p- 1

P.O . Bo x 331 , Millwood , V A 2264 6 (540 ) 837-160 2



### Ma y 24 , 201 3

C O 

# IIII II I II I IIIIIIIII I II I II I § i f

4013000004 1 — 

### = * 2 m o o * * o 

### Re : Testin

g Consen t Orde r fo r Ethylen e Dichloride ; Reques t fo r Modificatio n o f

Enforceabl

e Consen t Agreemen t an d Amendmen

t t o Stud y Pla n (Pocke t No
. OPPT

2003-0010

) Dea r Sirs : Th e HA P Tas k Forc e request s amodificatio n o f

th e Enforceabl

e Consen t Agreemen

t fo r Ethylen e Dichloride ("EDC") , 68 Fed
. Reg
. 3312 5 (Jun e 3 , 2003) , a

s amended

, 74 Fed
. Reg
. 3619 6 (Jul

y 22,2009) , an

d furthe r amende d b y Addendu

mModificatio n providedb y lette r date d Novembe

r 23 , 201 1 fro mMari aJ
. Do a(th e "ECA")
. Si

x copies o f

thi s submissio n ar e enclosed
. Pursuan t t o th e ECA an d th e Stud y Pla n fo r a n extende d one-generatio

n drinkin g wate r reproductive toxicit

y stud y o f ethylen e dichlorid

e i n rats , submitte

d Jul y 2 , 2012 , an

d amende d July 16 , 201 2 an

d Augus t 7 , 2012 , th

e experimenta

l star t dat e wa s August 14 , 2012 , an d th e fina l report , unles s asecon d generatio

n stud y wa s triggered , wa

s du e Jun e 28 , 2013
. A s th e stud y wa s abou t t o begin , however

, WI L discovere

d tha t i t wa s unabl e t o obtai n th e appropriat e glas s wate

r bottle s wit

h teflo n stoppers . I t

i s no t possibl e t o us e plastic bottle s becaus e EDC dissolve s them
. Th e proble mwith th e stopper s wa s deal t with last fall , bu t a n issu e regardin

g th e deliveredtarge

t dose s t o th e animals the

n arose . I n pre-testing , th

e formulate d concentrations resulte

d i n significantly lowe

r concentrations tha

t di dno t mee t th e expecte d drinkin g wate

r targe t dose s determine

d by th e PBP K modelin g fro mTie

r 1 studies
. Stability , solubility , an

d volatil e propertie s wer

e addresse d b y WI L t o determin

e wh y th e formulate d 

# Tas k Forc e

B Y HAN D Documen t Contro l Offic e Offic e o f Pollutio n Preventio

n an d Toxic s Roo m6428 U.S
. Environmenta

l Protection Agenc

y 120 0 PennsylvaniaAve. , N.W
. Washington , D C 2046

0



## CONTAIN S N O CB Ip . 2

Documen t Contro l Offic e Ma y 24,201 3 - Pag e 2



### concentrations wer

e lowe r tha n expected
. WI L no

w believe s tha

t th e issu e ha s bee n resolve d with a n improvedanalytica

l methodology
. As th e issue s appea r t o hav e bee n satisfactorily resolved , th e Tas k Force seek

