PUSHED IT.
OKAY.
COLLABORATION WITH STAKEHOLDERS,
IT'S VERY IMPORTANT AND I THINK
ALL OF FDA FEELS THAT WAY TO
COLLABORATE ACROSS SECTORS,
DISCIPLINES, NATIONALLY AND
INTERNATIONALLY.
WE SUPPORT THE IMPORTANCE THESE
COLLABORATIONS, I'LL TELL YOU
HOW CAN YOU COLLABORATE WITH THE
FDA IN A MINUTE, AND HERE ARE
POTENTIAL PARTNERSHIPS TO WORK
WITH CFSAN.
IT'S NOT ON THIS SLIDE BUT I
WORK ON A WHITE HOUSE INITIATIVE
ON CONTAMINANTS OF EMERGING
CONCERN UNDER OSTP.
COMING OUT OF THE WHITE HOUSE IS
AN INITIATIVE WE WORK ACROSS
FEDERAL AGENCIES ON ALL THESE
PROBLEMS THAT WE HAVE, IT'S NO
LONGER ONE AGENCY OR EVEN ONE
PART OF AN AGENCY, WE'RE ACROSS
AGENCIES, AND WHEN WE HAVE THESE
CROSS--AGENCY TALKS OUT POINT
OUT ICCVAM IS A VERY GOOD
EXAMPLE OF A CROSS-AGENCY, 17
AGENCIES WORKING TOGETHER.
YOU HAVE TO BE IN THE FEDERAL
GOVERNMENT TO UNDERSTAND HOW
UNIQUE AND IMPORTANT THAT IS.
SOMETIMES IT'S HARD TO JUST WORK
ACROSS YOUR OWN AGENCY.
I THINK KUDOS TO NICOLE AND DAVE
AND ALL THOSE THAT KEEP THAT
GOING, IT'S A GOOD EXAMPLE AS WE
WORK WITH NIEHS THROUGH THIS
CROSS-AGENCY LOOKING AT
CONTAMINANTS OF EMERGING
CONCERN.
THERE'S OTHERS WAYS.
WE HAVE PUBLIC/PRIVATE
PARTNERSHIP PARTNERSHIPS WHERE
WE'RE INVITED TO PARTICIPATE.
WE ALSO HAVE CDRH DEVELOPED
COLLECTIVE COMMUNITY WHERE 20 OR
SO PEOPLE INCLUDING FDA AND
OUTSIDE FDA TALK ABOUT SCIENCE
PROBLEMS TOGETHER.
WE COULD DO A MEMORANDUM OF
UNDERSTANDING ALTHOUGH THIS IS
USUALLY BETWEEN FEDERAL
AGENCIES, AND WE HAVE A
MEMORANDUM OF UNDERSTANDING WITH
TOX21 TO WORK BETWEEN US AND
EPA, NCATS, NIEHS, TO WORK ON
ALTERNATIVES.
WE JUST COMPLETED WHAT WAS A
MEMORANDUM OF UNDERSTANDING OR
AGREEMENT WITH NCATS TO DEVELOP
BETWEEN THE OF TWO US A
NEUROMUSCULAR JUNCTION ON A CHIP
FOR BOD TOX TESTING, PUTTING OUT
SOLICITATIONS, ALREADY OUT THERE
FOR ONE ACADEMIC LAB AND ONE
COMMERCIAL LAB TO DEVELOP A
NEUROMUSCULAR JUNCTION ON A CHIP
AND FDA WILL QUALIFY IT BASED ON
GOOD OR BETTER CRITERIA AGAINST
THE MOUSE LETHALITY TEST.
WE SEE THIS JUNCTION ON A CHIP
AS FOR A BIGGER SCOPE THAN JUST
BOT TOX TESTING FOR TOXIN
TESTING.
BECAUSE OF THAT AS WE WORK
MONTHLY WITH THE PEOPLE THAT GET
THE SOLICITATIONS TO MAKE SURE
THEY MEET FDA GOAL, SAME WITH
DARPA, INCLUDING OTHER FEDERAL
PARTNERS, DoD, OTHER CENTERS
TO MAKE SURE THAT WE'RE
DEVELOPING A TOOL THAT CAN MEET
A LOT OF PEOPLE'S NEEDS AND THEY
FEEL CONFIDENT IN THE DATA.
WE HAVE RESEARCH COLLABORATION
AGREEMENTS, JOINT RESEARCH
TOGETHER, WITH OUR PARTNERS, WE
HAVE SOME WITH ACADEMICS, SOME
WITH INDUSTRY, AND SO THEY ARE
NOT LIKE KIND OF SEGREGATED TO
JUST INDUSTRY.
IF SOMEONE HAD AN IDEA AND CAME
TO US, THIS IS ON SCIENCE ISSUES
THAT MIGHT LEAD TO REGULATORY
DECISIONS, AND THEN WE ALSO HAVE
CRADAs, TECHNOLOGIES ARE MOVED
INTO THE LABORATORY LIKE WE DID
WITH ORGANS ON THE CHIP, EMULATE
THE FOODS LAB, IN SEVERAL OF OUR
LABS.
WE ALSO HAVE -- WE ALSO HAVE A
CRADA WE'RE DEVELOPING WITH
CANADA TO MOVE THEIR
NEUROMUSCULAR CHIP.
WE TALK ABOUT CRITERIA TO ACCEPT
THE DATA.
IT'S A VERY GOOD WAY TO GET
SOMETHING, EVERYONE TO GET
SOMETHING OUT OF THESE
PARTNERSHIPS.
I MIGHT SAY THAT ANOTHER ONE WE
CREATED IS INTERNATIONAL LIAISON
GROUP ON METHODS FOR RISK
ASSESSMENT OF CHEMICALS AND
FOOD, A PARTNERSHIP WITH CFSAN,
FSA, AND CHINA, KOREA, JAPAN,
SINGAPORE AND CANADA, WE'VE
ALREADY HAVE A LIST OF PRIORITY
ITEMS.
THIS IS JUST THE PEOPLE THAT ARE
INVOLVED IN IT.
WE'RE DOING IT FOR THE FOOD
INDUSTRY, ACROSS THE GLOBAL,
NON-GUIDELINE STUDIES TO LOOK AT
MIXTURES, DEVELOPMENTAL NEURO,
RECENTLY LOOKED AT BUILDING
CONFIDENCE IN THESE METHODS,
WORKING TOGETHER.
SO IT INCREASES FDA'S ABILITY TO
ADOPT THESE WHEN WE GET GLOBAL
HARMONIZATION AND WE'RE WORKING
WITH THE U.K. TO LOOK AT IN
SILICO MODELS, PACKAGING
PROBLEMS, INCLUDING OF COURSE
PFOS, I WORK ON ASPRS WITH THE
ONTOX, RISK HUNTER, PRECISION
TOX, WE WERE TALKING YESTERDAY
WITH RISK HUNTER ON PARTNERSHIPS
THAT WE'RE GOING TO DO WITH
THEM, SPEAKING TO ONTOX TO TALK
ABOUT RAPID FRAMEWORK FOR
DEVELOPING CHEMICALS.
IF WE SEE SOMETHING WE WANT TO
USE A RAPID RESPONSE FRAMEWORK,
DEVELOPING THROUGH OSTP AS RAPID
FRAMEWORK AND MECHANIC MECHANIC
INFORMATION.
RIGHT NOW AOP FOR REGULATORS,
NICE LIBRARY OF DIFFERENT DATA,
BUT IF YOU PUT QUANTITATION IN
AND KNOW WHICH WAY IT GOES YOU
MAY HAVE A REGULATORY TOOL TO
USE LOOKING AT DIFFERENT
CHEMICALS, ONE THING WE'RE
EXPLORING.
AGAIN, PUTTING NOT ONLY SENIOR
PEOPLE BUT SOME JUNIOR PEOPLE ON
THAT TO WORK WITH EUROPEANS ON
THAT.
AND WE CONTINUE COMMUNICATION
LIKE TODAY, COMMUNICATE WHAT
WE'RE DOING.
WE'RE VERY HAPPEN TO MEET WITH
PEOPLE WHAT WE'RE DOING IN THE
FOOD INDUSTRY, ENCOURAGE
DIALOGUE, DISCUSSION,
PARTNERSHIPS, AND WE'RE
ENCOURAGING PEOPLE TO COME AND
TALK ABOUT METHODS.
I WILL TALK ABOUT -- I WASN'T
GOING TO MENTION DOG STUDIES BUT
WHAT WE DID SINCE IT WAS BROUGHT
UP BY EPA , THE ANTIQUATED RED
BOOK, HARD TO FIND ON THE WEB
FORTUNATELY, IT SUGGESTS FOR
DIRECT FOOD ADDITIVE YOU HAVE TO
DO RODENT AND NON-RODENT STUDY.
WE PULLED 160 -- HAVEN'T GOT AN
DOG STUDY SINCE 2018 BUT PULLED
160 DOG STUDIES WE DID RECEIVE
OVER THE COURSE OF OUR WHOLE
TIME AND LOOKED AT THEM.
WE PULLED OUT THE ONES THAT WE
SAID AN ADI ON, AND IF WE SET IT
ONLY ON RODENT STUDY WOULD HAVE
STILL APPROVED THAT PRODUCT.
IT LEFT ROOM TO SAY MAYBE WE CAN
PUT IN ALTERNATIVE INSTEAD OF
DOG STUDY, WE AREN'T EVEN
GETTING DOG STUDIES ANYMORE AND
WE DO HAVE A PAPER THAT'S
WRITTEN, LOST SOMEWHERE IN MY
E-MAILS, TRYING TO GET IT
PUBLISHED TO SAY, YES, THIS IS A
VERY GOOD PLACE TO PUT AN
ALTERNATIVE AND WE WELCOME IT.
SO, THAT WAS BACK ALSO -- WE
DEVELOPED -- LET ME SEE IF I CAN
GO BACK, A FOOD CHEMICAL,
PUBLIC/PRIVATE PARTNERSHIP FOR
WHAT -- AT LEAST USED BY FDA TO
PUT TOGETHER A GROUP OF PEOPLE
THAT TALK ABOUT SCIENCE, AND IT
HELPS US, YOU KNOW, IN THE FOOD
INDUSTRY, HELPS US WORK ON
ISSUES TOGETHER TO TALK TO
ISSUES OF ANYONE.
WE DO HAVE PUBLIC/PRIVATE
PARTNERSHIP, I-FISH AS CONVENER,
JUST PUT LENA ON IT.
ANOTHER WAY OF US -- GIVING US A
VALID WAY OF TALKING TO
STAKEHOLDERS, THERE'S 20
PUBLIC/PRIVATE PARTNERSHIPS IN
CDER, SEVERAL IN CDRH, VERY GOOD
HIGH SCHOOLS TO WORK WITH
EVERYBODY ON IT.
LEVERAGING RESEARCH, IDENTIFYING
WHAT GAPS WE WANT TO DO RESEARCH
ON.
THIS IS WHAT WE DO.
WE'RE RECOGNIZING IN OUR CENTER
AND HOPEFULLY THROUGHOUT FDA
THAT REGULATORS HAVE TO BE UP
FRONT IN NEW METHOD DEVELOPMENT.
WE LOOKED AT DEVELOPING GAPS.
CDER PUT OUT A PAPER A COUPLE
WEEKS AGO ON THEIR GAPS FOR WHAT
THEY NEED, AND WE ARE
CIRCULATING A LIST OF DRAFT GAPS
WHAT DATA WE NEED FOR FOOD,
INCLUDING COSMETICS, BOTANICAL,
ANYTHING WE REGULATE.
WE IDENTIFY GAPS, DELINEATE WHAT
TOOLS, AND WORK WITH OUR
RESEARCHERS OR RESEARCH PARTNERS
OUTSIDE OF THE AGENCY TO MAKE
SURE THAT WE DEVELOP A TOOL THAT
ANSWERS THOSE GAPS.
SO WE DON'T WANT TO DEVELOP
TOOLS AND TRY TO FIT THEM INTO A
REGULATORY PROGRAM.
WE WANT TO DEVELOP THE
REGULATORY GAPS AND HAVE THE
TOOLS.
I CAN'T GUARANTEE WE'RE ALWAYS
DOING THIS ON YOUR RESEARCH BUT
WE'RE TRYING.
WE DO THIS WITH NCTR.
THE LAST ONE IS OVERSIGHT BY
SENIOR MANAGEMENT.
WORKING AT FDA FOR A LONG TIME I
KNEW THAT IN THE PREDICTIVE
ROADMAP FOR FDA IF I DIDN'T PUT
IN SENIOR MANAGEMENT OVERSIGHT
IT MAY GO NOWHERE.
SO, IN THE PREDICTIVE ROADMAP
ACROSS THE AGENCY THEY HAVE TO
REPORT TO THE OFFICE OF CHIEF
SCIENTIST, AND WE HAVE TO REPORT
TO THE SENIOR MANAGEMENT IN THE
FOODS PROGRAM, INCLUDING
PROBABLY, I'M SURE YOU HEARD
ABOUT WHAT'S GOING IN THE FOODS
PROGRAM, THE NEW DEPUTY
COMMISSIONER FOR FOODS, WHEN
THAT PERSON COMES ON BOARD.
SO THAT EMPHASIZES THE
IMPORTANCE OF DEVELOPING THESE
PROGRAMS FOR THE FOODS PROGRAM
AND FOR ALL OF FDA BECAUSE ALL
OF THE CENTERS ARE REPORTING
BACK TO THE OFFICE OF THE
COMMISSIONER.
AND THEN OF COURSE WE WORK
ACROSS OUR CENTERS AS I'M
LOOKING AT SLIDES I SEE THINGS
WE CAN PARTNER WITH TOBACCO ON,
GIVING YOU CONFIDENCE THAT FDA
IS WORKING TOWARDS THIS GOAL OF
REPLACING ANIMAL STUDIES.
LIKE I SAID, WE DON'T HAVE ANY
ANIMALS IN OUR LAB ANYMORE,
EXCEPT FOR WORMS.
AND SO WE ENCOURAGE OUR
STAKEHOLDERS TO WORK WITH US.
THANK YOU FOR INVITING ME HERE
TODAY.
[APPLAUSE]
ANY QUESTIONS?
I'M OFF THE HOOK.
>> WE HAVE QUESTIONS IN THE
ROOM.
GO AHEAD.
>> THANKS, SUZIE.
LOTS OF GREAT WORK AS USUAL.
YOU MENTIONED MOUs AND CHIP
ABOUT AS GOOD AS OR BETTER
CRITERIA FOR VALIDATING AGAINST
MOUSE TEST.
IS THAT CRITERIA PUBLISHED?
>> IT WILL BE PUBLISHED.
WE'RE WORKING ON IT NOW.
EVERYTHING IS GOING TO BE
PUBLISHED.
ANYTHING THE GOVERNMENT DOES HAS
TO BE PUBLISHED.
WE WANT TO DO CASE STUDIES.
I WAS TALKING TO NICOLE ABOUT A
CASE STUDY TODAY.
ALL OF THESE GIVE US A WAY OF
TALKING TO PEOPLE LEGITIMATELY
WITHOUT SOMEONE CRITICIZING AND
SAYING YOU'RE TALKING TO THEM,
WHY AREN'T YOU TALKING TO ME.
LIKE YOU SEE WITH YOUR KIDS, WHY
DOES HE GET THIS AND I DON'T GET
THIS?
[LAUGHTER]
THE SAME THING.
>>OKAY.
>> WE'RE OPEN TO THESE
PARTNERSHIPS.
I'M ALWAYS LOOKING FOR
PARTNERSHIPS.
IT'S ONE OF MY JOBS.
>> ARE THOSE CRITERIA SIMILAR
TO WHAT I CAN VALUE -- ICCVAM IS
WORKING OR MORE DIRECT
VALIDATION?
>> IT'S A BIG QUESTION.
WHAT KIND OF CONCORDANT DATA WE
NEED, THAT'S A QUESTION THAT WE
NEED TO ANSWER, DO WE REALLY
NEED ANIMAL DATA, CONCORDANT
ANIMAL DATA, FOR EXAMPLE THAT'S
WHY WE'RE LOOKING AT
QUANTITATIVE ALPs, MAYBE WE
DON'T NEED THAT.
THAT'S ONE OF THE WORKSHOPS WE
SHOULD GET CONSENSUS ON, THROUGH
ICCVAM, A VERY GOOD TOOL TO GET
ALL THE AGENCIES TALKING
TOGETHER AND SUPPORTING EACH
OTHER ONE WE MAKE THESE
DECISIONS.
I'M NOT SURE WE NEED IT.
THERE'S SOME DISCUSSION AT FDA
DO WE NEED ANIMAL CHIPS TO DO
HUMAN CHIPS, DO WE NOT, HOW CAN
WE USE OTHER TOOLS.
WE WELCOME TALKING TO PEOPLE
ABOUT THEIR IDEAS.
THAT'S THE TOUGHEST AREA OF
QUALIFICATIONS, WHAT KIND OF
CONFIDENCE CAN YOU DEVELOP.
WE'RE OPEN TO COMMUNICATION ON
THAT.
>> THANKS, SUZIE.
>> ANYTHING ELSE?
>> THANKS, SUZIE.
JUST AS REMINDER CONTINUE TO
SEND QUESTIONS THROUGH THE
ICCVAM QUESTIONS E-MAIL.
SO NEXT PRESENTER IS PRESENTING
REMOTELY.
DR. DEANA HOLMES, WE CAN SEE
YOUR VIDEO, IF YOU CAN SHARE
YOUR SCREEN THAT WOULD BE GREAT
>> CAN YOU HEAR ME?
>> GREAT.
>> DO YOU SEE MY SCREEN?
>>NOT IN THE ROOM.
LET ME TRY AGAIN.
>> LOOKS LIKE IT'S WORKING.
YOU'RE ON YOUR SECOND SLIDE.
>> GOOD MORNING, EVERYONE.
I AM DEANA HOLMES.
THIS MORNING I'M GOING TO
PROVIDE A BRIEF UPDATE ON THE
NON-ANIMAL TESTING WORKING GROUP
AT THE SUBCOMMITTEE OF EXPERTS
ON THE GHS.
IN 2013 A WORKING PAPER WAS
SUBMITTED TO THE GHS PROPOSING
ESTABLISHMENT, PROPOSING SEVERAL
ACTIVITIES RELATED TO USE OF
NON-ANIMAL DATA SUCH AS IN
SILICO, IN VITRO, IN CHEMICO FOR
CLASSIFYING SUBSTANCES IN
MIXTURES.
USE OF A STEP WISE APPROACH,
WORKING GROUP AGREED TO BEGIN
WITH THE IRRITATION CHAPTER, TO
INCORPORATE NON-ANIMAL TEST
METHODS, AND THAT WORK WAG
COMPLETED IN 2019, UPDATE TO THE
CHAPTER, PUBLISHED IN GHS
REVISION 8.
WORKING GROUP UPDATED THE
IRRITATION CHAPTER AND THAT WORK
WAS COMPLETED IN 2021, UPDATES
WERE PUBLISHED IN THE 9th
REVISION, WORK WAS COMPLETED AT
THE END WAS COMPLETED DECEMBER
OF LAST YEAR.
PUBLISHED IN REVISION 10 OF THE
GHS.
WORKING GROUP IS STILL WORKING
ON MIXTURE CRITERIA, SKIN
SENSITIZATION, AND THAT WORK
SHOULD BE COMPLETED IN THIS
CURRENT BIENNIUM AND PUBLISHED
IN THE 11th REVISION OF GHS
AROUND 2025.
NOW, IN UPDATING SKIN
SENSITIZATION CHAPTER THE MAIN
OBJECTIVE WAS TO REVISE THE SKIN
SENSITIZATION CHAPTER TO BETTER
REFLECT INCREASED CAPABILITY,
AVAILABILITY, UTILITY FOR
CLASSIFICATION OF IN CHEMICO IN
VITRO TEST METHODS, DEFINED
APPROACHES, AND NON-TEST
METHODS, COMPUTER MODELS AND
READ ACROSS.
ONE OF THE KEY UPDATES WAS
INCLUDING A TIERED APPROACH TO
CLASSIFYING CHEMICALS,
INCORPORATED IN A SIMILAR
FASHION TO WHAT IS IN THE
CURRENT SKIN AND EYE CHAPTERS,
3.2 AND 3.3.
ALSO WEIGHT OF EVIDENCE
ASSESSMENT CAN BE APPLIED, AS
WELL AS OVERALL IF NO INDIVIDUAL
TIER RESULTS IN CLASSIFICATION.
THIS SLIDE SHOWS APPLICATION OF
TIERED APPROACH FOR SKIN
SENSITIZATION, STRUCTURE IS
BETTER DELINEATED IN THIS
UPDATE, AND PROVIDES ADDITIONAL
GUIDANCE ON HOW TO APPLY DEFINED
APPROACHES IN CHEMICO, IN VITRO,
AND NON-TEST METHODS DATA FOR
CLASSIFYING PURPOSES.
TIER 1 CLASSIFICATION IS BASED
ON HUMAN DATA.
STANDARD ANIMAL DATA WITH
ADDITION OF DEFINED APPROACHES
OR STAND-ALONE IN CHEMICO IN
VITRO METHODS.
IN ADDITION, TIER 2 NOW INCLUDES
CLASSIFICATION BASED ON
INCONCLUSIVE INFORMATION FROM
TIER 1 WITH ADDITION OF
NON-STAND-ALONE IN CHEMICO TEST
METHODS FROM DEFINED APPROACHES.
TIER 3 IS SIMILAR TO CURRENT
CHAPTER, CLASSIFICATION IS BASED
ON OVERALL WEIGHT OF EVIDENCE
ASSESSMENT BUT MAY INCLUDE SOME
ADDITIONAL INDICATORS.
IN ADDITION, IF LOWER TIER 2
SUGGESTS STRICTER CLASSIFICATION
AND THERE'S CONCERN OF
MISCLASSIFICATION YOU GO TO
TIER3, OTHERWISE CONCLUDE ON
HIGHEST CONCLUSIVE TIER.
IN LINE WITH CHAPTERS 3.3 AND
3.2, A NEW CHAPTER HOW TO
CLASSIFY SKIN
SENSITIZATIONATION, INCLUDING
COMPUTER MODELS, QUALITATIVE
STRUCTURE ACTIVITY
RELATIONSHIPS, AND QUANTITATIVE
STRUCTURE ACTIVITY
RELATIONSHIPS.
AS WELL AS READ-ACROSS USING
ANALOGUE AND CATEGORY
APPROACHES.
DEFINE APPROACHES CONSIST OF A
RULE-BASED COMBINATION OF DATA
OBTAINED FROM PRE-DEFINED SET OF
INFORMATION SOURCES.
AND IT IS RECOGNIZED THAT MOST
SINGLE NON-ANIMAL METHODS ARE
NOT ABLE TO REPLACE IN VIVO
METHODS, MOST REGULATORY
ENDPOINTS, THEREFORE DEFINED
APPROACHES CAN BE USEFUL
STRATEGIES AND COMBINING DATA
FOR CLASSIFYING SUBSTANCES AND
MIXTURE.
THE WORKING GROUP 3 SEVERAL
DEFINED APPROACHES HAVE BEEN
DEVELOPED FOR CLASSIFICATION FOR
SKIN SENSITIZATION ACCEPTED AT
THE NATIONAL LEVEL, VALIDATED
ACCORDING TO INTERNATIONAL
PROCEDURES, USE OF DEFINED
APPROACH GUIDELINES COULD BE
INCLUDED WITHIN TIERED APPROACH
FOR SKIN SENSITIZATION.
REGARDING CLASSIFICATION OF
MIXTURES, APPLICABILITY OF
NON-ANIMAL METHODS FOR THE
CLASSIFICATION OF MIXTURES BASED
ON DATA FOR THE WHOLE MIXTURE,
WAS DISCUSSED.
AS FOR OECD METHODS VALIDATION
IS LIMITED AND OECD EXPRESSED
UPFRONT CONSIDERATION COULD BE
GIVEN TO CONSIDERATION WHETHER
RESULTS WILL YIELD RESULTS
MEANINGFUL SCIENTIFICALLY.
SO GROUP IS CURRENTLY
CONSIDERING HOW TO INCORPORATE
RESULTS OF IN CHEMICO, IN VITRO,
DEFINED TESTING FOR MIXTURES
THAT DON'T CAST DOUBT ON THESE
METHODS.
THERE'S STILL A WORK IN WORK
HERE.
HOWEVER, THEY ARE EXPECTED TO
COMPLETE THIS WORK THIS
BIENNIUM.
WITH REGARD TO NEXT STEPS,
WORKING GROUP PLANS TO FURTHER
UPDATE CHAPTER 3.4 WITH FOCUS ON
NON-ANIMAL TEST METHODS FOR
RESPIRATORY SENSITIZATION.
HOWEVER THEY ARE HOLDING OFF ON
RECOMMENDATIONS, IT'S NOT
EXPECTED TO BE COMPLETED IN TIME
FOR WORKING GROUP TO INCORPORATE
DURING THIS CURRENT BIENNIUM.
HOWEVER, WORKING GROUP PLANS TO
CONTINUE UPDATING THE GHS TO
INCORPORATE NON-ANIMAL TEST
METHODS, AND ALL OF THE
CHAPTERS, WHERE APPROPRIATE, BUT
THEY ARE STILL EVALUATING WHAT
CHAPTER TO WORK ON NEXT.
SO THAT HASN'T BEEN DONE YET OR
HASN'T BEEN DECIDED YET.
SO THAT CONCLUDES MY
PRESENTATION FOR THIS MORNING.
BEFORE I END, I DO WANT TO ADD I
HAVE PROVIDED MY E-MAIL ADDRESS
HERE, AS WELL AS MY COLLEAGUE
JANET CARTER, HEAD OF DELEGATION
FOR U.S. ON GHS SUBCOMMITTEE WHO
HAS BEEN EXTREMELY ACTIVE IN
THIS WORKING GROUP AND HAS BEEN
INSTRUMENTAL IN DEVELOPING THE
UPDATES TO THE SKIN
SENSITIZATION CHAPTER.
SO, IF YOU DO HAVE SPECIFIC
COMMENTS OR QUESTIONS, FEEL FREE
TO E-MAIL JANET DIRECTLY OR OF
COURSE YOU CAN CONTACT ME AS
WELL.
THANK YOU.
[APPLAUSE]
>> THANK YOU VERY MUCH, DEANA,
A GREAT PRESENTATION.
WE HAVE A DISRUPTION IN AGENDA,
OUR COLLEAGUE FROM THE V.A.
OFFICE OF RESEARCH AND
DEVELOPMENT WAS NOT ABLE TO JOIN
US YET.
WE'RE STILL HOPING THAT THEY MAY
JOIN US LATER, BUT FOR NOW WHAT
WE'RE GOING TO DO IS WE'RE GOING
TO TAKE SOME QUESTIONS FOR SOME
PREVIOUS PRESENTERS.
ACTUALLY, DO YOU MIND?
(INAUDIBLE) OKAY, GREAT.
SO, WE HAVE A COUPLE QUESTIONS
ONLINE IN THE INTERIM.
DAVE, DO YOU WANT TO TAKE SNOWS.
>>FIRST IS ADDRESSED TO JOHN
BUT EITHER JOHN OR SUZIE COULD
ANSWER THIS.
HOW DOES CPSC AND FDA
COMMUNICATE ABOUT ANY METHOD
VALIDATIONS SO EVENTUALLY THOSE
VALIDATED METHODS CAN BE USED BY
FDA REVIEWERS?
>> JOHN, DO YOU WANT FIRST PASS
AT THAT?
>> WELL, I DON'T KNOW THAT WE
HAVE ANY FORMAL MEETINGS WITH
FDA ABOUT THIS BUT WE DO MEET
ANNUALLY ABOUT THE METHOD
ACCEPTANCE AND SUZIE AND I TALK
AT LEAST ONCE A MONTH AT OUR
ICCVAM MEETINGS, WE ARE UP ON
EACH OTHER'S VALIDATION, MAYBE
BETTER TO COORDINATE BETTER
SINCE LIKE I SAID BEFORE THE
MEDICAL DEVICE FOR FDA IS ON A
PRACTICAL LEVEL VERY SIMILAR TO
WHAT CPSC LOOKS AT, PRODUCTS ARE
METAL, PLASTIC, RUBBER, SO WE'RE
GOING TO BE LOOKING AT THOSE
PRODUCTS SIMILARLY IN OUR
TOXICITY REVIEWS.
SO, YEAH, WE COULD PROBABLY SET
UP SOMETHING MORE FORMAL IN OUR
EXCHANGES OF IDEAS BUT, YEAH,
ONCE A MONTH AT THE ICCVAM
MEETING WE ALWAYS BRING UP IDEAS
TO ONE ANOTHER.
SO WE ARE COMMUNICATING THOSE
IDEAS.
>> OKAY.
THE NEXT QUESTION IS FROM AMY
KYLE, UC-BERKLEY, ANY REPS COULD
ADDRESS.
HAS EPA OR ANYONE ELSE USED ANY
NAMs METHODS TO BETTER ASSESS
COMBINATIONS OF PESTICIDES THAT
FARM WORKERS OR COMMUNITY
RESIDENTS ARE EXPOSED TO?
CONCERNS PEOPLE ARE NOT EXPOSED
ONLY ONE PESTICIDE AT A TIME BUT
SEVERAL, AND TESTING AND
ASSESSMENT STRUCTURE DOES NOT
ADDRESS THIS VERY WELL, IF AT
ALL.
>> MONIQUE, WOULD YOU LIKE TO
TRY AND ADDRESS THAT QUESTION?
>> THANK YOU FOR THE QUESTION.
YEAH, MIXTURES AND FORMULATIONS
ARE ALWAYS A CHALLENGE,
ESPECIALLY BECAUSE ONCE A
FORMULATION IS SPRAYED, THAT
FORMULATION CHANGES ALMOST
IMMEDIATELY IN THE ENVIRONMENT
AND THIN CONTINUES TO CHANGE AS
IT CONTINUES TO DEGRADE AND SO I
ACTUALLY THINK OF NAMs AS A
SPACE, HAS A LOT OF OPPORTUNITY
TO ACTUALLY ADDRESS A LOT OF THE
CHALLENGES AND LIMITATIONS THAT
WE HAVE WITH TESTING MIXTURES
AND FORMULATIONS BECAUSE OF THE
HIGH-THROUGHPUT TESTING AND
ABILITY TO WORK THROUGH THE
DIFFERENT COMPONENTS AND THINGS
LIKE THAT SO I ACTUALLY SEE
NAMs AS HAVING THAT POTENTIAL.
I THINK WE HAVE TO WORK TOWARDS
THAT OBVIOUSLY.
BUT YEAH.
>> I'LL JUST ADD THERE'S A LOT
OF OPPORTUNITY HERE FOR WORKING
WITH EXPOSURE AND BIOMONITORING
STUDIES TO BETTER IDENTIFY WHAT
WORKERS ARE BEING EXPOSED TO.
AND THEN DESIGN STUDIES THAT CAN
MORE ACCURATELY REFLECT REAL
WORLD EXPOSURE CONDITIONS, BASED
ON THAT DATA AND BASED ON
PREDICTION MODELS THAT ARE
TRAINED OFF OF BIOMONITORING
DATA.
AND SO NICEATM HAS BEEN WORKING
WITH EPA NOT ONLY OFFICE OF
PESTICIDE PROGRAMS AND OPPT,
WITH ORD AND EXPO CAST MODELS TO
INTEGRATE EXPOSURE DATA FROM
BIOMONITORING PERSPECTIVE AND
FROM A PREDICTIVE MODELING
PERSPECTIVE INTO A LOT OF OUR
COMPUTATIONAL TOOLS AND SO ONCE
WE HAVE A BETTER HANDLE ON
VARIOUS EXPOSURE SCENARIOS WE
CAN START TO DESIGN BETTER
NAMs STUDIES TO ADDRESS THOSE.
SUZIE, DID YOU WANT TO ADDRESS
THAT?
>> FOOD IS A MIXTURE.
SO MIXTURES ARE VERY IMPORTANT
TO US.
YOU JUST DON'T EAT ONE THING.
THAT'S WHERE WE WOULD BE EXCITED
TO WORK WITH ICCVAM, ANY
PARTNERS ON MIXTURES, AND HOW DO
USE NAMs.
WE RECOGNIZE WE'RE NOT GOING TO
DO ANIMAL STUDIES ON EVERY
MIXTURE WE HAVE.
WE NEED NEW APPROACH METHODS TO
LOOK AT IT.
WE'RE LOOKING AT A GLOBAL LEVEL.
I THINK THAT'S A VERY IMPORTANT
AREA.
WHAT WAS THE QUESTION BEFORE?
DID WE WORK WITH -- I'M DONE?
>> NO, YOU'RE NOT.
ONE LAST QUESTION.
THIS IS ALSO FOR SUZIE FROM
ELIZABETH BECKER.
IN ADDITION TO AGENCY-WIDE
ADVANCING ALTERNATIVE METHODS
WORK GROUP, YOU MENTIONED CFSAN
HAS ITS OWN NAMs WORK GROUP.
COULD YOU COMMENT ON WHETHER
OTHER CENTERS HAVE ALSO
ESTABLISHED CENTER-SPECIFIC
NAMs WORK GROUPS?
>> I KNOW THEY WERE ASKED TO.
YOU ALREADY KNOW THAT WE HAVE
A -- CDER WORKS ON ICH, PARTLY
NAMs, THEY HAVE I-STAND,
BIOMARKER DDT PROGRAM, YOU HEARD
FROM JOHN ABOUT THE MEDICAL
DEVICE TOOL PROGRAM, WE HAVE A
PROGRAM, VET DRUGS IS WORKING ON
IT, CTP IS GOING TO TALK ABOUT
WHAT THEY ARE DOING.
I WAS SURPRISED LOOKING AT LUIS,
HOW MANY EXCITING THINGS.
WE'RE LOOKING ACROSS THE AGENCY,
ALSO THE COMMISSION, WHAT
EVERYBODY IS DOING ON NAMs, SO
WE SURVEYED ALL OF US, TRYING TO
WORK TOGETHER, AND THAT'S WHAT
OUR ALTERNATIVE METHODS WORK
GROUP DOES, THAT DONNA AND I
CHAIR, AND WE HAVE ON THAT ONE
NOT ONLY SENIOR PEOPLE ACROSS
AGENCY, REPRESENTATIVES FROM OUR
FIELD, NCTR, AND THEN TO JOHN'S
POINT UNDER THE CONTAMINANTS OF
EMERGING CONCERN, PART OF THAT
WE'RE LOOKING AT HOW WE WORK
CROSS-AGENCY ON SOME PROJECTS.
YOUR GROUP IS INVOLVED IN THAT I
THINK, CARLOS OR -- WE JUST --
YOU KNOW, EVERY FEDERAL AGENCY
HAS WORKED ON THIS CROSS-AGENCY,
HOW CAN WE ADDRESS SOME OF THESE
PROBLEMS, THIS IS AN INITIATIVE
WE'RE GETTING OUT OF THE WHITE
HOUSE SO I THINK YOU'RE GOING TO
SEE A LOT MORE OF COMMUNICATION
INSIDE THE FEDERAL GOVERNMENT
AND OUTSIDE THE FEDERAL
GOVERNMENT ON A LOT OF THESE
PROGRAMS.
>> THANKS, SUZIE.
WE HAD A QUESTION IN THE ROOM
EARLIER THAT WE DIDN'T GET TO.
DID YOU WANT TO ASK A QUESTION
NOW OR --
>>SURE, IF WE HAVE TIME.
>> OKAY.
>> YEAH, SORRY.
I WAS CURIOUS TO SEE IN TERMS OF
BIOTECH PRODUCTS LIKE GMOs,
GENE EDITING.
>> YOU WANT TO KNOW WHAT'S
GOING ON?
>> YEAH, IF YOU HAVE --
>>I MEAN, WE DO DO GMO FOODS.
>> RIGHT.
>> IT'S DIVIDED BETWEEN WHAT
USDA IS RESPONSIBLE FOR AND WHAT
CFSAN IS RESPONSIBLE FOR.
GMOS, THEY CAN COME IN WITH A
CONSULTATION ON WHAT WE'RE DOING
ON THAT.
AND THAT'S -- I THINK IT WOULD
BE A BIGGER PART, CFSAN AND
FOODS PROGRAM IS UNDERGOING A
REORGANIZATION AND THERE MIGHT
BE AN OFFICE OF SPECIAL FOODS,
THAT MIGHT COME UNDER THAT.
SO, SPECIAL FOOD THING.
SO IT IS SOMETHING THAT WE'RE
WORKING ON, AND WORK A LOT WITH
THE FOOD INDUSTRY ON THAT TOO
SO -- I HOPE THAT ANSWERS YOU.
>> YEAH.
>> OKAY.
THANKS, SUZIE.
WE'VE HAD A NUMBER OF QUESTIONS
OF INTEREST ACCESS TO THE SLIDES
AND VIDEO, AND SO WE CAN ADD
THESE DETAILS ON THE BREAK
SLIDE, BUT WE EXPECT A VIDEO
FROM THE MEETING TO BE POSTED ON
PAST EVENTS PAGE OF NIH
VIDEOCAST IN A WEEK OR SO, WE'LL
PUT A LINK ON THE MEETING WEB
PAGE ON THE NICEATM WEBSITE WHEN
IT'S AVAILABLE.
WE'LL BE POSTING THE SLIDES
PRESENTED TODAY AT A WEB PAGE
DEDICATED TO THIS MEETING WHEN
MADE COMPLIANT WITH GOVERNMENT
ACCESSIBILITY REQUIREMENTS,
PROBABLY IN MID-JUNE.
REGISTRANTS WILL BE NOTIFIED BY
E-MAIL WHEN THINGS ARE POSTED ON
THE WEB PAGE.
>> WE HAVE A SLIGHT CHANGE IN
THE AGENDA.
OUR DOI COLLEAGUE HAS GRACIOUSLY
AGREED TO MOVE UP INTO THIS
PRESENTATION SLOT FROM HER SLOT
AFTER LUNCH, SO NOW WE'LL BE
HEARING ABOUT THE DEPARTMENT OF
INTERIOR ALTERNATIVE APPROACHES,
SO JESSICA, OVER TO YOU.
>> THANK YOU VERY MUCH.
I'M JESSICA LEET, LOCATED AT
COLUMBIA ENVIRONMENTAL RESEARCH
CENTER, RESEARCH TOXICOLOGIST
WITH USGS WITHIN DOI.
I'M THE ALTERNATE REP, BARNETT
BRATNER COULDN'T BE HERE BUT I'M
HAPPY TO REPRESENT THE UPDATE
FOR DOI.
WE LIKE TO THROW THIS UP AS A
REMINDER OF HOW DOI IS A BIT
DIFFERENT THAN THE OTHER
AGENCIES THAT TYPICALLY DO AN
UPDATE FOR ICCVAM.
WE'RE NOT A REGULATORY AGENCY.
WE HAVE VERY LITTLE REGULATORY
RESPONSIBILITY, MOST OF OUR
MISSION IS ACTUALLY WITH
PROTECTING AND MANAGING NATURAL
RESOURCES, AND SO THAT INCLUDES
DIFFERENT ACTIVITIES, INCLUDING
RESEARCH THAT'S DIRECTED FOR
APPLICATION TO PROTECTING AN
MANAGING NATURAL RESOURCES.
THERE IS SOME ACTIVITY WITHIN
DOI FOR CHEMICAL REGISTRATION OF
NEW PRODUCTS FOR MANAGING
INVASIVE SPECIES.
ALSO, ENVIRONMENTAL CONTAMINANT
BIOMONITORING EFFORTS, AS WELL
AS NATURAL RESOURCE DAMAGE
ASSESSMENT, SO ASSESSMENTS OF
INJURY FOR LITIGATION, AS WELL
AS ASSESSMENTS OF RESTORATION.
AND THEN ALSO ALTERNATIVES FOR
LEAD SHOT IS ANOTHER AREA WHERE
WE HAVE TOXICITY TESTING, AND
USE ALTERNATIVE APPROACHES.
AND WE DO TRY TO IMPLEMENT AND
EMBRACE THE THREE Rs WHEN
POSSIBLE, SO THIS IS MY UPDATE
OF WHAT THOSE ACTIVITIES ARE
CURRENTLY.
SO, PRESENTATION FOLLOWS THOSE
FIVE AREAS THAT I JUST OUTLINED.
FIRST ONE IS UPDATE ACTUALLY
FROM THE COLUMBIA ENVIRONMENTAL
RESEARCH CENTER IN CONJUNCTION
WITH THE WATER SCIENCE CENTER IN
KANSAS, WHICH IS WHERE A LOT OF
THE HABs WORK IS DONE WITHIN
USGA, ALGAL BLOOMS, CAPACITY FOR
CHEMICAL END OF HABs WORK,
CHARACTERIZING DIFFERENT TOXINS
PRODUCED BY AGLGAL BLOOMS,
THERE'S A LOT WE DON'T KNOW.
THERE'S NOT EVEN REALLY VERY
MANY STANDARDS FOR THESE TOXINS,
THERE'S HUNDREDS OF DIFFERENT
TOXICS IN THESE BLOOMS
POTENTIALLY.
SO, IN ORDER TO INTRODUCE THE
SO-WHAT BIOLOGY END OF THE
RESEARCH, IS WHERE WE COME IN,
CONSISTENT EFFORTS TO IMPLEMENT
IN SILICO APPROACHES IN ORDER TO
POTENTIALLY SEE WHAT PREDICTIONS
MIGHT BE ABLE TO BE MADE WITH
SOME TOXINS, WE HAVE A LOT OF
INFORMATION ON CHEMICAL
STRUCTURE AND PROPERTIES,
HOWEVER THERE'S NOT A LOT OF
TOXICITY DATA.