s EP A approva l o f amodificatio n o f

th e EC A an d amendmen

t t o th e Stud y Pla n t o provid e fo r a n experimenta

l star t dat e o f Jul y 8 , 2013 , an

d afina l repor

t deadlin e (unles s asecon

d generatio n stud y i s triggered

) o f Jul y 21 , 2014
. W

e also see k approva l o f th e enclose d furthe r addendu mt o Appendi

x C t o th e Stud y Plan
. Thi s consist

s o f Protoco l Amendmen

t 2 , which include s clarificatio n o f severa l procedures containe

d withi n th

e initia l protocol , revisio n o f

th e statistica

l analysi s outlinedi n th

e protoco l t

o alig n with th

e recommendations o f EP A reviewers , an

d th e revise d stud y schedule
. Finally , w

e enclos e th e CV o f Dr
. Sawhne y Coder , emergenc

y contac t fo r th e study , a s a n addendu mt o Appendi

x A t o th e Stud y Plan
. Th e stud y wil l b e conducte

d pursuan t t o th e protoco l a

s amende d by Protocol Amendment

s 1 an d 2
. W e look forwardt o hearin g fromEPA
. Sincerely ,

Pete r E
. Voytek , Ph.D
. Manage r
Enclosures
cc : Joh

n E
. Schaeffe

r W
. Caffey Norman , Esq
.

4819-6034-2036.1
.p . 3



# |EWIL R E 

# SEARC H

PROTOCO L ATTACHMEN T 2 Stud y Number : WIL-417005 Sponsor: HA

P Tas k Forc e Titl e o f Studv : A n Extende

d One-Generatio

n Drinkin g Wate

r Reproductiv

e Toxicit y Stud y o f Ethylen e Dichloride i n Rat

s Protocol Modifications : 1 ) 1 Objective : Th e followin g i s adde

d to thi s section : Animal s wil l no

t b e paire d mor e tha n once . I f warranted , Fi animal s ma y b e mate d t o produc e asecon d generatio

n (se e Sectio n 7.16)
. 2 ) Th e followin g personne

l i s adde d t o th e protocol : 2. 8 Contributin

g Scientis t(Statistica

l Analysis) : Le s Freshwater

, MS BioSTAT Consultants , Inc
. 52 8 Wes t Centr e Avenu e Portage , M I 4902

4 Tel : (269 ) 329-797 6 Email : LesFreshwater@biostat.ne t 3) 3 Stud

y Schedule : Th e followin g date

s ar e update d i n th e protocol : Propose d Experimenta

l Startin g (Anima l Receipt ) Date : 2 5 Jun e 201 3 Propose d Experimenta

l Star t Date : 8 Jul

y 201 3p . 4

Pag e 2 o f 14 WIL-417005

Protocol Attachmen

t 2 Propose d Experimenta

l Completion/Terminatio

n Date : 2

9 Apri l 201 4 Propose d Audite dDraf

t Repor t Date : 2

7 Ma y 201 4 4 ) 6. 3 Drinking Water : Th e secon d sentenc e o f thi s paragrap

h i s replace

d wit h th e following : Revers e osmosis-treate

d ta p wate r (wit h tes t substanc e adde d during th

e treatmen

t perio dfo r

th e animals assigne

d t o Group s 2-4) wil l b

e availabl e a d libitu mt

o al l animal s an

d wil l b e provide d fro mstandar

d glas s wate

r bottle s with meta

l sippe r tubes an d n o plastic o r rubbe r fittings
. 5 ) 7.4. 4 Treatmen

tRegimen : Thi s sectio

n i s replace

d wit h th e following : Untreate d o r tes t substance-treate

d drinkin g wate

r formulation s wil l b

e offere da d libitu mvi astandar

d glas s wate

r bottle s wit

h meta l sippe r tubes an d n o plastic o

r rubbe r fittings, an

d supplie d fo r th e duratio n o f th e study , a s note d i n Sections 7.4.4. 1 an d 7.4.4.2
. Fres

h vehicl e an d tes t substanc e drinkin g wate

r formulation s wil l b

e provideda

t leas t weekly
. 6 ) 7.5. 1 Preparatio

n o f TestSubstance-Treate

d Drinking Water : Th e thirdsentenc

e i s replace

d wit h th e following : Tes t substanc e formulation s wil l b

e prepare d a t leas t weekly
. 7 ) 7.5. 3 Stability o f

Test Substance-Treated Drinkin g Water : Thi s sectio

n i s replace

d with : Stabilit y o f th e formulated tes

t substanc e i n drinkin g wate

r wa s assesse d i n a concurren t stud y (WIL-417006 ; Stanton , Draft ) afte r 8 an d 1 5 day

s o f roo m temperatur

e storag e a t concentrations bracketin

g thos e use d i n th e curren t stud y an d wil l no t b e assesse d i n thi s study
.Pag e 3 o f 1 4 WIL-417005