AND SO I WAS INTERESTED IN
NICOLE'S COMMENT ABOUT
INCORPORATING BIOMONITORING DATA
INTO THESE PREDICTION MODELS, SO
WE'RE DEFINITELY GOING TO BE
PURSUING IF THERE ARE IN SILICO
APPROACHES TO PRIORITIZE WHAT
TOXINS, YOU KNOW, MIGHT BE MOST
BIOACTIVE OR OF CONCERN, AND
ALSO WE HAVE ZEBRAFISH ASSAYS
ESTABLISHED THAT CAN ALSO BE
USED FOR PRIORITIZING AND
CHARACTERIZING TOXICITY OF THE
DIFFERENT TOXINS THAT WE DO HAVE
AVAILABLE, AND SO WORKING
CLOSELY WITH CHEMISTRY TO FILL
IN DATA GAPS FOR TOXICITY WITH
THE HABs WORK.
THERE ARE EFFORTS GOING ON
MOSTLY CONCENTRATED AT UMass,
WHICH IS A CENTER ON THE UPPER
MISSISSIPPI RIVER, THEY DEAL A
LOT WITH INVASIVE CARP ISSUES.
AND SO THERE ARE EFFORTS TO
PRIORITIZE COMPOUNDS FOR
MANAGING THESE INVASIVE SPECIES,
BUT WITH AS MINIMAL IMPACT AS
POSSIBLE ON NON-TARGET SPECIES.
AND SO THERE IS A LOT OF WORK IN
VITRO, WITH THE GILL FISH CELL
LINE IN ORDER TO PRIORITIZE THE
COMPOUNDS THAT ARE BEING
PROPOSED FOR REGULATION, OR FOR
REGULATORY ACCEPTANCE, WITH
THESE NAMs METHODS IN ORDER TO
BETTER INFORM, YOU KNOW, THOSE
BEST CHEMICALS TO HIT THOSE
TARGETS BUT WITHOUT HITTING OUR
NON-TARGETS PARTICULARLY
ENDANGERED FISH SUCH AS THE
PADDLEFISH.
AND ALSO THAT GROUP IS USING,
AGAIN, SOME IN SILICO, YOU KNOW,
METHODS AS WELL, USING SPECIES
SENSITIVITY DISTRIBUTION THAT
WAS PRESENTED BEFORE WITH THE
EPA PRESENTATIONS FOR
REGISTRATION.
THERE'S BIOMONITORING EFFORTS,
BIOLUMINESCENT YEAST ASSAYS,
ASTRO GENICITY OF FIELD SAMPLES,
WITHIN USGS THERE'S ABILITY TO
NOT ONLY TEST INDIVIDUAL
COMPOUNDS BUT ALSO WE'RE LOOKING
AT TESTING FIELD SAMPLES, FIELD
EXTRACTINGS TO GET AT REAL WORLD
MIXTURE QUESTION OF WHAT KIND OF
BIOACTIVITY IS OUT IN THESE
FIELDS, SAMPLES IN ORDER TO
PRIORITIZE AREAS OF INTEREST OR
CONCERN.
AND THEN I WANTED TO BRING AN
UPDATE FROM EASTERN ECOLOGICAL
SCIENCE CENTER.
THEY HAVE BEEN WORKING FOR A
LONG TIME IN DISEASE PREVALENCE,
AND BIOMONITORING FOR DISEASE
PREVALENCE WITH PARTICULARLY
BASS, LARGE AND SMALLMOUTH BASS.
THERE IS A LOT OF CONCERN ABOUT
BLOTCHY BASS SYNDROME, ANGLERS
GET THESE BASS AND THEY HAVE
THESE BLACK SPOTS ON THEM.
AND EVERYBODY IS LIKE, WHAT'S
GOING ON HERE?
THEY HAVE IDENTIFIED NOVEL
ADENOVIRUSES THAT ARE ACTUALLY
PRESENT IN THESE BLOTCHES, AND
SO USING ACTUALLY IMAGES FROM
ANGLERS AND CELL PHONE
TECHNOLOGY WE CAN INCREASE THE
OCCURRENCE DATA FOR WHERE
THESE -- WHERE THE BLOTCHY BASS
SYNDROME IS OCCURRING BUT
WITHOUT SO MUCH HEAVY ACTUAL
SAMPLING OF THOSE FISH.
SO NO NEED TO ACTUALLY, YOU
KNOW, SACRIFICE THESE ORGANISMS
BUT HAVING ANGLERS THAT ARE
ALREADY OUT DOING THOSE
ACTIVITIES TAKING RECORD OF
THOSE AND INCORPORATING THAT
INTO OUR CURRENT DATA FOR
BLOTCHY BASS SYNDROME.
AND ALSO YOU CAN SEE HERE, IF IT
WILL PLAY, THERE'S A VIDEO
SHOWING YOU THAT ACTUALLY THIS
SWAB METHOD, YOU CAN SEE
COLORATION THAT ACTUALLY IS ON
THE SWAB FROM THIS SAMPLING.
AND STATE FISHERIES, MANAGERS,
HAVE ACTUALLY BEEN TRAINED TO
USE THIS APPROACH TO SAMPLE
AGAIN NON-INVASIVELY, NOT
HARMING THE ORGANISM, IN ORDER
TO TRACK THESE DIFFERENT
VIRUSES.
AND SO I WANTED TO GIVE THAT AS
PART OF THE UPDATE BECAUSE IT IS
RELEVANT TO THE THREE Rs
APPLICATION BECAUSE, YOU KNOW,
INSTEAD OF SACRIFICING MORE
ANIMALS OR CAUSING MORE HARM TO
ANIMALS WE'RE ACTUALLY MAKING AN
ATTEMPT TO REDUCE THAT BY DOING
NON-INVASIVE SAMPLING METHODS OR
MINIMALLY INVASIVE, DEFINITELY
NON-LETHAL.
COUPLE OTHER APPROACHES IN THE
WORK A GILL SAMPLING METHOD,
NON-LETHAL TO TRACK DIFFERENT
PATHOGENS IN THE FISH.
AND THEN ACTUALLY AT SERT USING
A.I. MODEL TO TRAIN TO
AUTOMATICALLY IDENTIFY AND COUNT
DIFFERENT WHITE BLOOD CELL TYPES
THAT YOU CAN SEE AN EXAMPLE OF
HERE IN THIS IMAGE, IN ORDER TO
INCREASE THE THROUGHPUT FOR
ANALYSIS AND REDUCE NEED FOR
EXPERTISE FOR THAT ONE ENDPOINT
IN A FISH HEALTH ASSESSMENT SO,
AGAIN, GETTING, YOU KNOW, IMMUNE
RESPONSE OR FISH HEALTH DATA, A
LOT QUICKER AND BLOOD SAMPLES
CAN BE TAKEN NON-LETHALLY,
INCREASING EFFORTS TO GET MORE
INFORMATION OVER A WIDER
GEOLOGICAL SCALE BUT WITH MORE
MINIMAL SAMPLING EFFORTS AND
PARTICULARLY WITH SACRIFICING OR
HARMING THE ORGANISMS.
ALSO ALONG THOSE LINES, AND I
KNOW I PRESENTED THIS BEFORE,
BUT JUST WANTED TO GIVE AN
UPDATE THAT USGS IN PARTICULAR
HAS VERY ACTIVE PROGRAMS USING E
DNA, ENVIRONMENTAL DNA, CELLS
THAT SLOUGHED OFF FROM ORGANISMS
THAT CAN THEN BE SAMPLED WITH
PARTICULAR WATER SAMPLING
TECHNIQUES, AGENCIES HAVE BEEN
TRAINED, FOR A VARIETY OF
APPLICATIONS SO SPECIES
MONITORING AND SURVEYING AGAIN
YOU'RE GREATLY REDUCING THE
IMPACT THAT YOU'RE HAVING ON THE
HABITAT SO A LOT LESS
DESTRUCTIVE HABITAT, OR LESS
DESTRUCTIVE ON THE HABITAT OF
THE ORGANISMS, FOR INSTANCE
MUSSELS, OR HELL BENDERS, THINGS
LIKE THAT, SO REDUCES THAT
IMPACT ON THE HABITAT WITH THE
SAMPLING USING e-DNA INSTEAD,
AND DIFFERENT ECOLOGICAL
QUESTIONS, ALSO GETTING BACK TO
TOXICOLOGY SIDE CAN ALSO USE IT
IN COORDINATION WITH CHEMICAL
SAMPLING, LOOKING AT
CONCENTRATIONS OF CONTAMINANTS,
AND USING META BARCODING
APPROACHES TO LOOK AT SHIFTS IN
THE ECOLOGICAL STRUCTURE IN THAT
PARTICULAR ENVIRONMENT.
AS I MENTIONED BEFORE WE ALSO
HAVE ONGOING EFFORT FOR
REPLACEMENT OF LEAD SHOT.
I BELIEVE IT'S LIKE 13 DIFFERENT
LEAD SHOT ALTERNATIVES APPROVED
OVER THE LAST 25 YEARS, USING NO
TOXICITY TESTING BECAUSE WE HAVE
THIS ALTERNATIVE APPROACH SET
UP, IN ORDER TO USE EXISTING
INFORMATION TO DO A RISK
ASSESSMENT AND GO THROUGH THAT
APPROVAL PROCESS.
AND THEN I ALSO WANTED TO ADD
THIS, AT THE END, A LITTLE BIT
OF AN UPDATE ON DOI AND OUR
APPROACH FOR INCORPORATING
METRICS, YOU KNOW, OF HOW WE'RE
IMPLEMENTING THE THREE Rs
REDUCING ANIMAL USE, WE REALLY
WANT TO, AS I SAID, CONTINUE TO
REDUCE ANIMAL USE AND IMPACT ON
THE ORGANISMS FOR OUR
ECOTOXICOLOGY RESEARCH, AND
TESTING BUT WITHOUT COMPROMISING
THE DATA THAT WE NEED FOR
DECISION MAKING.
WE REALLY DECIDED -- DISCOVERED
THAT FIRST OF ALL WE NEEDED TO
DEFINE TOXICITY TESTING IN DOI
BECAUSE WE HAVE A LOT OF
ACTIVITIES THAT DON'T FALL UNDER
TRADITIONAL ACTIVITIES LIKE
REGULATORY TOXICITY TESTING, FOR
EXAMPLE, AND SO WE HAVE INCLUDED
PRODUCT APPROVAL, ECOTOXICOLOGY
LABORATORY AND FIELD RESEARCH AS
WELL AS BIOMONITORING AND DAMAGE
ASSESSMENT THAT INJURY
ASSESSMENT IN WHAT WE DEFINE AS
TOXICITY TESTING.
WE SURVEYED DOI, SCIENTISTS IN
DOI ANOTHER IMMEDIATE HURDLE
COORDINATING COMMUNICATION
WITHIN DOI WHO IS DOING ANIMAL
TESTING, WHO IS DOING TOX
TESTING, AND USING ANIMALS AND
WHAT DO YOU KNOW ABOUT NAMs,
HOW ARE YOU IMPLEMENTING THEM,
ARE YOU IMPLEMENTING THEM, DO
YOU HAVE THE INFORMATION AND
RESOURCES YOU NEED TO DO SO?
WE'VE DONE INITIAL SURVEYS,
OFFERED A TRAINING COURSE
THROUGH AWIC, THEY WERE GRACIOUS
TO HELP US DEVELOPING A TRAINING
COURSE FOR DOI FOCUSED ON
ECO-TOX TESTING AN
IMPLEMENTATION OF NAMs AS
OPPOSED TO MORE BROAD AWIC
TRAINING THAT MEANS OUR TRAINING
REQUIREMENTS SO WE'RE TRACKING
FOLKS THAT HAVE TAKEN THAT
TRAINING THAT INCLUDES MORE
INFORMATION WITH NAMs.
AND THEN WE'RE ALSO IN THE
PROCESS OF UPDATING TRACKING OF
WHICH STUDIES, SO STUDY PLANS
THAT COME IN THAT ARE USING
THESE NAMs, IN THEIR
APPROACHES, AND REDUCING THEIR
ANIMAL USE THAT WAY, ALSO AS I
SAID COORDINATING ALL THESE
THINGS HAS BEEN A CHALLENGE, AND
SO WE'RE ALSO IN THE PROCESS OF
ATTEMPTING TO FORMULATE A
WEBSITE THAT CAN BE USED BY DOI
SCIENTISTS AS WELL AS
PUBLIC-FACING WEBSITE THAT WOULD
ALLOW THE PUBLIC TO SEE WHAT
ACTIVITIES DOI SPECIFICALLY IS
DOING IN THESE EFFORTS.
BUT ALSO PROVIDING INFORMATION
FOR DOI SCIENTISTS IN A
CONCENTRATED AREA THAT'S
SPECIFIC TO THE WORK THEY DO
THAT WOULD GIVE THEM MORE
INFORMATION ON THE NAMs
APPROACHES THAT ARE AVAILABLE.
THAT'S ALL I HAVE.
THANK YOU.
[APPLAUSE]
>> THANK YOU.
WE HAVE TIME FOR QUESTIONS.
WE'LL START WITH THE ROOM IF
THERE'S ANY QUESTIONS FOR
JESSICA IN THE ROOM, AND THEN
FOLLOWING THAT WE'LL GO TO SOME
ADDITIONAL QUESTIONS THAT HAVE
COME IN ONLINE IN THE INTERIM
TIME.
FIRST ANY QUESTIONS FOR JESSICA?
>> YEAH, HI.
ALISON HARRILL, EPA.
I HAD A QUESTION ABOUT SOME IN
VITRO STUDIES THAT YOU'RE DOING
WITH GILL CELLS.
YOU SHOWED YOU'RE DOING SOME
HIGH-THROUGHPUT ASSAYS BUT I
DIDN'T SEE A LOT OF DETAIL ON
WHAT PHENOTYPES YOU'RE LOOKING
FOR, WONDERING IF YOU CAN GIVE
MORE CONTEXT AROUND THE STUDIES
THAT YOU'RE DOING.
>> I'M ACTUALLY NOT DOING THOSE
STUDIES.
I'M PERSONALLY NOT DOING THOSE
STUDIES BUT CAN GET YOU IN
CONTACT WITH THE GROUP AT
UMass THAT IS DOING THAT
RESEARCH AND THEY COULD GIVE YOU
MORE INFORMATION FOR SURE
>>I'D BE REALLY INTERESTED IN
THAT BECAUSE WE'RE STARTING TO
DO SIMILAR WORK AT EPA.
>> OKAY, YEAH.
YEP, I CAN GET THAT YOU CONTACT
INFORMATION SO YOU GUYS CAN
COORDINATE.
>> AWESOME, THANK YOU.
>> YEAH.
>> I THINK WE HAD A COUPLE
QUESTIONS ONLINE FOR PREVIOUS
PRESENTERS.
>> JUST ONE FOR ANNA LOWIT.
TIFFANY STATES I'D LIKE TO LEARN
WHERE OPPT IS HEADED WITH THE
STAKEHOLDER ACCEPTANCE OF THE
EYE IRRITATION AND RESPIRATORY
SENSITIZATION NON-ANIMAL
METHODS.
>> YEAH, THANKS FOR THE
QUESTION, TIFFANY.
SO WE DID PRESENT AT THE SOT
ONGOING WORK WE HAVE WITH OUR
EXTERNAL COLLABORATORS ON EYE
IRRITATION SO THAT WAS IN MY
PRESENTATION, AND THAT POSTER
CAN BE FOUND ON THE SOT WEBSITE
STILL, OR I CAN SEND IT TO THOSE
INTERESTED.
WE'RE ACTIVELY WORKING
INTERNALLY ON SIMILAR FRAMEWORKS
FOR SKIN IRRITATION, AND ARE
JUST STARTING TO THINK ABOUT
SKIN SENSITIZATION SPACE AND HOW
TO BRING IN THE NEW DEFINED
APPROACH, AND MAKE THE MOST OF
THE ONGOING EFFORTS AT OECD IN
THE SERA MODEL.
THIS RESPIRATORY SENSITIZATION
WORK IS IN MY MIND FROM A
REGULATORY POINT OF VIEW
MULTIPLE YEARS AWAY FROM USE.
THERE ARE A COUPLE GROUPS
WORKING ON THESE ASSAYS AND THE
OECD IS GOING TO DEVELOP A STATE
OF THE SCIENCE PAPER ON WHERE
THEY ARE AND WHAT ADDITIONAL
WORK MAY OR MAY NOT NEED TO BE
DONE IN TERMS OF CONFIDENCE
BUILDING AND THERE ARE PROBABLY
PEOPLE IN THIS ROOM WHO KNOW THE
STATUS BETTER THAN I DO.
THERE'S REASON TO BE OPTIMISTIC
BUT I THINK WE'RE SEVERAL YEARS
AWAY FROM HAVING A TOOL THAT WE
CAN USE.
>> OKAY.
ANY ADDITIONAL QUESTIONS FROM
ONLINE YET?
NOPE?
OKAY.
SO WE ARE ACTUALLY BREAKING FOR
TWO HOURS FOR LUNCH.
PARTIALLY BECAUSE THE NATCHER
CENTER AT NIH HAS NOT REOPENED
THEIR CAFETERIA YET POST-COVID
FOR OUR IN-PERSON ATTENDEES WE
HAVE A SHUTTLE TO TAKE YOU TO A
CAFETERIA ON THE OTHER SIDE OF
THE NIH CAMPUS.
FOR THOSE ONLINE, YOU GET A NICE
TWO-HOUR BREAK TO CATCH UP ON
E-MAILS AND COME BACK AND JOIN
US AT 1:20 P.M.
WE WILL BE KICKING OFF IN THE
AFTERNOON WITH AN EXCITING
UPDATE FROM CHARLES KOVATCH,
OECD COORDINATOR, WITH GREAT
CONTENT IN PRESENTATIONS AFTER
LUNCH.
FOR THOSE WHO ARE WATCHING THE
WEBCAST, PLEASE FEEL FREE TO
SEND YOUR QUESTIONS TO THE
ICCVAM QUESTIONS NIEHS E-MAIL
ADDRESS AND WE'LL ADDRESS THOSE
AFTER LUNCH DURING ONE OF THE
DISCUSSION SECTIONS.
FOR NOW WE'LL BREAK FOR TWO
HOURS, SEE YOU BACK AT 1:20 P.M.
THANKS.
WE ARE NOW GOING TO START WITH OUR
AFTERNOON SESSION.
SO, FIRST CAN I JUST DOUBLE
CHECK, CHARLES, THAT -- GO ON.
FIRST, WELL, I NEEDED THOSE.
THANKS, DAVE.
IT'S OKAY, I'LL DO IT.
CAN I FIRST DOUBLE CHECK,
CHARLES, THAT YOU'RE ONLINE AND
WE CAN HEAR YOU?
>> YES, I'M ONLINE.
CAN YOU HEAR ME?
>>I CAN.
YOU COME IN LOUD AND CLEAR.
THANK YOU SO MUCH.
>> PERFECT.
>> OKAY.
SO, ARE YOU SEEING YOUR SLIDES
AS THEY SHOULD BE PROJECTED?
>> NO, I DON'T.
>>OKAY.
>> YES, I DO.
WELL, ALMOST.
>> HOW ABOUT NOW?
IT'S ON THE FIRST SLIDE?
>> I SEE THE SLIDES.
IT'S NOT ON MY MAIN COMPUTER,
IT'S WEIRD, LIKE ON THE
SUBWINDOW, BUT AS LONG AS
EVERYBODY ELSE CAN SEE THEM,
WE'RE FINE.
>>WE'RE GETTING THE FEEDBACK
THAT IT IS BEING PROJECTED ON
THE WEBCAST APPROPRIATELY SO
IT'S OKAY.
SO, IF YOU WANT TO JUST GO AHEAD
AND TELL ME WHEN YOU'D LIKE ME
TO GO TO THE NEXT SLIDE I'D BE
HAPPY TO DO THAT FOR YOU.
ALL
RIGHT.
>> ALL RIGHT.
YOU CAN STILL HEAR ME?
>>YOU SOUND GREAT.
>> ALL RIGHT.
WELL, HI, FOLKS.
CHARLES KOVATCH, NATIONAL
COORDINATOR TO THE OCWNT, ALSO
EPA OFFICE OF CHEMICAL SAFETY,
POLLUTION PREVENTION.
I WISH I COULD BE WITH YOU THERE
TODAY.
HOWEVER, WE HAVE A BUG OF THE
BIOLOGICAL KIND KEEPING US AT
BAY.
NEXT SLIDE.
GREAT.
I ALWAYS THINK IT'S GOOD TO
START WITH AN OVERVIEW, REMINDER
OF OF OECD STANDS FOR.
IT'S A COLLABORATIVE BODY THAT
WORKS ON A NUMBER OF ISSUES.
IT'S BEEN AROUND SINCE THE
'50s, SO EPA -- THE UNITED
STATES IS A MEMBER COUNTRY TO
THE OECD, SPECIFICALLY LOOKING
AT CHEMICALS, BIOTECHNOLOGY
COMMITTEE.
WE'RE ONE OF THE MEMBER
COUNTRIES WORKING UNDER THE CDC,
A NUMBER OF TOPICS, WE'RE
SPECIFICALLY SUPPORTING THE
MUTUAL ACCEPTANCE OF DATA.
TWO PILLARS ARE TEST GUIDELINES
AND GOOD LABORATORY PRACTICE.
SO, FROM THE WNT PERSPECTIVE,
WHAT WE'RE WORKING ON, EACH YEAR
WE MEET, MEMBER COUNTRIES WORK
TO DEVELOP AND THEN APPROVE AND
HARMONIZE THE TEST GUIDELINES
THAT WILL BE ADOPTED AND USED BY
MEMBER COUNTRIES, IN SUPPORTING
THAT.
NEXT SLIDE PLEASE.
SO WE HELD A MEETING LAST MONTH,
ANDING BIG THANKS TO NICOLE WHS
THERE IN PERSON.
I WAS PARTICIPATING REMOTELY.
IT WAS A GOOD MEETING OVERALL, A
GOOD MEETING FOR US.
WE SAW A NUMBER OF DOCUMENTS
THAT WERE ADDS, SPSF PROPOSALS
TO THE WORKPLAN, GUIDELINES,
TEST GUIDELINES THAT WERE
APPROVED, I'LL TOUCH ON A FEW
AREAS THE UNITED STATES WAS
SPECIFICALLY INVOLVED ON THOSE
DOCUMENTS, MENTIONED ANY
BUSINESS WE INTRODUCED AND TOUCH
BASE ON OTHER ITEMS THAT ARE
COMING AND THINGS OF NOTE THAT
YOU MIGHT FIND INTERESTING.
NEXT SLIDE.
SPSFs, SO I PROVIDED HERE A
LIST OF THE DIFFERENT PROPOSALS
THAT WERE APPROVED BY THE WNT
FOR ADDITION TO THE WORK PLAN.
YOU'LL SEE ON THIS SLIDE THE
NUMBERS, ONE OF THEM WAS --
NUMBER 5 WAS REMOVED.
EVEN THOUGH THERE ARE 12 GOING
TO THE WORKPLAN MEMBERSHIP TEAM,
THE CORRECTIONS TO TEST
GUIDELINES, THAT'S NOT
NECESSARILY ADDED TO THE WORK
PLAN BUT PART OF THE FORMALITY
OF THE WNT PROCESS BUT I HAVE IN
FRONT OF ME 12 ADDED TO THE WORK
PLAN.
THE U.S. IS LEAD OR CO-LEAD ON
TWO.
FIRST WHICH ANNA MENTIONED IN
HER TALK THIS MORNING IS A
DETAILED REVIEW PAPER,
FACILITATE DEVELOPMENT OF TEST
METHODS, RESPIRATORY
SENSITIZATION POTENTIAL.
OUR CURRENT UNDERSTANDING, THE
PAPER WILL TALK ABOUT OUR
CURRENT UNDERSTANDING OF THE
MECHANISMS OF RESPIRATORY
SENSITIZATION SUMMARIZING MODELS
AND DIFFERENT APPROACHES AND HOW
IT ADDRESSES OUR REGULATORY
NEEDS.
SO WHAT'S THE CURRENT STATUS
TODAY, AND I WILL SAY EVEN FROM
THE FIRST CONVERSATION THERE WAS
A LOT OF INTEREST AND SUPPORT
FOR THIS PROJECT.
IT'S FILLING A GAP AND A NEED
FOR WHICH THERE'S CURRENTLY NO
HARMONIZED APPROACH.
SO WE LOOK FORWARD TO
DEVELOPMENT OF THIS PROJECT.
THAT'S ALL I CAN SAY ABOUT THIS
ONE, IT JUST STARTED BUT WE'RE
EXCITED TO BE CO-PARTNER WITH
THE CO-LEADS.
THE OTHER ONE I WANT TO MENTION
IS REVISION OF GUIDANCE DOCUMENT
34, VALIDATION OF ACCEPTANCE.
GD 34 IS THE FOUNDATIONAL
GUIDELINE FOR APPROVAL OF TEST
GUIDELINES, AND AS A WAY TO MAKE
ANY CHANGES FOR ANY UPDATES TO
TEST GUIDELINE OECD DOCUMENTS
HAVE TO MAKE A PROPOSAL.
SO THE UNITED STATES WITH
EUROPEAN COMMISSION AND DENMARK
ARE CO-LEADS ON THIS EFFORT, ALL
OTHER COUNTRIES WILL BE ENGAGED
ON THIS BUT NONETHELESS WE'RE
THE CO-LEADS TO ADDRESS A LOT OF
POINTS OF THE TEST GUIDELINE
PROCESS, WHERE, YOU KNOW, IT'S
BEEN 20 YEARS SINCE THE DOCUMENT
WAS DEVELOPED, AND SO HOW -- AS
WITH ANY PROGRAM THERE'S A
NATURAL EVOLUTION, SO WHERE IS
THE TEST GUIDELINE PROGRAM
SUPPORTING OUR CURRENT NEEDS AND
MAYBE THINGS THAT NEED TO BE
REFRESHED, SPECIFICALLY WHERE
CAN WE TURN TO UPDATE THE TEST
GUIDELINE PROGRAM TO BETTER
RECEIVE NAMs.
I'LL SPEAK MORE ABOUT THIS LATER
BUT THAT'S A TEASE FOR NOW.
NEXT SLIDE PLEASE.
AS I MENTIONED, A NUMBER OF TEST
GUIDELINES AND GUIDANCE
DOCUMENTS WERE APPROVED BY
CONSENSUS AT THE MEETING.
WE'LL HIGHLIGHT ONE HERE,
REVISION OF TEST GUIDELINE 240,
MEDAKA AS IT'S KNOWN, DESCRIBES
TEST BASED ON DISH EXPOSED OVER
MULTIPLE GENERATIONS TO GIVE
RELEVANT ECOLOGICAL HAZARD AND
RISK ASSESSMENT FOR CHEMICALS.
SO THIS GROUP THAT WAS CO-LEAD
AT U.S. AND JAPAN WORKED
TOGETHER TO REVISE THE DOCUMENT,
YOU KNOW, UPDATE SOME COMPONENTS
OF IT AND SPECIFICALLY ADD
ANOTHER ENDPOINT WHICH IS
EXTENDING THE SECOND GENERATION
BEYOND HATCH TIME SO AGAIN
REALLY PLEASED WITH HOW THIS
DOCUMENT TURNED OUT AND REALLY
APPRECIATE THE COLLABORATIVE
NATURE WE HAD WITH JAPAN.
NEXT SLIDE PLEASE.
THIS IS GROUPING OUT DIFFERENT
DOCUMENTS APPROVED.
MORE ON THE HEALTH AND STATE
SIDE.
MONIQUE MENTIONED THIS DOCUMENT
IN HER TALK ON DNT.
UNITED STATES IS ACTIVELY
ENGAGED WITH NUMEROUS
ACTIVITIES, AND THIS DOCUMENT,
THIS DEVELOPMENTAL NEUROTOXICITY
AND IN VITRO TESTING BATTERY
AIMS TO DESCRIBE ASSAYS THAT
COMPRISE THE BATTERY IN TERMS OF
NEURODEVELOPMENT, PROVIDES
CRITERIA THAT WILL ALLOW
EVALUATION OF THE RELEVANCE OF
THE DATA TO DEVELOPMENTAL
NEUROTOXICITY.
DOCUMENT SUPPORTS REGULATORY
OBLIGATION, HELPS ADDRESS THE
CHALLENGES TO INTERPRET DNT
DATA, ALSO HIGHLIGHTS ADVANTAGES
OF NAMs.
IT SERVES AS AN IMPORTANT
MILESTONE FOR US, INTERNATIONAL
RECOGNITION OF UTILITY OF
NAMs, FOR DNT AND IT'S
HOPEFULLY TO ENCOURAGE
EXPLORATION OF HOW NAMs CAN BE
USED FOR REGULATORY PURPOSES.
GREAT MILESTONE FOR THIS BODY OF
WORK.
NEXT SLIDE PLEASE.
SO THIS SLIDE YOU'LL SEE SOME --
FOUR TOPICS, GREEN CHECK MARKS.
WHAT'S INTERESTING IS IT'S
SHOWING CONTINUITY, IF YOU WERE
HERE LAST YEAR I MENTIONED THESE
FOUR TOPICS.
AND SO IT'S INTERESTING TO SEE
LIKE THERE HAS BEEN PROGRESS
OVER THE PAST YEAR.
GREEN CHECK MARK INDICATES THIS
IS WHAT WE TALKED ABOUT LAST
YEAR, WHAT HAS HAPPENED OVER THE
PAST YEAR.
AND WHERE WE'RE HEADED.
SO, THE OMICS FRAMEWORK WAS A
MODULE, AND SO THOSE HAVE BEEN
DEVELOPED, DRAFT HAS BEEN I
GUESS YOU COULD SAY MADE
AVAILABLE.
AND NOW U.S. IS INVOLVED IN
TRIALS TO INCORPORATE DIFFERENT
DATA SOURCES INTO THIS
FRAMEWORK.
WE THINK IT INCREASES
REPRODUCIBILITY OF OMICS
ANALYSIS, AND WE'RE EXCITED THAT
THIS REGULATORY TOOL WILL BE
AVAILABLE, STILL IN THE TRIALING
STAGE TO CONFIRM ITS UTILITY,
CHECK FOR BUGS, AND IMPROVE
GUIDANCE DOCUMENT.
HOWEVER, WE EXPECT THIS COULD BE
COMING OUT AND MADE AVAILABLE
SOON.
IN THE MEANTIME YOU CAN FOLLOW
THE WEB LINK AND SEE WHERE THEY
ARE.
THYROID METHOD, DISRUPTION
GROUP, LAST YEAR JUST FORMED SO
WORKING ON VALIDATION
ACTIVITIES, THYROID DESTRUCTION,
BATTERIES OF ASSAYS, HELD A
MEETING LAST WEEK, FIRST BIG
MEETING, TO DISCUSS OUTCOME OF
ASSAYS DISCUSSED AND NEXT STEPS.
WNT WILL BE INFORMED OF WHAT
THEY DISCUSSED AND I'M SURE MADE
AVAILABLE IN THE NEAR FUTURE.
NEXT ONE IS -- LAST YEAR, THIS
IS THE LAST TIME YOU'LL SEE THIS
ACRONYM, EAGMST, REPLACED BY
ESCA.
IT WAS AN ADVISORY GROUP, A LOT
OF ACTIVITY, BUT IT NEEDED TO BE
REVISED, REFRESHED TO BETTER
HELP SUPPORT WNT AND WPHA, A
WORKING PARTY FOR HAZARD
ASSESSMENT, NOW ESPA IS
RESPONSIBLE FOR WPHA AND WNT,
ADVISORY CAPACITY, LOOKING
FORWARD, APPLICATION OF EMERGING
SCIENCE.
WHAT'S REALLY EXCITING IS THAT
IT WILL BE LIKE, YOU KNOW, MORE
COORDINATION, MORE TRANSPARENCY,
MORE DIRECTION IN A WAY, WHERE
THERE WAS -- THERE WERE A LOT OF
PROJECTS HAPPENING, MAYBE FOLKS
DIDN'T UNDERSTAND HOW THEY
ALIGNED OR WERE SUPPORTED.
NOW WITH INCREASED COORDINATION
AND TRANSPARENCY LOOKING AT
DEVELOPING NEW AOPs, IATAs
OR NAMs, THERE'S A MORE FORMAL
PROCESS, OPERATING MODEL FOR
DIRECTED WORK.
WHAT'S ALSO INTERESTING IS WE'VE
HEARD TODAY ABOUT THE WORK WITH
NAMs.
WE HEARD FROM CPSC, FDA, AND
OTHERS, AND THIS IS WHERE ESCA
IS GOING TO MIRROR WHERE THE
UNITED STATES IS MOVING TOWARDS
MORE COORDINATED, THROUGH
ICCVAM, LOOKING AT METHODS AND
NEW SCIENCE FOR CHEMICAL SAFETY
ASSESSMENT.
AND SO THE NEXT ONE, I TOLD YOU
I'D GET BACK TO THIS.
EMERGING TECHNOLOGIES IS THE
GUIDANCE DOCUMENT 34.
SO WE'RE WORKING TOWARDS
IMPROVING TEST GUIDELINE PROGRAM
AND REVIEW OF NAMs, AND THIS
PROPOSED REVISION TO DOCUMENT 34
WILL ENTAIL RECOMMENDATIONS
DERIVED FROM WNT, FROM THE
WORKSHOP THAT WE HELD FROM
PRACTICAL EXPERIENCE, AND OTHER
LESSONS LEARNED, PUBLISHED
WITHIN THE LITERATURE, ON WHERE
CAN THE PROGRAM AND THE PROCESS
BE IMPROVED.
OVER THE PAST YEAR THE WNT AND
U.S. TEAM, ALLISON, YOU'RE IN
THE ROOM AS WELL, ON THIS
STEERING GROUP TO, YOU KNOW, TRY
TO FIND OUT HOW CAN WE APPROACH
THIS LARGE TOPIC, RECOGNIZING
IT'S GOING TO BE A LONG
CONVERSATION, WE HELD SIX
WEBINARS LAST YEAR, TRIED TO GET
EVERYBODY -- LIKE WHEN WE SAY
REPRODUCIBILITY, WHAT DO WE
MEAN?
DO WE ALL -- ARE WE THINKING THE
SAME THING?
HOW DO WE DEFINE WHERE THERE
MIGHT BE A CHALLENGE ON ISSUE OR
BARRIER, AND THEN LET'S RESTORE
SOME WAYS TO OVERCOME.
SIX WEBINARS LAST YEAR, YOU CAN
GO TO THE WNT WEB PAGE AND
REVIEW ALL OF THOSE COVERING
GOOD IN VITRO METHOD PRACTICES,
ECOTOXICOLOGY, PROBABILISTIC
MODELING, WE DISCUSSED ALL THOSE
TOPICS AND THEN USED WHAT WE
LEARNED FROM THOSE WEBINARS,
INFORM OUR STRUCTURE FOR
DISCUSSION AT THE WORKSHOP HELD
IN DECEMBER 2022, TALKING ABOUT
THE SAME THINGS, TEST READINESS,
PERFORMANCE STANDARDS, BATTERIES
OF ASSAYS, INCENTIVIZING
VALIDATION STUDIES, THOSE
DISCUSSIONS THEN WILL HELP US
FOR THIS YEAR SO NOW THAT THE
SPSF PROPOSAL HAS BEEN APPROVED
WE WILL BE MOVING FORWARD WITH
SOME RECOMMENDATIONS THAT CAME
OUT OF THE WORKSHOP TO TACKLE
AND ADDRESS THESE TOPICS TO SEE
HOW THEY SHOULD BE OR WHERE THEY
NEED TO BE IF THEY NEED TO BE
UPDATED OR REVISED IN THE
GUIDANCE DOCUMENT, JUST AS A
GENERAL RULE OF PRACTICE AS WELL
AS BETTER ACCOMMODATE FOR
NAMs.
WHAT'S EXCITING WE HAVE THIS
BODY HERE, RIGHT?
THROUGH THE WORK THAT WE'RE
DOING ACROSS THE FEDERAL
GOVERNMENT BUT INDIVIDUALLY AND
COLLECTIVELY AND THROUGH ICCVAM
THAT WE'RE GOING TO HELP INFORM
THE REVISIONS TO GUIDANCE
DOCUMENT 34.
THERE'S GOING TO BE A LONG
CONVERSATION AND WE LOOK FORWARD
TO WORKING WITH EVERYBODY HERE
ON AS WE REVISE THAT DOCUMENT.
NEXT SLIDE PLEASE.
WRAPPING UP WITH A FEW OTHER
ITEMS, WANTED TO NOTE, THE OTHER
WORKING PARTIES, GOOD LABORATORY
PRACTICES, THEY PUBLISHED A
DOCUMENT, GLP AND CLOUD
COMPUTING, OUTLINES
RESPONSIBILITIES, COMPLIANCE TO
GLP PRINCIPLES USING CLOUD-BASED
SOLUTIONS.
WHAT'S INTERESTING, YOU CAN'T
SET A STANDARD FOR MUST USE A
CERTAIN TYPE OF SYSTEM, BUT WHAT
THEY ARE TRYING TO DO IS
RECOGNIZING WITH WHATEVER RISKS
AND VULNERABILITIES WITH YOUR
SYSTEM AND ENSURING YOUR DATA
INTEGRITY, WHAT THEY ARE ALSO
MOVING TOWARDS ARE STARTING
DISCUSSIONS ON GLP FOR EMERGING
TECHNOLOGIES, NOT TRYING TO MEET
CERTAIN I GUESS TECHNICAL
PERFORMANCE, MORE LIKE A
CHECKLIST OR DECISION TREE WHERE
INSPECTORS OF EMERGING
TECHNOLOGIES AND TEST FACILITIES
TO ENSURE HAVE YOU THOUGHT HOW
YOU'RE ADDRESSING VULNERABILITY,
THAT'S A HEADS UP, SOMETHING
THEY HAVE DEVELOPED AND SEE THAT
COULD BE POTENTIAL FOR FURTHER
DISCUSSION IN THE FUTURE.
LAST TWO ITEMS ARE ANY OTHER
BUSINESS, SO AT THE END OF THE
WNT MEETING THERE'S AN
OPPORTUNITY FOR PEOPLE TO
INTRODUCE ANY OTHER BUSINESS.
SO THE UNITED STATES, WE OFFERED
TWO DIFFERENT TOPICS FOR ANY
OTHER BUSINESS.
ONE WAS A RECAP OF A WORKSHOP
HELD IN MARCH OF THIS YEAR
PROVIDING STATUS WHERE, YOU
KNOW, ESPECIALLY ROADMAP AND
INTEGRATION OF ECGs, WE HAD
CO-ORGANIZERS FROM NATIONAL
TOXICOLOGY PROGRAM, AS WELL WITH
JOHNS HOPKINS CENTER FOR
ALTERNATIVES ANIMAL TESTINGS,
REPRESENTATIVES AND PARTICIPANTS
FROM ACROSS FEDERAL GOVERNMENT,
AS WELL AS SOME OF OUR PHARMA
PARTNERS AND TALKING ABOUT SOME
CHALLENGES TO IMPLEMENTATION
LIKE DATA CURATION TERMINOLOGY
ISSUES, LACK OF VALIDATION, AND
GENETIC DRIFT OR OTHER
BIOLOGICAL FACTORS.
SO PROVIDING AN UPDATE FROM THAT
MEETING.
AND THEN THE HISTORICAL CONTROL
DATA, ANOTHER TOPIC WE
INTRODUCED, LOOKING AT --
THERE'S A GROUP WHO WILL LIKELY
BE PRESENTING SPSF THIS FALL
THAT IS LOOKING AT IN VIVO
HISTORICAL NEGATIVE CONTROL
DATA, SPECIFICALLY FOR THIS
GROUP LOOKING AT GENETIC
TOXICOLOGY, BUT I THINK WHAT'S
TELLING IS THAT WHAT THEY ARE
FINDING THAT, YOU KNOW, WE DON'T
HAVE A LOT OF GUIDANCE HOW TO
USE HISTORICAL CONTROL DATA AND
EVALUATE THE QUANTITY AND
CALCULATE INTERVALS THAT ARE
ACTUALLY HERITABLE.
IT HAS BROADER APPLICATION
BEYOND THEIR FOCUS OF GENE TOX,
SO IT'S SOMETHING WE'RE
INTERESTED IN SEEING HOW IT
EVOLVED AS WELL.
IT DOES PROMPT ME TO REMIND
EVERYBODY IF YOU HAVE AN IDEA
THAT YOU WOULD LIKE TO SEND
FORWARD, THE SPSF PROPOSALS ARE
DUE TO THE SECRETARIAT BY
NOVEMBER 15 OF THIS YEAR, 2023.
YOU CAN FIND MORE INFORMATION AT
THE LINK OR CONTACT ME DIRECTLY.
NEXT SLIDE, WHICH IS QUESTIONS.
I DON'T KNOW IF WE'RE TAKING
THOSE NOW OR WAITING TILL LATER.
>> SURE, WE CAN TAKE QUESTIONS
NOW.
I WILL JUST, FORGIVE ME,
CHARLES, MAKE ONE SMALL
CORRECTION.
>> OH, PLEASE DO, YEAH.
>> WE'RE CO-LEADING THE GD 34
REVISION PROJECT WITH EUROPEAN
COMMISSION AND NETHERLANDS, NOT
DENMARK.