Protocol Attachmen

t 2 8 ) 7.5. 4 Homogeneit

y an d Concentratio

n o f Tes tSubstanc

e i n th e Drinking Water : A s pe r stud y directo r notificatio n date

d 4 Octobe

r 2012 , th

e requiremen

t fo r homogeneit

y assessmen

t i s remove da s th e tes t substanc e i s solubl e i n th e wate r t o a concentratio

n o f 8 mg/mL , which i s highe

r tha n th e expecte d highes t concentratio

n i n th e vehicle
. 9) 7.1 1 Assignmen

to f F i Animals t

o Cohorts : Th e first sentenc e o f paragrap h 3 i s replace

dwit h th e following
. Assignmen

t o f same-se x littermate s t

o aparticula

r Cohor t wil l b e avoided
. 10 ) 7.14.3. 1 Males : Thi s sectio

n i s replace

dwit h th e following : Recorde dindividually o

n atwice-weekl

y basis , beginnin

g 1 wee k prio r t o th e initiatio n o f

tes t substanc e administration , unti l euthanasia
. 11 ) 7.14.3. 2 Females : Thi s sectio

n i s replace

dwit h th e following : Recorde dindividually o

n atwice-weekl

y basis , beginnin

g 1 wee k prio r t o th e initiatio n o f

tes t substanc e administration , unti l evidenc e o f copulation i s observed, an do n gestatio n day s 0 , 3 , 7 , 10

, 14, 1 7 an

d2 0 an dlactatio n day s 1 , 4 , 7 , 10, 14 , 1 7 an d21
. Female s wit h n o evidenc e o f matin g o r tha t fai l t o delive r wil l continu

e t o b e weighe d o n atwice-weekl

y basis unti l th

e schedule

d euthanasia
. 12 ) 7.14,4. 1 Males : Thi s sectio

n i s replace

dwit h th e following : Recorde dindividuall y o

n atwice-weekl

y basi s o n th e day s o f bod y weigh t collection , beginnin g 1 wee k prior t o th e initiatio n o f

tes t substanc e administration , unti l euthanasia
.Pag e 4 o f 14 WIL-417005

Protocol Attachmen

t 2 13 ) 7.14.4. 2 Females : Thi s sectio

n i s replace

d wit h th e following : Recorde d individually o

n atwice-weekl

y basis o n th e day s o f bod y weigh t collection , beginnin g 1 wee k prio r t o th e initiatio n o f

tes t substanc e administration , unti l th

e star t o f th e matin g periodan

do n gestatio n day s 0 , 3 , 7 , 10, 14 , 1 7 an

d2 0 an dlactation day s 1,4 , 7 , 10, 14, 1

7 an d21
. Fo r female s wit

h n o evidenc e o f matin g o r tha t fai l t o deliver , individua

l foo d consumptio

n wil l continu

e t o b e weighe do n atwice-weekl

y basis unti l th

e schedule d euthanasia
. 14 ) 7.14.5. 1 Males : Thi s sectio

n i s replace

d wit h th e following : Recorde d (by weight

) individuall y o

n atwice-weekl

y basis o n th e day s o f bod y weigh t collection , beginnin

g 1 wee k prio r t o th e initiatio n o f

tes t substanc e administration , unti l euthanasia
. 15 ) 7.14.5. 2 Females : Thi s sectio

n i s replace

d wit h th e following : Recorde d (b y weight ) individually o

n atwice-weekl

y basis o n th e day s o f bod y weigh t collection , beginnin

g 1 wee k prior t o th e initiatio n o f

tes t substanc e administration , unti l th

e star t o f th e matin g perio dan

do n gestatio n day s 0 , 3 , 7 , 10, 14 , 1 7 an d2 0 an dlactatio n day s 1,4 , 7 , 10, 14 , 1 7 an