THAT BEING SAID, IT WAS
IMPORTANT PART OF THE ENTIRE WNT
DISCUSSION THAT BECAUSE AS YOU
INDICATED THIS IS SUCH A
FOUNDATIONAL DOCUMENT FOR
VALIDATIONAL METHODS INTENDED TO
GO INTO OECD TEST GUIDELINES,
EXPECTATION IS THE EXPERT GROUP
FORMED TO REALLY OVERSEE AND
CONTRIBUTE TO THE REVISION OF GD
34 WILL BE COMPRISED OF THE
ENTIRE WNT AND WHATEVER SUBJECT
MATTER EXPERTS ON VALIDATION
THAT RESPECTIVE COUNTRIES DECIDE
TO NOMINATE, A SMALL
♪ -- SMALL NOTE THERE.
ANY QUESTIONS FOR CHARLES, IN
THE ROOM OR ELSEWHERE?
THANK YOU, CHARLES.
THAT WAS EXCELLENT.
SO I WANT TO MAKE A NOTE THAT WE
HAVE HAD A NUMBER OF QUESTIONS
COME IN ONLINE, OVER THE LUNCH
BREAK.
SO WE WILL GET TO THOSE
QUESTIONS BEFORE WE TAKE OUR
MID-AFTERNOON BREAK.
SO WE UNFORTUNATELY STILL DON'T
HAVE OUR COLLEAGUES FROM THE
V.A. OFFICE OF RESEARCH AND
DEVELOPMENT SO WE'RE GOING TO GO
TO -- AS YOU ALL WILL RECALL,
OUR COLLEAGUE FROM THE
DEPARTMENT OF THE INTERIOR WAS
KIND ENOUGH TO SWITCH HER
PRESENTATION TO BEFORE LUNCH, SO
NOW WE'RE GOING TO GO TO DR.
ELIJAH PETERSEN FROM NATIONAL
INSTITUTE OF STANDARDS AND
TECHNOLOGY.
YOU'LL BE SHARING YOUR SLIDES
DIRECTLY, IS THAT CORRECT?
>> SURE.
I CAN DO THAT.
CAN YOU HEAR ME OKAY?
>>WE CAN HEAR YOU GREAT.
AND WE CAN SEE YOU VERY WELL.
>> OH, GOOD.
LET'S SEE.
I'M NOT SEEING HOW TO SHARE WHAT
I WANT TO BE SHARING.
>> YOU DON'T SEE THE GREEN
SHARE SCREEN BUTTON?
I DO BUT MY PRESENTATION IS
NOT POPPING UP.
I DID E-MAIL STEPHEN SO
HOPEFULLY YOU SHOULD HAVE IT.
>> OKAY.
>> I COULD TRY TO SHARE MY
SCREEN AND GO OVER THE
PRESENTATION.
MAYBE I'LL TRY THAT.
IS THAT WORKING?
>>LOOKS GREAT, YEP.
>> OKAY.
GREAT.
MY APOLOGIES FOR NOT BEING IN
PERSON.
I'M ALSO, LIKE CHARLES, I HAVE A
BIT OF A BIOLOGIC BUG RUNNING
AROUND THIS HOUSEHOLD SO I
DIDN'T WANT TO GET EVERYONE ELSE
SICK.
SO I'LL JUMP RIGHT IN.
HAPPY TO SHARE ON BEHALF OF
MYSELF AND MY COLLEAGUE JOHN
ELLIOTT WHAT WE'VE BEEN UP TO AT
NIST WITH MEASUREMENT SCIENCE
ACTIVITIES AND ICCVAM.
SO, I THINK WE WORKED ON A
TECHNICAL FRAMEWORK MANUSCRIPT,
A GOVERNMENT-WIDE EFFORT WITH A
NUMBER OF COLLEAGUES FROM
DIFFERENT AGENCIES INCLUDING
NIST AND INTERNATIONAL
COLLEAGUE, HAPPY TO SHARE THAT,
THIS PAPER DISCUSSING QUALITY
SIDE OF HELPING DEVELOP METHODS
PUBLISHED LAST YEAR IN ALTEX,
CAME OUT IN THE JANUARY EDITION
THIS YEAR.
I'LL SHARE MORE ABOUT THAT.
SO, AGAIN, REALLY A
COLLABORATIVE EFFORT, A NUMBER
OF AGENCIES.
THE GOAL HERE IS TO -- WAS TO
DESCRIBE A FRAMEWORK FOR HOW TO
TAKE SOMETHING FROM -- THERE'S
SO MANY METHODS PUBLISHED IN THE
LITERATURE, A SMALL FRACTION
WITH STEPS TO ENABLE TO BE A
STANDARD, USED FOR MORE ROBUST
TESTING, LESS OF INFORMATION
ABOUT THAT ALREADY IN THE
LITERATURE, INCLUDING SOME LISTS
SUCH AS KEY CONSIDERATIONS,
APPLY BASIC QUALITY TOOLS TO
IMPROVE CONFIDENCE IN NAMs.
AND STEPS YOU CAN UNDERTAKE, HOW
RELATE TO EACH OTHER.
WE DISCUSSED IMPROVE CONFIDENCE
DECISIONS, INSTEAD OF POSITIVE
OR NEGATIVE CALL COULD HAVE THAT
IN ADDITION TO INFORMATION ABOUT
THE RISK, FOR EXAMPLE, BEING A
FALSE POSITIVE OR FALSE NEGATIVE
RESULT.
SO THAT'S SOMETHING WE THINK
IS -- WE WANTED TO DESCRIBE AS A
HELPFUL OPTION TO CONSIDER.
IT SHOULD BE NOTED THAT THERE
CAN BE TRADEOFFS.
FOR EXAMPLE, MAYBE FOR SOME CASE
MORE CONTROLS COULD LEAD TO
HIGHER COST OR FEWER CHEMICALS
TESTED FOR EXPERIMENT.
THAT'S REALLY GETTING INTO
CONSENSUS PROCESS DISCUSSING
WITH COLLEAGUES ABOUT IS IT
WORTH IT, IN THIS CASE FOR THIS
CONTEXT AND USE.
SOMETIMES IT MAY BE, SOMETIMES
OTHER FACTORS MAY BE
PRIORITIZED.
NOW, BRIEFLY A CASE STUDY
APPLYING THIS FRAMEWORK TO AN
ASSAY.
IT WAS FROM AN INTERAGENCY
AGREEMENT WITH OURSELVES AND
NATIONAL INSTITUTE OF DENTAL AND
CRANIOFACIAL RESEARCH, LAST FEW
YEARS.
WE HAD A WORKSHOP BACK IN -- A
NUMBER IN 2021 WITH FEEDBACK IT
COULD BE INTERESTING TO TAKE AN
ASSAY THAT LOOKS AT TISSUE AND
OCCLUSAL TISSUE THROUGH THE
FRAMEWORK.
A CASE STUDY, ORAL CONSTRUCTS,
HOW THIS EXPERIMENT WORKS, YOU
WILL ADD SOMETHING DIRECTLY ON
THE TISSUE, AND LOOK AT THE
CHANGE IN VIABILITY SUCH AS WITH
MPT ASSAY.
YOU MAY KNOW THERE ARE
IRRITATION ASSAYS THAT HAVE BEEN
APPROVED THROUGH ISO FOR
EPIDERMAL TISSUE BUT NOT DONE
FOR FOR ORAL MUCOSAL TISSUE.
ONE OF THE THINGS THAT'S REALLY
VALUABLE ABOUT THESE TISSUES,
YOU CAN TEST POLAR AND NON-POLAR
SOLVENTS, UNLIKE ADHERENT
ASSAYS, SOME OTHER NAMs WORK,
IF YOU ADD SOMETHING, IT'S A
CHALLENGE FOR NON-POLAR
SOLVENTS.
THAT'S A DISTINCT POSSIBILITY.
ANOTHER THING THAT'S REALLY
INTERESTING ABOUT THIS PROJECT
IS WE'RE REALLY LIMITED IN TERMS
OF THE NUMBER OF TISSUES THAT WE
HAVE.
YOU CAN MAKE AN ORDER AND GET
ONCE EVERY TWO WEEKS OR SO.
AND YOU CAN ORDER THEM IN
ALIQUOTS OF 24 TISSUES, AND
THOSE COST AROUND $2,000 OR SO.
AND SO YOU REALLY THOUGHT
CAREFULLY ABOUT EVERY SINGLE
CONSTRUCT AND TRADEOFFS OF
DIFFERENT CONTROLS AND SO ON.
BECAUSE WE'RE REALLY, YOU KNOW,
IT'S VERY DIFFERENT FROM HAVING
96 WELLS.
WITH 24 ONLY YOU NEEDED TO THINK
JUDICIOUSLY ABOUT HOW WE WANTED
TO USE THEM.
SO THIS IS AN EXAMPLE OF CAUSE
AND EFFECT FOR MTT ASSAY HOW
WE'RE ASSESSING VIABILITY CHANGE
AFTER RESULT OF RELEVANT
MATERIALS, SOME ARE SIMILAR TO
CAUSE AND EFFECT ITEMS IN THE
PAST SUCH AS PLATE READER, AS
YOU KNOW FROM PREVIOUS
PRESENTATIONS, PAYING A LOT OF
ATTENTION, WE'VE BEEN LOOKING AT
THINGS LIKE, WELL, FOR EVERY
CONSTRUCT HOW MANY WELLS SHOULD
WE DO IN OUR FINAL 96 WELL PLATE
FROM THE PLATE READER, HOW MANY
TIMES UP AND DOWN BEFORE WE'RE
TRANSFERRING OVER, COULD THERE
BE CHANGES WITH TIME FROM THE
FIRST TO THE LAST SAMPLE THAT
WE'RE DOING THAT COULD THEN LEAD
TO UNEXPECTED BIASES IN RESULTS
AND SO FORTH.
PIPETTING, INS AND OUTS.
POSITIVE CONTROL IS AN
INTERESTING DISCUSSION WITH THIS
ASSAY BECAUSE WHAT'S SUGGESTED
TO LOOK AT A TIME SERIES, NOT
CONCENTRATION SERIES IN TERMS OF
CONTROLS, AND ALSO INTEG --
INTERROGATE TO HAVE THE
CONFIDENCE WE WANT, 24 PER
EXPERIMENT, ARE YOU TO CHOOSE
CAREFULLY.
THERE'S MORE NUANCE AND DETAILS
I'LL GET INTO, SHOWING A LITTLE
BIT OF DATA, NEGATIVE CONTROLS,
TO GIVE A FLAVOR OF WHAT WE'VE
BEEN UP TO.
LET'S GO THERE NOW.
SO ONE OF THE THINGS WE'RE
LOOKING TO, A NON-DESTRUCTIVE
APPROACH TO LET US KNOW ARE
THINGS FUNCTIONING AS WE THINK
THEY ARE, WHAT WE'RE GETTING
FROM OUR SUPPLIER.
AND SO ON THE LEFT YOU CAN SEE
THE BLANKET INSERTS, WHEN WE USE
CHAMBER BASED SYSTEM, CONSISTENT
RESULTS, SO THAT WAS GOOD.
THERE'S VARIABILITY IN TISSUES,
BY FACTOR OF TWO ACROSS
EXPERIMENTS.
WE DIDN'T FIND THESE IMPACTED
OUR MTT RESULTS, CLEAR IT
DOESN'T MEAN, 800 OR 1800.
THERE WAS YOU'LL NOTICE ONE IN
BLUE, ESSENTIALLY ZERO FOR OUR
TIER MEASUREMENT INDICATING
FUNCTION, RAISING A RED FLAG IN
TERMS OF WHAT'S GOING ON HERE.
CURIOUS TO SEE HOW SAME TISSUES
IN TERMS OF NEGATIVE CONTROL FOR
MTT ASSAY.
AND YOU CAN SEE SAME DAY WE HAD
ALSO VERY LOW MTT RESULTS, ONE
WITH LOW TEER VALUE, A HEADS UP
SOMETHING'S NOT LOOKING QUITE
RIGHT.
WE'RE NOT SURE WHAT HAPPENED,
PRESUMABLY A SHIPPING ISSUE OR
LEFT ON A HANGER TOO LONG,
SOMETHING UNCLEAR HAPPENED
THERE.
MTT ASSAY, SCRATCH YOUR HEADS,
IS MTT GONE BAD, DID WE FORGET
TO ADD IT?
WHAT WAS HAPPENING?
SINCE WE HAD THE TEER TO BACK IT
UP IT GAVE US CONFIDENCE IT WAS
SOMETHING IN THE CONSTRUCTS,
SOMETHING WASN'T QUITE RIGHT.
YOU CAN SEE THERE'S A REASONABLE
RANGE FOR NEGATIVE CONTROL FOR
MTT ASSAY, ALSO GOT GOOD
COEFFICIENT OF VARIATION WHERE
TYPICALLY SOMETIMES IT COULD BE
AS LOW AS 2%, OR LESS THAN 8% IN
TERMS OF JUST VARIABILITY FOR
OUR NEGATIVE CONTROLS.
SO THIS IS -- THINGS ARE LOOKING
CONSISTENT.
VARIABILITY, TISSUE VARIABILITY,
ALSO FROM JUST THE PIPETTING
STEPS THEMSELVES.
NEXT SLIDE.
THIS IS A TECHNICAL COMPONENT,
HOW CAN WE LOOK AT THE
BIOLOGICAL RELEVANCE, TALKING
ABOUT HOW THAT'S A STRATEGIC
QUESTION BECAUSE YOU COULD HAVE
A NAM GIVING THE SAME RESULT,
BUT LAST THIS COMPARED TO THE
PAST WHICH OFTEN FOR MANY CASES
IS INDEED EXPERIMENTS, HOW CAN
WE RELATE TO TWO, SOMETHING
WE'RE CONSIDERING TESTING A
RANGE IN THIS ASSAY.
SO, AS I WAS SAYING, THIS ASSAY
IS UNIQUE.
THERE'S SOME -- LIMITED NUMBER
OF SAMPLES AND FREQUENCY, WE
CAREFULLY THINK ABOUT USING
EVERY LAST CONSTRUCT ABOUT
THOSE.
APPLIED A LOT THE OF CONCEPTUAL
TOOLS TOWNS ASSAY.
ROBUSTNESS TESTING, WRAP THIS UP
AND WRITE A PAPER.
WE'VE LOOKED AT DIFFERENT
THINGS.
DIVING MORE INTO THE TOPIC,
PLEASE REACH OUT TO ME, I'M
HAPPY TO HAVE A DISCUSSION AND
SHOW YOU SOME MORE OF THE
NUANCES HERE.
MADE A LOT OF CONTROL CHARTS,
POSITIVE CONTROLS, NEGATIVE
CONTROLS, TESTED MULTIPLE LEVEL
COMPOUNDS.
ONE THING THAT'S BECOME
INTERESTING BASED ON
UNCERTAINTIES OF NEGATIVE
CONTROL, UNCERTAINTY OF TEST
COMPOUND, HOW DO YOU SET A
THRESHOLD FOR POSITIVE OR
NEGATIVE USING STATISTICAL
MODEL, AND IT'S INTERESTING THAT
HOPEFULLY WE COULD THEN WITH
TRADITIONAL ANIMAL DATA LOOKING
AT IRRITATION BECAUSE IT'S
ALMOST LIKE THERE'S UNCERTAINTY
AND SOME TYPE SCALE WITH IN
VITRO AND IN VIVO DATA, HOW CAN
THEY LINK UP WITH OUR
SENSITIVITY OF ASSAYS IS
HOPEFULLY GIVING SOMETHING
SIMILAR TO WHAT A TRADITIONAL
ASSAY WOULD PROVIDE.
THAT'S ALL I HAVE.
I'M HAPPY TO HAVE ANY QUESTIONS.
[APPLAUSE]
>> THANKS VERY MUCH, ELIJAH.
DO WE HAVE ANY QUESTIONS IN THE
ROOM FOR ELIJAH?
OKAY.
GREAT.
THANK YOU.
SO THEN I THINK WHAT WE'LL DO IS
WE'RE GOING TO GO TO THE
QUESTIONS THAT HAVE COME IN
ONLINE.
THERE WE GO.
GREAT.
WELL DONE.
LET ME GO BACK TO THIS SLIDE.
DAVE, DO YOU WANT TO --
>>SURE.
>>READ OUT THE QUESTIONS THAT
CAME IN ONLINE PLEASE.
>>FIRST IS FOR SUZIE
FITZPATRICK WHO HAD TO GO TO AN
ON-SITE MEETING AT THE FDA THIS
AFTERNOON.
BUT THE QUESTION WAS, THIS COMES
FROM SHERMAN McFARLAND,
POSTDOC AT THE TOXICOLOGY POLICY
GROUP AT JOHNS HOPKINS BLOOMBERG
SCHOOL OF PUBLIC HEALTH.
SHERMAN ASKS, I WANTED TO
CONFIRM WHETHER SUZANNE
FITZPATRICK SAID THE FDA HAS NOT
DONE ANIMAL TEST SIX 2016.
TO CLARIFY I BELIEVE IT WAS DOG
SINCE 2018 BUT WE CAN SHARE AND
CONFIRM AS ACCURATE.
ALSO HE ASKS FOR JESSICA LEET,
HOW GILL SAMPLING IS PERFORMED
AND WHAT IS GILL SAMPLING?
>> THANKS.
THEY JUST TAKE A SMALL CLIP OF
THE GILL FROM THE FISH, IT'S
NON-LETHAL, AND THEY CAN HEAL
FROM THAT.
SO IT'S, YOU KNOW, A MINIMALLY
INVASIVE SAMPLING TECHNIQUE.
WHAT THEY ARE TRYING TO GROUND
TRUTH RIGHT NOW IS USING THAT TO
TRACK THE VIRAL PATHOGENS AND
THEIR MOVEMENT.
>> I HAVE A FOLLOW-UP QUESTION
ON THAT.
SO IT'S CURRENTLY BEING USED TO
TRACK PATHOGENS, BUT IS THERE
POTENTIAL TO USE IT AS A
BIOMONITORING OPTION?
>>YEAH, I'M NOT SURE WITH THAT
SAMPLING IF YOU COULD GET GOOD
LIKE HISTOLOGY, FOR EXAMPLE,
FROM IT BUT DEFINITELY ANY
MOLECULAR ENDPOINTS, SO THEY ARE
DOING SEQUENCING FROM THOSE
SAMPLES, AND SO POTENTIALLY
COULD BE MONITORED, YOU KNOW,
OTHER THINGS AS WELL.
>> OKAY.
THANKS.
>> NEXT QUESTION IS GENERAL
QUESTION FROM BRANDON WHITE.
NEW TRAINEE IN TOXICOLOGY, IS
THERE A CENTRAL PLACE ALL YOUR
ORGANIZATIONS LOOK TO FOR
GUIDANCE ON THE SCIENCE RESULTS
OF NAMs?
IS THERE A SINGLE PLACE TO GO
TO, TO REVIEW THE AOPs AND
NAMs BEING CONSIDERED FOR
REGULATORY USE.
NICOLE, YOU CAN START.
>> YEAH, I CAN PROVIDE A BIASED
ANSWER TO THAT WHICH IS THAT
NICEATM WEBSITE IS AN EXCELLENT
RESOURCE, AT LEAST AS A STARTING
POINT.
WE HAVE A PAGE ON THE WEBSITE
THAT LISTS THE CURRENT
REGULATORY ACCEPTED ALTERNATIVE
METHODS, LOTS OF PAGES WITHIN
THAT SITE FOR PROJECTS UNDER
DEVELOPMENT, LINKS TO DIFFERENT
OTHER EXTERNAL RESOURCES, AS FAR
AS AOPs THE OECD WEBSITE HAS A
WEALTH OF INFORMATION, AND ALSO
AOP KNOWLEDGE BASE AND AOP WIKI
BASED ON SEARCHABLE THINGS LIKE
MOLECULAR ENDPOINT, MOLECULAR
TARGET, ADVERSE EFFECT.
MY ANSWER IS GOING TO BE START
WITH THE NICEATM WEBSITE AND
THEN MAYBE NAVIGATE OUT FROM
THERE.
>> OKAY.
>> ONE OTHER THING I'LL MENTION
IS THAT THE -- OUR EUROPEAN
PARTNERS, JOINT RESEARCH CENTER
HAS A GREAT WEBSITE.
AS PART OF THEIR WEBSITE THEY
HAVE WHAT'S CALLED THE T.S.A.R,
TRACKING SYSTEM ON ALTERNATIVE
THOUGHTS AND REGULATORY
ACCEPTANCE MAYBE, I DON'T KNOW
WHAT THE R STANDS FOR.
IT'S A DATABASE OF ALTERNATIVE
METHODS, WHERE THEY ARE IN THE
DEVELOPMENT, VALIDATION AND
REGULATORY INFORMATION PROCESS.
>> I'M ASSUMING THE NEXT IS FOR
CHARLES KOVATCH.
CAN YOU HEAR?
ARE YOU AUDIBLE?
>> YES.
>> GREAT.
FROM GINA LINTO.
HOW DOES ONE NOMINATE A PERSON
TO AN EXPERT GROUP?
>> THANKS FOR THE QUESTION.
WHAT'S ALSO GREAT ABOUT THAT
QUESTION IS IT'S ALWAYS WELCOME
TO HAVE PEOPLE INTERESTED IN
SERVING ON EXPERT GROUPS,
OFTENTIMES THEY CAN BE WITH ARM
TWISTING AND CAJOLING, RIGHT,
CAN BE A LONG TIME.
EXPERT GROUPS CAN BE --
REPRESENTATIVES ON EXPERT GROUPS
FROM GOVERNMENT, FROM INDUSTRY,
DIFFERENT ORGANIZATIONS,
ACADEMIA.
SO LOTS OF FOLKS SERVE ON EXPERT
GROUPS.
I THINK SPECIFICALLY FOR
SOMEBODY WHO IS FROM INDUSTRY I
THINK THE BUSINESS COMMUNITY,
SOMETIMES GOING THROUGH BEAC,
THE BUSINESS COMMUNITY'S OECD,
THEY HAVE A LOT OF
REPRESENTATIVES, THE AMERICAN
COUNCIL IN THE U.S. IS ONE GROUP
IS ACTIVE FOR BEAC, ALSO THROUGH
COUNCIL ON ANIMAL PROTECTION IN
OECD, REPRESENTS A NUMBER OF
PEOPLE IN DIFFERENT
ORGANIZATIONS THAT PARTICIPATE
ON EXPERT GROUPS.
SO TWO MECHANISMS FOR
NON-FEDERAL FOLKS.
I THINK TO GET ON AN EXPERT
GROUP, I WOULD SUGGEST YOU REACH
OUT DIRECTLY.
SOMETIMES THERE ARE REQUESTS FOR
INDEPENDENT EXPERT GROUP
MEMBERS, AND OTHER TIMES THERE
ARE SPECIFIC FEDERAL REQUESTS,
LIKE DOES THIS PERSON REPRESENT
THE UNITED STATES GOVERNMENT, SO
I THINK IF YOU HAVE A QUESTION,
SOMETHING SPECIFICALLY, REACH
OUT TO ME AND I CAN HELP STEER
YOU IN THE RIGHT DIRECTION.
>> THANK YOU, CHARLES.
>> GREAT.
KEEP YOURSELF UNMUTED BECAUSE WE
HAVE ONE OTHER QUESTION FROM AMY
KYLE FROM UC-BERKELEY.
WHAT KINDS OF POLICIES OR
PROCESSES DOES OECD USE TO GUARD
AGAINST BIAS INFLUENCING REVIEWS
AND CONSULTATIONS, IS THERE
INTERNATIONAL STANDARD THAT THEY
DON'T REFLECT PERSONAL OR
INSTITUTIONAL INTEREST?
>> IF I REMEMBER THE FIRST
HALF, READ IT AGAIN, GUARDING
AGAINST BIAS?
>> SURE.
GUARDING AGAINST BIAS OR
ECONOMIC INTEREST INFLUENCING
REVIEWS AND CONSULTATIONS OECD
SPONSORS.
>> INTERESTING QUESTION.
I WOULD INVITE OTHERS IN THE
ROOM, NICOLE AND ANNA, IF YOU'RE
STILL THERE, TO HELP WITH THIS.
THERE'S A LOT OF PERSPECTIVES
WITH YOUR QUESTION.
CLEARLY, EVERYBODY PARTICIPATING
ON THE MEMBER COUNTRIES HAVE
SOME BIAS OR ECONOMIC INTEREST,
RIGHT?
EVEN THE U.S.
WE HAVE OUR PRIORITIES FOR
ENSURING, YOU KNOW, OUR NEEDS
ARE MET, OBLIGATIONS TO TOSCO,
FISHRA, COSMETIC ACT, WE'RE
COMING IN WITH SPECIAL INTEREST,
HOWEVER THERE'S CONSENSUS FOR
ANYTHING TO MOVE FORWARD, SO
WE'VE HAD OPPORTUNITIES,
SITUATIONS WHERE, YOU KNOW,
THE -- MAYBE EUROPEAN COUNTRIES
ARE ADVOCATING FOR SOMETHING
THAT DOESN'T ALIGN WITH THE U.S.
REGULATORY PRIORITIES, OR OUR
PROGRAMS, AND SO WE HAVE TO WORK
THOSE OUT, WE CAN REACH
CONSENSUS.
IT'S A GENERIC ANSWER BUT
THERE'S TRUTH IN THE FACT WE ALL
DO COME WITH SOME SENSE OF BIAS
BUT THAT'S GETS HARMONIZED, IN
OUR MUTUAL AGREEMENT OF THE --
AND CONSENSUS OF TEST GUIDELINES
THAT GO FORWARD.
THE SECOND QUESTION WAS ANALYSES
SCIENTIFICALLY BASED -- REPEAT
THAT AS WELL.
>> IS THERE AN INTERNATIONAL
STANDARD TO ENSURE THAT ANALYSES
ARE SCIENTIFICALLY BASED AND DO
NOT REFLECT PERSONAL OR
INSTITUTIONAL INTERESTS?
>> I'M GOING TO TURN TO NICOLE,
MAYBE YOU COULD HELP ME.
>> SURE, YEAH, ABSOLUTELY.
FIRST, I'LL JUST SAY I AGREE
WITH YOUR ANSWER ON THE FIRST
HALF OF THE QUESTION.
I THINK THAT EVEN THOUGH IT'S
SOMETIMES A PAINFUL PROCESS, THE
REQUIREMENT AT THE WNT TO
ACHIEVE 100% CONSENSUS BEFORE
THE ANY METHOD IS ADOPTED INTO A
TEST GUIDELINE OR GUIDANCE
DOCUMENT IS APPROVED THAT FALLS
UNDER WORKING PARTY, THAT 100%
CONSENSUS REALLY ENSURES THAT NO
INDIVIDUAL COUNTRY OR INDIVIDUAL
REGION'S BY AS IS
OVERREPRESENTED, BECAUSE THERE'S
THIS LEGAL FRAMEWORK OF THE
MUTUAL ACCEPTANCE OF DATA WHICH
REQUIRES THAT ANY DATA THAT'S
SUBMITTED UNDER AN OECD TEST
GUIDELINE IS CONSIDERED BY ANY
MEMBER COUNTRY SO ACHIEVING THAT
CONSENSUS CREATES THAT BALANCE
AND I THINK REALLY PROTECTS
AGAINST ANY BIAS.
IN TERMS OF THAT INTERNATIONAL
SCIENTIFIC STANDARD I MEAN
THAT'S REALLY THE ROLE OF THE
OECD EXPERT GROUPS, AND SO THE
EXPERT GROUPS CONSIST AGAIN OF
SUBJECT MATTER EXPERTS THAT ARE
NOMINATED FROM THE REGIONS
REPRESENTED BY THE 38 DIFFERENT
MEMBER COUNTRIES.
SO HAVING THAT GLOBAL SPREAD OF
EXPERTS AND THAT VERY DIVERSE
REPRESENTATION ACROSS DIFFERENT
REGIONS ENSURES HIGH QUALITY
SCIENTIFIC REVIEW, BUT THEN
THERE'S ALSO OTHER STANDARDS,
CHARLES TALKED ABOUT A COUPLE IN
HIS PRESENTATION.
SO GOP STANDARDS, THE FRAND
DECLARATION BASICALLY MEANS THAT
YOUR METHOD HAS TO BE REASONABLY
ACCESSIBLE, SO IT CAN'T BE, YOU
KNOW, A PROPRIETARY METHOD WITH
A SUPER HIGH LICENSING FEE
THAT'S ONLY AVAILABLE THROUGH
ONE CRO IN THE ENTIRE WORLD,
RIGHT?
SO THEY HAVE PUT A LOT OF THESE
STANDARDS IN PLACE TO ENSURE NOT
ONLY HIGH SCIENTIFIC QUALITY BUT
REASONABLE ACCESS TO METHODS
THAT ARE CODIFIED IN OECD TEST
GUIDELINES.
ANY OTHER QUESTIONS FROM ONLINE
OR IN THE ROOM?
NO?
OKAY.
WE'RE GOING TO TAKE OUR BREAK,
JUST A FEW MINUTES EARLY.
AND SO WE'LL TAKE A SLIGHTLY
EXTENDED BREAK OF 20 MINUTES,
AND WE'LL BE BACK HERE AT 2:30.
I WILL PUT UP THAT PLACEHOLDER
SCREEN AND WE WILL SEE YOU ALL
IN 20 MINUTES.
>> WE'RE GOING TO GET STARTED
AGAIN.
THE AFTERNOON SESSION, WE HAVE
TWO MORE TALKS FOR YOU THIS
AFTERNOON, AND VERY EXCITED
ABOUT THEM.
FIRST LET ME PULL UP THE FIRST
PRESENTATION.
SO, SHARI PRICE WILL TALK ON
BEHALF OF THE NATIONAL CANCER
INSTITUTE, CART T CELL IN VITRO
SAFETY TESTING STRATEGIES.
OVER TO YOU.
THANKS.
LET ME HIDE THE CONTROLS.
YOU SHOULD BE ABLE TO CLICK.
>> GREAT.
THANK YOU SO MUCH.
I'M GOING TO TALK ABOUT, LIKE
NICOLE SAID, SAFETY TESTING
STRATEGIES FOR CAR T CELLS.
ACTUALLY THIS IS GOING TO BE AN
EXAMPLE OF THE NAMs EFFORT.
THIS IS ACTUALLY -- WE DO IN
VITRO TESTING IN OUR LAB, THIS
IS AN EXAMPLE OF THE EFFORTS
PEOPLE ARE INTERESTED IN.
WHAT I WANT TO EMPHASIZE IS IN
THIS CASE ACTUALLY USING THESE
IN VITRO METHODS FOR SAFETY
TESTING OF CAR T CELLS MAKES A
LOT OF SENSE.
I'LL EXPLAIN WHY.
ONE OF THE THINGS THAT HAS TO
HAPPEN BEFORE CAR T CELLS GO
INTO HUMANS BEFORE FIRST IN MAN
YOU NEED TO ASSESS BINDING OF
THE CAR T CELLS.
WE'RE GOING BACK IN TIME TO TALK
ABOUT MONOCLONAL ANTIBODIES
FIRST.
1997 FDA POINTS TO CONSIDER
DOCUMENT THEY STATE CLEARLY THAT
NON-TARGET BINDING OF A
MONOCLONAL ANTIBODY PARTICULARLY
THOSE THAT ARE PHARMACOLOGICALLY
ACTIVE CAN HAVE VERY SERIOUS
CONSEQUENCES.
THEREFORE YOU NEED TO TEST FOR
ON AND OFF-TARGET BINDING BY
SOME WAY BEFORE YOU GO INTO
HUMANS.
SO HOW DOES THIS APPLY TO CAR T
CELLS?
IF WE GO TO -- IS THIS THE
MOUSE?
DOES IT SHOW UP?
GREAT.
IF WE GO TO AN ANTIBODY,
THINKING ABOUT THE CDR, THIS IS
THE PART OF THE ANTIBODY THAT IS
BINDING TO TARGET, THE PART THAT
PEOPLE CARE ABOUT.
WHEN THAT BINDING DOMAIN BINDS
IN THE WRONG PLACE, AND CALLS IN
THE CAVALRY, YOU CAN HAVE
UNINTENDED TOXIC EFFECTS.
SO WHEN THEY MAKE CHIMERIC
ANTIGEN RECEPTOR CAR T CELLS
THEY USE IT AS BINDING DOMAIN
FOR GENETICALLY MODIFIED T CELL,
THEN THIS CAR, AS IT'S CALLED,
HAS SOME ACTIVATION DOMAINS.
ONE THIS IS SCFE BINDS TO HAR
GET THAT LEADS TO BINDING OF T
CELL AND YOU GO FOR YOUR, Q
UOTE, THERAPEUTIC OUTPUT.
RECOGNIZE CANCER CELL AND KILL
IT.
IN THE CASE OF CAR TS, THE
DOMAIN IS DERIVED FROM CDR, YOU
NEED TO LOOK AND UNDERSTAND
WHERE THE CDR IS BINDING, IS IT
BINDING TO TARGET OR SOMETHING
ELSE OR IN PLACES WE EXPECT, OR
IN PLACES WE DIDN'T EXPECT?
WHEN WE THINK ABOUT HOW CAR Ts
WILL BIND YOU CAN HAVE ON TARGET
ON TUMOR, WHAT YOU WANT TO
HAPPEN, BUT IF YOU BUST UP TUMOR
CELLS TOO FAST YOU CAN END UP
WITH CYTOKINE RELEASE SYNDROME,
THINGS LIKE THAT.
YOU CAN HAVE ON TARGET OFF TUMOR
BINDING, A GOOD EXAMPLE WOULD BE
IF YOU'RE TRYING TO KILL SOME
KIND OF B CELL LYMPHOMA USING
SOMETHING THAT'S TARGETED TO
CD19 YOU MIGHT ALSO BE KILLING
HEALTHY B CELLS, OR ANOTHER
EXAMPLE THIS IS A GOOD ONE, WHEN
YOU'RE TRYING TO KILL SOME KIND
OF CANCER WITH HER-2 ANTIBODY
BUT END UP WITH CARDIOVASCULAR
TOXICITY BECAUSE IN THE EARLY
DAYS NOBODY BOTHERED TO LOOK TO
SEE HER-2 IS EXPRESSED BY
CARDIOMYOCYTES AND HEPATOCYTES
AND SCHWANN CELLS, EXPLAINING
SEEMINGLY OFF-TARGET TOXICITY
ORIGINALLY OBSERVED IN ANTI-HER2
DIRECTED COMPOUNDS.
FINALLY OFF TARGET OFF TUMOR
BINDING, SOME PRECEDENT IN THE
CAR T REALM, MOST FAMOUS WAS DUE
TO CROSS-REACTIVE BINDING WITH
PROTEIN TITAN, SO IN THIS
INSTANCE CAR T WAS DIRECTED
AGAINST MAY JAY 3, CROSS REACTED
WITH TITAN, SEVERAL PEOPLE GOT
VERY SICK, SEVERAL PEOPLE DIED.
AND SO WE MOVED FORWARD.
AT THAT TIME THEY DIDN'T THINK
THERE WAS A WAY TO ACTUALLY TEST
THE ON AND OFF TARGET BINDING OF
CAR Ts BECAUSE YOU HAD TO TEST
THE WHOLE T CELL, THAT'S NOT
REALLY THE CASE.
SO, HOW THEN CAN YOU TEST HOW A
CAR T IS GOING TO BIND?
IF WE GO BACK INTO THE ANTIBODY
WORLD AND THINK ABOUT TISSUE
CROSS-REACTIVITY STUDIES THAT'S
THE GOLD STANDARD APPROACH TO
ASSESSING ON AND OFF TARGET
BINDING.
THAT'S DONE USING
IMMUNOLABELLING WHERE YOU TAKE A
TISSUE, APPLY THE ANTIBODY,
USING STANDARD
IMMUNOHISTOCHEMISTRY
METHODOLOGY, LOOK UNDERSTOOD A
MICROSCOPE, LOOK WHERE IT'S
STAINED, REPORT OUT ON THAT.
IN THE CASE OF CAR T YOU CAN'T
USE THE ENTIRE CAR T TO STAIN
BECAUSE IT'S BIG AND CLUNKY.
IF THEY ARE DOING
IMMUNOLABELLING TO ASSESS CAR T
BINDING THEY TAKE THE SCFV OFF
THE EXTRACELLULAR DOMAIN AND
MAKE IT INTO
IMMUNOHISTOCHEMISTRIATION WITH
FC FUSION PROTEIN AND USE LIKE
AN ANTIBODY.
THAT'S FINE, YOU CAN GET SOME
ABOUT HISTOLOGIC YAM CONTEXT OUT
OF WHERE THAT CDR IS BINDING BUT
YOU'RE NOT REALLY ACTUALLY
LOOKING AT THE FINAL CLINICAL
CANDIDATE.
WHEN YOU CUT CDR OFF OR CUT
EXTRACELLULAR DOMAIN OFF, ANDS
PUT IT ON TAIL, YOU'RE MAKING
PERMANENT CHANGE TO THE MOLECULE
AND CAN POSSIBLY AND LIKELY ARE
CHANGING ITS BINDING
CHARACTERISTICS.
SO ANOTHER WAY CAN YOU DO THIS
IS USING ARRAY-BASED SCREENS.
THERE'S A LIBRARY OF KNOWN
MEMBRANE PROTEINS TO TRANSFECT,
EXPRESS, YOU CAN TAKE AN
ANTIBODY OR ANTIBODY SURROGATE
OR THE WHOLE CAR T AND USE IT
ESSENTIALLY TO STICK IT DOWN AND
SEE WHERE IT STUCK ON THIS SET
OF TRANSFECTED CELLS AND THEN
THIS IS AN EXAMPLE OF WHAT A HIT
LOOKS LIKE.
EXPECTING TO SEE A HIT IN THE
PLACE USING THE TARGET THAT
YOU'RE TRYING TO SEE, AND IF YOU
HAD SOMETHING THAT WAS AN
OFF-TARGET BINDING YOU WOULD SEE
THAT TOO.
THERE ARE PEOPLE THAT DO PROTEIN
CLIP SCREENS, POPULAR BUT LOST
FAVOR, IN SITU HYBRIDIZATION
ONLY TELLS YOU WHERE THE TARGET
MIGHT BE EXPRESSIONED, FLOW
CYTOMETRY, ET CETERA.
IN OUR LAB WHAT WE'RE GOING TO
TRY AND DO IS USE HUMAN INDUCED
PLURIPOTENT STEM CELLS DERIVED
CELLS, RATHER, AS MODEL OF
NORMAL CELLS IN A CO-CULTURE
SYSTEM WITH CAR Ts, THIS IS
THE WAY THIS ASSAY WILL LOOK.
CELL
CELL TYPES ARE INTENDED TO BE
BROADLY REPRESENTED FOR
TOXICITY, ENDOTHELIAL, NEURON,
HEPATOCYTE, ET CETERA.
SORRY, MY THROAT IS DRY.
THE WAY THIS ASSAY LOOKS IS
WE'VE GOT OUR DIFFERENTIATED
PLURIPOTENT STEM CELLS IN DISH,
CAR Ts TO THE DISH.
IF CAR Ts DO NOT RECOGNIZE
THEIR TARGET AND DO NOT BIND,
EVERYBODY STAYS HAPPY.
WE HAVE A GOOD DAY.
IF THE CAR Ts RECOGNIZE
SOMETHING IS TARGET, THEY BIND
AND ACTIVATE, AND THEN THEY
KILL.
AND SO THIS IS WHAT WE'RE IN THE
BUSINESS OF DOING.
DID THE CAR T BIND, DID IT
ACTIVATE, DID IT KILL?
THOSE ARE THE THREE QUESTIONS WE
WANT TO KNOW.
SO WE HAVE -- AS A PRECEDENT FOR
THIS STYLE OF ASSAY THERE WAS A
PAPER PUBLISHED BY FRY ET AL. IN
2021 USING A CD33 SPECIFIC CAR T
CELL, USED A PANEL OF
PLURIPOTENT STEM CELL DERIVED
CELL TYPES THEY DIFFERENTIATED,
USED POSITIVE CONTROL, 14 CELL,
CO-CULTURE ASSAY, READOUT IN
THIS CASE WAS FOR T-CELL
ACTIVATION LOOKING AT INTERFERON
GAMMA RELEASE.
INTERESTINGLY, THIS WAS THE ONLY
STUDY THAT WAS USED TO SUPPORT
THE IND FILING, ONLY SAFETY
STUDY.
THEY DIDN'T DO ANIMAL STUDIES.
LET'S TALK ABOUT HOW CAN YOU DO
AN ANIMAL STUDY WITH A CAR T
CELL?
YOU'VE GOT A HUMAN CAR T CELL
GENETICALLY MODIFIED WITH HUMAN
CHIMERIC ANTIGEN RECEPTOR,
RIGHT? YOU PUT THAT INTO AN
ANIMAL, YOU'RE GOING TO HAVE A
BIG PROBLEM.
IT'S GOING TO REJECT.
YOU'LL HAVE GRAFT-VERSUS-HOST, A
BIG MESS, NOT RELEVANT, THEN
INTO IMMOW COMPROMISED MOUSE.
IN THE CASE OF THESE CAR T
CELLS, IF WE CAN USE MORE OF
THESE IN VITRO MODELS IT MAKES A
LOT MORE SENSE THAN USING
FURTHER AND FURTHER AND FURTHER
ENGINEERED ANIMALS.
SO ANYWAY, THIS IS A PRECEDENT
FOR THE ASSAY.
THIS IS WHAT OUR WORKFLOW LOOKS
LIKE.
WE PLATE THE CELLS ON DAY ZERO.
ALLOW THEM TO MATURE FOR ANY
NUMBER OF DAYS, THEY VARY BY
CELL TYPE.
FOR EXAMPLE ENDOTHELIAL CELLS
NEED THREE DAYS.
NEURONS NEED 14.
BUT THEN AFTER MATURATION PERIOD
ENDED WE ADD THE EXPERIMENTAL
CAR T OR CONTROL CAR T CELLS,
AND WE WATCH FOR A PERIOD OF 3
DAYS.
WE HAVE SEVERAL DIFFERENT TOOLS
TO HELP US.
WE DO HAVE A HAMILTON STAR
LIQUID ROBOTIC HANDLER TO GET
PLATED, WE DO CONTINUOUS
MONITORING, LDH RELEASE,
CYTOTOXICITY, ASSAYS AS
COMPANIONS.
AND WE ALSO DO CYTOKINE RELEASE.
SO, AS I MENTIONED, CELL TIMES
THAT WE'RE -- TYPES IN THIS
SCREEN ARE INTENDED TO BE
BROADLY REPRESENTATIVE.
THE SIX CELL TIMES HERE STARTING
AT CARDIOMYOCYTES DOWN TO
HEPATOCYTES ARE THOSE ALREADY
PUBLISHED IN THE TERRY FRY
PAPER.
WE DO HAVE AN INTEREST IN
PERIPHERAL NEURONS AND WORK
GOING ON THAT.
COMING FROM A CLASSIC TISSUE
CROSS-REACTIVITY BACKGROUND
THOUGH, I BELIEVE IT'S GOING TO
BE NICER TO EXPAND THE PANEL A
LITTLE BIT, PARTICULARLY WHERE
WE CAN LOOK AT MICROGLIA,
PARTICULARLY WHERE WE CAN LOOK
AT INTESTINAL EPITHELIUM, BIG
HITERS IN THE WORLD OF TOX.
LET'S TALK ABOUT WHAT READOUTS
WE'RE DOING.
IF YOU LOOK AT CO-CULTURE ASSAYS
YOU GET THIS READOUT OF T-CELL
ACTIVATION, YOU'LL GET T-CELL
ACTIVATION PLUS DEGRANULATION
BUT NEVER ANSWERED THE QUESTION
DID THE T CELLS KILL THE TARGET?
AND THAT'S WHAT MATTERS, RIGHT?
WHO CARES IF YOU ACTIVATE.
IF
IT DIDN'T -- IF IT DIDN'T KILL
ANYTHING WHO CARES.
WE HAVE A MAESTRO Z INSTRUMENT,
CONTINUOUS IMPEDANCE.
IF THE CELLS ARE CONFLUENT AND
LAY DOWN FLAT THEY WILL IMPEDE
AN ELECTRICAL CURRENT.
SO IF YOUR CELLS ARE CONFLUENT,
HEALTHY, FLAT, THERE'S A HIGH
IMPEDANCE MEASURED IN OHMS.
IN I MAKE THEM ANGRY OR SICK OR
DIE THEY WILL ROUND UP AND LET
GO OF THE PLATE AND WILL WILL BE
LESS IMPEDANCE, THAT WILL DROP,
USE IT AS SURROGATE FOR
CYTOTOXICITY.
WHEN YOU HAVE T CELLS IN A PLATE
AND TARGET CELLS YOU NEED TO
TELL THE DIFFERENCE BETWEEN
WHAT'S DYING, RIGHT? STANDARD
CYTOTOXICITY ASSAY ANYTHING
COULD BE DYING BUT ONLY THE
TARGET CELLS ARE STUCK TO THE
PLATE MAKING THE IMPEDANCE
READING.
TO THE RIGHT IS ACTUALLY WHAT
IMPEDANCE TRACING LOOKS LIKE.
TIME ZERO, ATTACH AND START
SPREADING.
MATURING OVER ALL THIS TIME.
ALL THE BLIPS HERE ARE WHEN YOU
TAKE THE PLATE OUT TO FEED CELLS
OR IMAGE THE CELLS, ET CETERA.
SO RIGHT HERE AT THIS TIME
POINT, WE ADDED STOREOSPORIN,
CELLS GET SICK AND IMPEDENTS
DROPS OUT.
IF YOU ADD DETERGENT IT DROPS TO
ZERO.
AT LOW DOSE YOU GET A
CONCENTRATION OF CELLS THAT
SPREAD OUT AND GET HUGE LIKE
GIANT PANCAKES AND IMPEDANCE
GOES WAY UP, THAT'S WHAT LOW
DOSES ARE UP HERE, AND CURVES
ARE HIGHER DOSES OF STOREOSPORIN
FROM WHERE THE CELLS WERE DYING.
THAT'S ONE READOUT THAT WE HAVE.
WE ALSO WILL FOLLOW THESE CELLS
ALONG WITH IMMUNOHISTOCHEMISTRY,
SO WE CAN DO
IMMUNOHISTOCHEMISTRY, DIGITAL
IMAGE ANALYSIS, WESTERN BLOTS,
FLOW CYTOMETRY, A FEW EXAMPLES
SHOW THE STAINING, PICTURES ON
THE OPERA PHOENIX WITH THESE
CELLS.
OUR FAVORITE IS THIS CD31
STAINING OF hIPSC DERIVED
ENDOTHELIAL CELLS, YOU CAN SEE
THEM MAKING THE CONNECTIONS.
WE LIKE THAT ONE.
IT'S IMPORTANT TO MAKE SURE THAT
YOUR CONTROL CELLS SUPPLIED
ACTUALLY REALLY ARE EXPRESSING
THE TARGET BEFORE YOU START THE
ASSAY.
IF YOU GET A HIT SOMEWHERE YOU
CAN GO BACK AND ASK THE
QUESTION, DID THIS CELL TYPE
THAT WE WEREN'T EXPECTING TO
HAVE A BINDING, DID THIS CELL
TYPE ACTUALLY EXPRESS A TARGET
AS WELL.
WE HAVE SEVERAL BIOCHEMICAL
READOUTS THAT INCLUDE STANDARD
CYTOTOXICITY ASSAYS.
OUR FAVORITE IS THE REALTIME LDH
GLOW ASSAY BECAUSE IT'S KINETIC
AND YOU CAN SEE WHAT'S HAPPENING
ALMOST FROM THE TIME YOU START
THE CO-CULTURE AND ALSO THAT ONE
IS NICE BECAUSE YOU ONLY SAMPLE
TINY BITS OF THE MEDIA AT ONE
TIME.
AND THEN ALSO CYTOKINE RELEASE,
AND SO THIS IS ACTUALLY AN
EXAMPLE OF CYTOKINE RELEASE FROM
A CO-CULTURE OF hIPSC
CARDIOMYOCYTES, CO-CULTURED WITH
CD33 CAR T OR UNTRANSDUCED CAR
T.
AND WHAT YOU CAN SEE HERE IS
THAT YOU HAVE THE HIGHEST AMOUNT
OF CYTOKINE RELEASE, POSITIVE
CONTROL, CD33 POSITIVE, A LITTLE
BIT OF CYTOKINE RELEASE WITH
DOWDY NEGATIVE CONTROL CELL.
THAT HAS MORE TO DO PROBABLY
WITH THE FACT THE CELLS ARE
HIGHLY METABOLICALLY ACTIVE AND
DENSITY IS SO HIGH THEY ARE JUST
DYING ON THEIR OWN.
WHAT'S IMPORTANT IS WHEN YOU
LOOK WITH THE CAR T, THERE IS NO
CYTOKINE RELEASE.
WITH EITHER THE CD33 CAR T OR
WITH THE UNTRANSDUCED CONTROL.
SO IF WE'RE GOING TO DO A STUDY,
A SCREENING STUDY, TO EVALUATE
ONE OF THESE, THE FIRST THING WE
HAVE TO DO IS PILOT WORK.
IN THE PILOT WORK WE WOULD BE
DOING CO-CULTURES OF THE CAR T
OR NEGATIVE CONTROL WITH
POSITIVE AND NEGATIVE CONTROL
CELLS TO WHETHER OR NOT THE T
CELL CAN KILL POSITIVE CONTROL
CELLS BEFORE WE SCREEN.
WE MIGHT INCLUDE RATIOS, HAVE TO
CONFIRM WHETHER OR NOT ANY
REPORTER GENES ARE BEING
EXPRESSED IN OUR HANDS, WHETHER
THE TARGET EPITOPE IS EXPRESSED
IN OUR HANDS.
WE ALSO HAVE TO LOOK AT PLATE
BINDING KINETICS OF THOSE
CONTROL CELLS IF THEIR ADHERENT.
A LOT OF TIMES IF YOU LOOK AT
CO-CULTURES, ASSAYS, YOU'LL PUT
YOUR CONTROL CELLS DOWN IN A
WELL, WAIT FOR AN HOUR, AND PUT
THE CAR Ts IN.
FOR OUR CONTINUOUS MONITORING
IMPEDANCE MONITORING TO WORK
THEY NEED TO START AS CONFLUENT
MONOLAYER.
WE NEED TO UNDERSTAND WHAT THE
PLATE BINDING KINETICS LOOK LIKE
AND AS WE'VE COME TO LEARN, AS
WE WORKED OUR WAY THROUGH THESE
DIFFERENT hIPSC DERIVED CELL
TYPES EVERY CELL TYPE HAS ITS
OWN BINDING KINETICS.
THEY ALL LOOK COMPLETELY
DIFFERENT.
THEN WE NEED TO DO A COUPLE
PILOT CO-CULTURE STUDIES TO MAKE
SURE THE IMPEDANCE, CYTOKINE
RELEASE AND ASSAYS WERE LOOKING
GOOD, LOOKING AT TARGET CELLS,
EFFECTOR CELLS, YOU NEED TO KNOW
IF YOU HAVE SPONTANEOUS LDH
RELEASE OR SOMETHING LIKE THAT.
CO-CULTURE WITH AN UNTRANSDUCED
OR T CELL THAT'S TRANSDUCED WITH
RELEVANT CAR, POSITIVE CONTROL
CELLS WHICH OF COURSE NEED TO
DIE EVERY TIME DO YOU A
CO-CULTURE EXPERIMENT TO SHOW
YOUR ASSAY IS WORKING, NEGATIVE
CONTROL CELLS THAT NEED TO NOT
DIE WHEN YOU DO YOUR EXPERIMENT
TO MAKE SURE YOU'VE GOT
SPECIFICITIES, MEDIAN ONLY,
TOTAL LYSIS CONTROL.
OPTIMIZATION WOULD HAPPEN DURING
THE PILOT WORK.
AFTER PILOT WORK GETS DONE, WE
WOULD GO INTO THE MAIN SCREEN.
WE WOULD PUT THESE PLATES INSIDE
OF THESE CONTINUOUS IMPEDANCE
MONITORING MACHINES.
WE ACTUALLY JUST GOT DELIVERED
SOME NEW ONES, SO WE'RE GOING
FROM CAPACITY OF TWO PLATES TO
TEN.
OUR LOGISTICS WOULD LOOK LIKE
THIS.
THERE'S A STAGGERED START. THEY
NEED TO CULTURE FOR THE SAME
TIME, THE IDEA IS START IN
STAGGERED WAY BECAUSE PLATING IS
DIFFICULT.
AND ESTABLISH THE CO-CULTURES.
SO YOU'RE NOT THAWING PRECIOUS
SAMPLES OF T CELLS OVER AND OVER
AGAIN.
AND AS I SAID BEFORE WE WOULD
WATCH THEM OVER ABOUT 72 HOURS
AND END THE EXPERIMENT.
THIS IS WHAT LOGISTICS LOOKS
LIKE.
AND THEN TOTAL STUDY PLANS, WE
WOULD START WITH PILOT STUDY AND
IF OF COURSE LOOKS GOOD AND
WE'VE GOT EVERYTHING TWEAKED AND
OPTIMIZED AND GO INTO THE MAIN
STUDY, PRIMARY SCREEN, WHICH
WOULD HAVE LOW LOGISTICS LIKE E
PREVIOUS SLIDE, IMPEDANCE,
CONTINUOUS MONITORING, COMPANION
TIE SO TOXICITY ASSAY OF SOME
KIND, SOME AMOUNT OF IMAGING TO
MAKE SURE WHAT WE'RE READING OUT
IS WHAT WE'RE SEEING WITH OUR
EYES.
AND THEN ALSO CYTOKINE RELEASE
ASSAY.
IF YOU HAVE AN UNEXPECTED HIT
SOMEWHERE THEN YOU NEED TO GO
THAT CELL TYPE AND SAY, WELL,
DOES THE CELL TYPE HAVE THE
TARGET?
CAN YOU FOLLOW THAT UP WITH
WESTERN BLOTS, FLOW CYTOMETRY OR
IHC TO SEE IF THE TARGET IS
EXPRESSED, FOLLOWED WITH
ADDITIONAL CO-CULTURES TO TEASE
OUT SENSITIVITY AND TIMING.
THE THING THAT'S IMPORTANT,
WE'RE COMING AT THIS BINDING
THING, WITH ORTHOGONAL DATASETS
WITH A WEIGHT OF EVIDENCE
APPROACH.
AND THAT REGULATORS LIKE TO SEE
THAT.
SO, AS FAR AS QUESTIONS AND
CONSIDERATIONS THAT PEOPLE NEED
TO THINK ABOUT BEFORE THEY DO
THIS STUDY, IF A STUDY IS COMING
TO US, WE DO HAVE TO GET
APPROVAL BY OUR BIOSAFETY
COMMITTEE SO THERE IS A CERTAIN
AMOUNT OF INFORMATION THAT NEEDS
TO BE SHARED, LIKE WHAT IS THE
LENTIVIRUS OR WHAT TYPE OF
VECTOR ARE YOU USING TO EXPRESS
THE CAR, INFORMATION ABOUT THE
CELL TYPES, THAT KIND OF THING.
WE WOULD NEED INFORMATION LIKE
THAT.
IF THERE'S ALREADY AN
ESTABLISHED KILLING ASSAY FOR
CONTROL CELLS, IT'S NICE TO
SHARE IT BECAUSE THAT PROVIDES
US WITH A SPRINGBOARD FOR ASSAY
OPTIMIZATION.
AND OTHER CONSIDERATIONS THAT
MIGHT BE SPECIFIC TO THAT
PARTICULAR CAR T.
SO, JUST SO EVERYBODY
UNDERSTANDS, OUR GROUP CURRENTLY
FUNDS -- CURRENTLY SUPPORTS THE
NEXT PROGRAMS, WHICH IS THIS
BULLET POINT DOWN HERE, NEXT
PROVIDES RESOURCES BUT NOT MONEY
FOR APPROVED SIZES, PEOPLE APPLY
TO BE IN THAT PROGRAM.
AND THEN NCI ALSO HAS THIS OTHER
CONSULTATION AS MUCH AS THAT'S
AVAILABLE IF ANYBODY WANTS TO
SEE IT.
AND THAT IS THE END.
>> THAT WAS GREAT.
THERE'S A QUESTION ONLINE.
I'M GOING TO TAKE PRIORITY AND
GIVE MYSELF PRIORITY.
[LAUGHTER]
THAT CAME OUT WRONG.
I'M JUST CURIOUS ABOUT THE CELL
SOURCING.
ARE THESE ALL THE I CELLS FROM
CDI OR DO YOU HAVE
DIFFERENTIATION PROTOCOLS YOU'RE
USING TO TAKE iPSCs AND TAKE
THEM TO HOMOGENOUS POPULATIONS
DOWN DIFFERENT LINEAGES AND HOW
ARE YOU ENSURING LIKE
HOMOGENEITY OF THE OUTCOME?
>> WE'RE WORKING WITH FCDI AND
SO WHEN THOSE CELLS COME TO YOU
FROM FCDI THEY ARE PARTLY
DIFFERENTIATE AND YOU'RE
FINISHING IT OUT.
SOME CELL TYPES THAT I MENTIONED
LIKE PNEUMOCYTES, TYPE 1, RENAL
EPITHELIAL CELLS ARE NOT REALLY
AVAILABLE IN hIPSC FORMAL,
THEY WOULD BE MORE LIKE PRIMARY
CELLS WHICH IS LESS FAVORITE BUT
I STILL THINK IT'S A GOOD IDEA
TO LOOK AT THEM FROM A TOX
PERSPECTIVE.
>>IN TERMS OF LIKE CO-CULTURE
CONDITIONS, TO BE ABLE TO
CULTURE ALL OF THESE DIFFERENT
CELL TYPES TOGETHER THAT ALL
HAVE FAIRLY UNIQUE SORT OF NEEDS
AND REQUIREMENTS HOW ARE YOU
WORKING THAT OUT?
>>GOOD QUESTION.
WE DO EVERYTHING IN 96 WELL
PLATES, ONE CELL TYPE PER PLATE.
ONCE YOU'VE GOT ENOUGH REPEATS,
SO YOU HAVE A DECENT ENOUGH N
AND ENOUGH CELLS ALONE, THIS
CELL ALONE, THAT CELL ALONE,
LYSIS CONTROLS, ET CETERA, IT
FILLS UP A PLATE OR SOMETIMES
TWO PLATES REAL FAST.
YEAH, IT'S PRETTY -- CAN BE
LABOR INTENSIVE, SO, YEAH.
>> THANKS.
WE HAVE AT LEAST ONE QUESTION
ONLINE.
>> TWO QUESTIONS.
FIRST ONE IS MAYBE SOMEWHAT
RELATED TO NICOLE'S.
ELLEN BERG, HAVE YOU CONSIDERED
DOING ASSESSMENTS ON HUMAN
PRIMARY CELLS, IN ADDITION TO
iPSC DERIVED CELLS,
DIFFERENTIATED LONG AND
EXPENSESSIVE, PRIMARY CELLS MAY
CAPTURE MORE ADULT-LIKE
PHENOTYPES.
>> YES, WE LIKE CDFI CELLS
BECAUSE THEY ARE SO WELL
CHARACTERIZED, AND AS I SAID
WHEN YOU BUY THEM, THEY COME
ALREADY PART WAY DONE, IF YOU
WILL, SO YOU'RE FINISHING IT AND
NOT HAVING TO SPEND WEEKS OR
MONTHS OR YEARS OPTIMIZING A
MATURATION PROTOCOL.
AND, YES, I AGREE ABOUT PRIMARY
CELLS.
AS I SAID, IF WE COULD GET ALL
OF THE CELL TYPES THAT I WANT
FROM FCDI NICE AND NEAT THAT
WOULD BE GREAT BUT SINCE THEY
ARE NOT AVAILABLE RIGHT NOW I'M
WILLING AND INTERESTED TO GO OUT
INTO THE PRIMARY REALM AS WELL.
I GOT MY START IN PRIMARY
EPITHELIAL CELLS ANYWAY.
>> APRIL KNOB HAS A QUESTION,
HOW DID REGULATORS REACT TO IND
AS ONLY SAFETY DATA, WAS THERE A
HIGH DEGREE OF SCRUTINY OR
EXTENSIVE QUALIFICATION.
>> THAT WAS FROM THE FRY GROUP,
CD33, BEFORE MY TIME HERE, BUT
THEY DID TAKE THE CD33 CAR T
FORWARD INTO HUMANS, SO I HAVE
TO BELIEVE THAT IF THERE WAS ANY
PUSHBACK THAT IT PROBABLY WASN'T
TERRIBLE AND IF THEY HAD ANY
THEY GOT THROUGH IT.
THAT'S AS FAR AS I KNOW, CD33
CAR T IS STILL MAKING ITS WAY
THROUGH THE PIPELINE.
>> MULTIPLE CAR T PROJECTS HAVE
BEEN APPROVED.
>> THERE HAVE BEEN MULTIPLE CAR
T PRODUCTS THAT HAVE BEEN
APPROVED IN THIS MANNER, SO ...
>> THANK YOU.
>> THANK YOU SO MUCH.
NOW FOR OUR LAST PRESENTATION OF
THE AFTERNOON, FROM THE NICEATM
GROUP, KAMEL MANSOURI IS GOING
TO TALK ABOUT SOME NICEATM
COMPUTATIONAL RESOURCES AND
TOOLS WE'VE BEEN DEVELOPING
UNDER INTEGRATED CHEMICAL
ENVIRONMENT AND OPPERA.
>> THANKS, NICOLE.
THANKS, EVERYONE, FOR BEING
HERE, ALSO ONLINE WITH US THIS
AFTERNOON.
I'LL BE TALKING ABOUT THE
NICEATM COMPUTATIONAL TOOLS, AND
I WILL START WITH ICE, WHICH
IS -- WELL, LET'S SEE.
THIS IS ONLINE, RIGHT?
SO, I DON'T SEE MY LITTLE NOTES.
SO, ICE IS A FREE AND PUBLIC
ONLINE RESOURCE FOR HIGHLY
CURATED DATA, AND IT ALSO
PROVIDES A LOT OF COMPUTATIONAL
TOOLS FOR EXPLORING THAT DATA AS
WELL AS DOING A LITTLE BIT OF
UTILIZATION AND ANALYSIS AS
WELL.
AS YOU CAN SEE HERE, THESE ARE
THE DIFFERENT TOOLS THAT WHEN
YOU GO ONLINE ON THE ICE
WEBSITE, THIS IS WHAT WE'RE
GOING TO SEE.
YOU CAN CHOOSE ONE OF THESE
TOOLS TO PERFORM LIKE DIFFERENT
SEARCHES ON THE DATABASE, AS
WELL AS DOING THE ANALYSIS,
EXPLORATION OF THE DATA AS WELL
AS SEARCHING THE DIFFERENT
HIGHLY CURATED IN VIVO, IN
VITRO, AND IN SILICO
PREDICTIONS, AND RUNNING PBK
MODELS, I'LL TALK ABOUT THAT
LATER.
THE DIFFERENT TOOLS THAT YOU
HAVE ON ICE, FOR EXAMPLE,
EXPLORATION OF THE DATA COMING
FROM THE TOX CAST AND TOX21, YOU
CAN DO SOME CHEMICAL SIMILARITY
ANALYSIS AND THE LIKE
VISUALIZATION USING DIFFERENT
CURVE FITTING TOOLS THAT YOU
HAVE AVAILABLE, AS WELL AS
EXPLORING THE CHEMICAL EXPOSURE
AND USE DATASETS THAT YOU HAVE
ON ICE THAT ARE HIGHLY CURATED,
COMING FROM DIFFERENT SOURCES
LIKE EPA AND OTHER AGENCIES.
YOU CAN ALSO DO LIKE PREDICTING
TISSUE CONCENTRATION, SO ICE IS
ALWAYS BEING UPDATED.
ONLY THE DATASETS THEMSELVES
THAT EXIST ARE USUALLY CURATED
AND RECURATED AND DATA IS BEING
ADDED CONTINUOUSLY, BUT ALSO THE
FEATURES THAT ARE PROVIDED ON
ICE ARE ALSO USUALLY UPDATED.
AND SOME OF THE LATEST FEATURES
THAT YOU CAN FIND IN THE LATEST
VERSION 4.0, AND ICE, ARE FOR
EXAMPLE THE PBK AND IVE THOLES
HAVE ENHANCEMENTS AND NEW MODELS
LIKE GESTATIONAL MODEL THAT WAS
IMPLEMENTED FROM THE EPA STTK
PACKAGE.
AND A FEW OTHER ENHANCEMENTS
LIKE POSSIBILITY NOW TO LIKE
SELECT IN DIFFERENT UNITS ON
THOSE MODELS.
THE EXPOSURE PREDICTIONS ARE
ALSO NEW ADDITION TO ICE, LIKE
THE EPA'S SEEM3, EVALUATION OF
MODELS, AND SEVERAL OTHER
EXPOSURE PREDICTIONS ARE NOW
ACCESSIBLE THROUGH THE ICE
SEARCH DATABASE.
ON THE ICE INTERFACE AS WELL AS
THROUGH THE API, REST API, THAT
YOU CAN EMBED TO YOUR OWN
SCRIPTS OR TOOLS FOR AUTOMATIC
SEARCHING AND DOWNLOADING OF
DATA.
IN BETA VERSION NOW WE HAVE A
COMPLETELY REDESIGNED SEARCH
INTERFACE, THAT PROVIDES NEW
UTILIZATION OPTIONS, AND LAST
BUT NOT LEAST THE CHEMICAL NAME
SEARCH, BEFORE WE HAD
IDENTIFIERS, BUT WE KNOW CERTAIN
CHEMICALS HAVE DIFFERENT
IDENTIFIERS, ALSO HAVE DIFFERENT
SYNONYMS, SO IN COLLABORATION
WITH EPA WE HAVE NOW THE
POSSIBILITY TO SEARCH CHEMICALS
USING THEIR SYNONYMS.
AND THAT'S ALSO IMPLEMENTED IN
THE ICE REST API.
SO, FOR THE GESTATIONAL MODEL ON
ICE IT'S ONE OF THE MODELS, BBK
MODELS IN ADDITION TO OTHER
COMING FROM THE SDDK IMPLEMENTED
NOW USING THE -- IN A MORE USER
FRIENDLY WAY, ON ICE, KNEEING IT
REQUIRES A LITTLE BIT OF
KNOWLEDGE AND SCRIPTING IN R OR
OTHER LANGUAGES BUT ON ICE YOU
CAN RUN IT WITHOUT HAVING TO
WRITE ANY CODE THROUGH ITS USER
FRIENDLY INTERFACE.
SO THE RESULTS CAN BE VISUALIZED
ALSO ON THE ICE DASHBOARD, AND
YOU HAVE LIKE DIFFERENT
FILTERING OPTIONS TO SELECT
COMPARTMENTS AND DIFFERENT
PLOTTING OPTIONS AS WELL.
SO, LIKE I SAID THROUGH THE NEW
GESTATIONAL MODEL YOU CAN DO
IVIVE AND PREDICT THE MATERNAL
OR FETAL EADs, EQUIVALENT
ADMINISTERED DOSE FOR MULTIPLE
CHEMICALS, NOT JUST FOR ONE
CHEMICAL.
YOU HAVE THE EXPOSURE OVERLAY
TOOL IN AN IVIVE JUST ADDED IN
ICE 4.0, YOU HAVE THIS OVERLAY
OPTION FOR POPULATION LEVEL
EXPOSURE PREDICTION DERIVED FROM
THE SEEM34 MODEL, COMING FROM
SDK, YOU CAN RUN COMPARISONS AND
ANALYSIS AND VISUALIZATION OF
THE RESULTS.
AND THIS IS THE NEW SEARCH
INTERFACE THAT WAS UPDATED.
IT'S STILL IN BETA VERSION.
WE'RE STILL WORKING ON LIKE
IMPROVING AND ENHANCING IT, BUT
IT'S INTERACTIVE VISUALIZATION
TOOL THAT ALLOWS USER TO SCOPE
AND BREAK DOWN DIFFERENT QUERIES
AND VISUALIZE LIKE COMPARTMENTS
OF DATA AND THEIR INTEGRATION
WITHIN THE DIFFERENT DATASETS
AND VISUALIZATION OF THE
DISTRIBUTION OF DATASETS THAT
ARE USUALLY USEFUL FOR EXPLORING
THE DATA.
AND LIKE I SAID, LAST BUT NOT
LEAST, THIS IS HOW YOU CAN
SEARCH FOR CHEMICALS USING THEIR
SYNONYMS INSTEAD OF USING
I.D.s, YOU CAN JUST PUT THE
SYNONYMS DIRECTLY ON THE
INTERFACE AND THEN LOOK FOR THEM
AND THEY WILL BE PULLED OUT BY
THEIR STRUCTURES.
THE SECOND PART OF THE
PRESENTATION IS ABOUT OPERA, THE
FREE AND OPEN SOURCE SUITE OF
QSAR MODELS.
JUST LIKE FIRST DEVELOPED
INITIALLY AT THE EPA, AND
CURRENTLY, IT'S MAINLY
MAINTAINED BY NICEATM BUT STILL
IN CLOSE COLLABORATION WITH EPA
AND OTHER AGENCIES.
SO IT WAS AND STILL ALWAYS BASED
ON THE FIVE OECD PRINCIPLES FOR
QSAR MODELING AND VALIDATION,
CLOSE ATTENTION TO ALGORITHMS WE
USE, APPLICABILITY, ACCURACY,
TRANSPARENCY, VALIDATION, AND
MECHANISTIC INTERPRETATION,
WHICH IS A VERY IMPORTANT STEP,
ESPECIALLY WHEN THE QSAR MODELS
ARE TO BE USED TO SUPPORT
REGULATORY PURPOSES.
SO LIKE I SAID, THIS IS LIKE THE
GENERAL APPROACH FOR OPERA BASED
ON THE FIVE OECD PRINCIPLES, ALL
DATA MUST BE HIGHLY CURATED, THE
SOURCE, CODE SOURCE IS OPEN AND
FREE AND AVAILABLE ON GITHUB.
ALL THE ALGORITHMS ARE
TRANSPARENT AND WE USE THE MOST
SIMPLE ALGORITHMS POSSIBLE AND
ONLY INCREASE COMPLEXITY IF THE
MODEL OR DATA REQUIRES IT.
THE APPLICABILITY DOMAIN IS WELL
DEFINED FOR EACH ONE OF THE
MODELS AND IT DEPENDS ON THE
MODEL AND THE DATASET SO WE
DON'T HAVE LIKE
ONE-SIZE-FITS-ALL APPLICABILITY
DOMAIN.
AND THE PREDICTIONS ARE NOT ONLY
AVAILABLE THROUGH THE
APPLICATION STAND-ALONE VERSION
BUT ALSO THROUGH DIFFERENT
RESOURCES LIKE THE ICE I JUST
PRESENTED ON IN THE FIRST PART
OF THE PRESENTATION, BUT ALSO
EPA'S COMPTOX CHEMICALS
DASHBOARD, RECENTLY THROUGH THE
FDA'S PRECISION TOX RESOURCE,
AND OF COURSE THE STAND-ALONE
APPLICATION.
SO IN ITS LATEST VERSION LIKE WE
DO FOR ICE, OPERA IS ALWAYS
UPDATED.
WITH EACH UPDATE WE ADD NEWLY
CURATED DATASETS TO THE MODELS
AND UPDATE MODELS.
AND WE ALSO RETRAIN WHEN IT'S
NECESSARY, THE MODELS, REALLY
FIND APPLICABILITY DOMAIN BUT WE
ALSO ADD NEW MODELS TO THE LIST.
SO WE RECENTLY UPDATED SOME OF
THE PHYSCHEM AND ADDED NEW ADME
PROPERTIES LIKE FRACTION,
INTRINSIC CLEARANCE, AND CACO2
PERMEABILITY.
AND IN ADDITION TO ADDING JUST
HIGHLY CURATED DATASETS, COMING
FROM PUBLIC DOMAIN, WE ALSO
FOCUS ON SPECIFIC CHEMICALS OR
CLASSES OF CHEMICALS OF HIGH
IMPORTANCE TO REGULATORS, SINCE
OPERA WAS FROM DAY 1 DESIGNED TO
SUPPORT REGULATORY PURPOSES.
SO, PFAS IS OF COURSE ONE OF
THOSE CHEMICAL CLASSES, AND IN
THE LATEST VERSION, ACTUALLY
THIS ANALYSIS WAS DONE BY AND
INDEPENDENT LAB, AND IT WAS EVEN
ON A VERSION PRIOR TO THE LATEST
VERSION, SO THESE LATEST --
THESE ANALYSES ARE COMPARISONS
WE HOPE ARE EVEN BETTER NOW WITH
THE LATEST ADDITION OF PFAS BUT
EVEN IN THE PREVIOUS VERSION AS
WE CAN SEE HERE THAT OPERA IS
DOING BETTER THAN OTHER TOOLS
THAT SOME ARE EVEN COMMERCIAL
TOOLS, LIKE BETTER ACCURACY FOR
PFAS CHEMICALS.
SO LIKE I SAID, OPERA IS
AVAILABLE ON GITHUB.
YOU ONLY NEED TO GO TO GITHUB,
AND THEN SELECT THE LATEST
RELEASE.
AND THAT'S HOW YOU GET THE
LATEST PACKAGE OF OPERA.
AND IF YOU WANT TO BE ALWAYS
UPDATED AND KNOW ABOUT THE
LATEST VERSION, YOU JUST NEED TO
CLICK WATCH, AND YOU'LL RECEIVE
NOTIFICATIONS WHENEVER A NEW
VERSION IS AVAILABLE.
SO, WHEN YOU GO TO GITHUB,
YOU'LL HAVE TO SELECT WHICH
OPTIONS SUITS YOUR NEEDS,
BECAUSE OPERA IS AVAILABLE IN
COMMAND LINE VERSION AND HAS
USER FRIENDLY GRAPHICAL
INTERFACE, ALSO AVAILABLE FOR
LINUX AND WINDOWS.
AND VERSION 3.0 WE'RE PLANNING
TO HAVE ALSO A VERSION FOR MAC,
WE STILL DON'T HAVE IT BUT WE
HAVE ALSO EMBEDDABLE LIBRARIES
IN DIFFERENT LANGUAGES, SO LIKE
JAVA, C, C++ THAT YOU CAN EMBED.
OPERA IS DEVELOPED UNDER THE
M.I.T. LICENSE, YOU CAN TAKE THE
CODE AND EMBED IN ANY TOOL, FREE
OR COMMERCIAL, DOESN'T MATTER.
YOU HAVE THE FULL RIGHT TO USE
THE CODE AND USE THE APPLICATION
IN THE BEST WAY THAT SUITS YOUR
NEEDS.
THE INPUT OPTIONS WE ALSO MADE
IT EASIER TO RUN OPERA.
SO IF YOU DON'T HAVE THE QSAR
READY STRUCTURES YOU CAN PUT
YOUR STRUCTURES, AND OPERA WILL
STANDARDIZE CHEMICAL STRUCTURES
TO GET THE QSAR-READY VERSION
CONSISTENT WITH THE WAY THE
MODEL WAS TRAINED FOR HIGHEST
CONSISTENCY AND ACCURACY.
IF YOU DON'T HAVE THE STRUCTURE
AT ALL, YOU DON'T HAVE TO LOOK
SOMEWHERE ELSE.
YOU JUST NEED TO PUT -- CREATE A
TEXT FILL, DOT-TXT FILE, PUT CAS
NUMBERS, INCHI KEY, YOU CAN MIX
IF YOU DON'T HAVE CAS NUMBER,
JUST DTXSID, OPERA WILL FIGURE
AND GET THE QSAR VERSION.
YOU CAN INPUT IN SMILES, SDF,
MOL FORMAT, OPERA WILL PROCESS
AND PARSE IT.
SO, THAT WAS ABOUT THE INPUT.
NOW FOR THE OUTPUT, YOU DON'T
JUST GET THE PREDICTED VALUE.
THIS IS VERY IMPORTANT STEP.
I HIGHLY RECOMMEND THAT THE
USERS DO NOT JUST TAKE THE
PREDICTION, AND USE IT WITHOUT
PAYING ATTENTION TO THE OTHER
INFORMATION THAT OPERA PROVIDES.
NOT JUST FOR OPERA, FOR ANY QSAR
MODEL.
YOU NEED TO TAKE A LOOK AT
APPLICABILITY DOMAIN, ACCURACY
INDEX FOR EACH PREDICTION.
IF YOU WANT TO GO FURTHER YOU
CAN TAKE A LOOK AT THE
CONFIDENCE INTERVAL WHICH WE
ADDED TO OVERLAY THE INHERITED
VARIABILITY OF THE DATA BECAUSE
WE KNOW ALL EXPERIMENTAL DATA
COMES WITH VARIABILITY.
WE IMPLEMENTED AND MADE IT
AVAILABLE THROUGH OPERA
PREDICTIONS SO THAT YOU HAVE AN
INTERVAL, AND THAT GIVES AN
ESTIMATE OF THE UNCERTAINTY
ABOUT EACH ONE OF THE
PREDICTION, PREDICTION-SPECIFIC
AND MODEL-SPECIFIC, YOU DON'T
GET THE SAME INTERVAL FOR ALL,
CAN YOU GO FURTHER AND SEE HOW
SIMILAR THEY ARE AND THIS IS AN
IMPORTANT FACT THAT WHEN I SAY
SIMILAR I DON'T MEAN
STRUCTURALLY LIKE VISUALLY
SIMILAR BUT SIMILARITY IS
DEPENDENT ON THE SPECIFIC
ENDPOINT, MEANING THAT IT'S VERY
RELATIVE AND ONLY THE
DESCRIPTORS THAT WERE SELECTED
AS THE HIGHEST IMPORTANT
DESCRIPTS FOR FOR THAT ENDPOINT
ARE USED TO DETERMINE SIMILARITY
FOR FIVE NEAREST NEIGHBORS.
AND YOU GET A LOT OF OTHER
INFORMATION, LIKE THE INCHI KEY,
PREDICTED AND EXPERIMENTAL
VALUES AS WELL.
PREDICTIONS, THEY ARE AVAILABLE
ON NICEATM'S ICE.
YOU CAN DOWNLOAD THEM IN BATCH
MODE AND YOU CAN TAKE A LOOK AT
THEM ONE BY ONE.
YOU CAN ALSO ACCESS THEM THROUGH
THE EPA'S DASHBOARD, AND YOU CAN
ALSO DOWNLOAD THEM IN BATCH
MODE, INPUT THE CAS NUMBER OR
DSS TOX IDs, AND RUN THEM, OR
USE THE INTERFACE TO LOOK AT
SPECIFIC MODELS AND THEIR
PREDICTIONS.
JUST RECENTLY WE WORKED WITH THE
EPA TO ADD OPERA AND MAKE IT
AVAILABLE ON THE PRECISION
PLATFORM AS WELL.
NOW YOU HAVE OPERA, LATEST
VERSION OF OPERA, RUNNING THERE.
AND IN ADDITION TO THOSE ONLINE
RESOURCES, IF YOU ARE FAMILIAR
WITH THE OECD QSAR TOOLBOX NOW
WE HAVE A PLUG-IN FOR OPERA
THAT'S AVAILABLE TO ADD TO THE
OECD TOOLBOX, SO YOU CAN GET
OPERA PREDICTIONS WITHIN THE
TOOLBOX AND COMPARE THEM WITH
OTHER TOOLS AS WELL.
WITH THAT, THANK YOU, EVERYONE,
FOR YOUR ATTENTION.
THIS IS THE GREAT TEAM THAT WE
HAVE BEHIND ALL THIS GREAT WORK.
IF WE DON'T HAVE ALL THE
PICTURES HERE, THE TEAM IS
ALWAYS EXPANDING AND GROWING, SO
PROBABLY THE PICTURE IS MISSING
A FEW PEOPLE.
THANKS TO THE NICEATM GROUP, AND
THANK YOU ALL.
[APPLAUSE]
>> THANKS, KAMEL.
DO WE HAVE ANY QUESTIONS IN THE
ROOM FIRST OF ALL?
JOHN?
>> YEAH, THANKS, GREAT, KAMEL.
ICE AND OPERA, ARE THEY
AVAILABLE ONLINE AND DOWNLOAD?
>> BOTH WHAT?
>> AVAILABLE DOWNLOAD AND
ONLINE?
OR JUST ONLINE?
>> ICE IS ONLY AVAILABLE
ONLINE.
>> ONLINE, OKAY.
>> JUST LIKE THE EPA DASHBOARD.
OPERA, IF YOU WANT TO RUN OUT
USUAL COMPUTER YOU HAVE TO
DOWNLOAD AND INSTALL IT.
IT'S AN APPLICATION.
IF YOU JUST WANT TO ACCESS
PREDICTIONS YOU CAN EITHER GO ON
ICE AND YOU'LL SEE THE
PREDICTIONS FOR SPECIFIC MODELS
OR IN THE EPA DASHBOARD AS WELL,
YOU CAN SEE PREDICTIONS THAT ARE
ALREADY SAVED AND UPLOADED
THERE.
>> JUST TO ADD TO THAT, THE ICE
DATA ARE AVAILABLE
PROGRAMMATICALLY THROUGH A REST
API, SO YOU CAN -- IF YOU WANT
TO ACCESS COMPUTATIONAL
TOXICOLOGY TOOLS AND WORKFLOWS,
THEN YOU HAVE TO GO THROUGH THE
DASHBOARD AS A HUMAN, BUT IF YOU
JUST WANT TO PULL THE DATA FROM
THE DATABASE YOU CAN DO THAT
PROGRAMMATICALLY THROUGH THE
API.
>> SOUND GOOD.
THANKS.
>> ANY QUESTIONS ONLINE, DAVE?
>> YEAH, THERE'S ONE FROM AMY
KYLE FROM UC-BERKELEY.
ARE YOU INCLUDING PERSISTENCE IN
THE TRAITS YOU'RE WORKING ON?
>> THERE ARE MODELS OF
ENVIRONMENTAL FATE, YES, LIKE
SOIL DEGRADATION, A FEW MODELS
THERE, YES.
>> OKAY.
>> THANK YOU ALL.
>> OKAY.
SO, THAT CONCLUDES DAY 1 OF THE
ICCVAM PUBLIC FORUM.
THANK YOU FOR YOUR
PARTICIPATION.
AND WE'RE VERY EXCITED FOR DAY 2
TOMORROW.
WE'VE GOT LOTS OF REALLY GREAT
TALKS ON THE AGENDA TOMORROW.
WE ALSO HAVE QUITE A NUMBER OF
PUBLIC COMMENTS FROM A VARIETY
OF DIFFERENT STAKEHOLDERS THAT
WILL BE EITHER PRESENTING SLIDES
OR JUST PROVIDING ORAL PUBLIC
COMMENTS, AND THOSE WILL BE
HAPPENING DURING THE MORNING
TOMORROW SO NOT TO BE MISSED.
SO, WE WILL RECONVENE AT 9:00
A.M. SHARP TOMORROW.
EVERYONE, HAVE A WONDERFUL
AFTERNOON AND EVENING.
WE'LL SEE YOU TOMORROW.
[APPLAUSE]