d21
. Fo r female s wit

h n o evidenc e o f matin g o r tha t fai l t o deliver , individua

l wate r consumptio

n wil l continu

e t o b e weighe do n atwice-weekl

y basis unti l th

e schedule

d euthanasia
. 16 ) 7.14.6. 2 Bod y Weights : Thi s sectio

n i s replace

d wit h th e following : Eac h pu p wil l b e weighe do n PN D 1 , 4 (befor

e culling) , 7 , 14 an

d21 , o n atwice

weekl y basi s followin g weaning , an

do n th e da y o f euthanasia
.Pag e 5 o f 14 WIL-417005

Protocol Attachmen

t 2 17 ) 7.14.6. 3 Foo d Consumption : Thi s sectio

n i s replace

d wit h th e following : Cag e foo dconsumptio

n wil l b e recorde d o n PN D 21 , 2 4 an d 28 (th e day s o f bod y weigh t collection)
. Individua

l foo dconsumptio

n wil l b e recorde d o n atwice-weekl

y basis o n th e day s o f bod y weigh t collection , beginnin

g o n PN D 28 (whe

n th e animal s ar e individuall y housed

) unti l th e da y prior t o euthanasia
. 18 ) 7.15 Developmenta

l Neurotoxicit

y (F i Cohor

t2A) : Th e firs t sentenc e o f th e secon d paragrap

h i s replace

d wit h th e following : Th e functiona

l observationa

l batter y test s wil l b e counterbalance

d acros s testin

g times , sexes , an

d treatmen

t groups . Moto

r activit y an d auditor y startl e respons e test s wil l b e counterbalance

d wit h respec t t o cag e assignment

, testin g times , sexes , an

d treatmen t groups . 19 ) 7.14.6. 4 Wate r Consumption : Thi s sectio

n i s replace

d wit h th e following : Cag e wate r consumptio

n (b y weight ) wil l b e recorde d o n PN D 21 , 2 4 an d 28 (th e day s o f bod y weigh t collection)
. Individua

l wate r consumptio

n (b y weight ) wil l b e recorde d o n atwice-weekl

y basis o n th e day s o f bod y weigh t collection , beginnin

g o n PN D 28 (whe

n th e animals ar

e individuall y housed

) unti l th e da y prio r t o euthanasia
. 20 ) 7.20. 1 Motility/Viabilit y Assessment : Th e fourt h an d fift h sentence

s o f thi s sectio

n ar e revise d a s follows : A smal l sampl e wil l b e loade d into a100-u

mchambe r fo r determinatio

n o f motility
. Becaus e sper mmotilit y ca n b e affecte d by temperatur

e shock , al l slide s an

d diluents wil l b e warme d prio r t o us e i n a n incubator

, an d motility determination s wil l b e performed unde

r constan t temperatur

e (approximatel

y 37°C ) usin

g th e Hamilton

Thorn e HTM-IVO S Versio

n 14 computer-assiste

d sper manalysi s (CASA ) system .p . 8

WIL-417005 Pag e 6 o f 14 Protocol Attachmen t 2 21 ) 8. 4 F i Offspring Schedule d fo r Neuropathology/Brai n Weigh tMeasurement

s (Cohort s 2 A an d 2B ) Th e followin g i s adde

d t o thi s section : Due to the large number

of animals to be perfused

for neuropathological

assessment, perfusions for

Cohorts 2A and

2B will be performed

over several days. The perfusions will

be performed

such that both sexes and

all treatment

groups will

be approximately equally represented across each day. The order of perfusions each day will also be counterbalanced by sex and treatment

group (i.e., 1 male from Group 1, 1 male from Group 2, 1 male from Group 3, 1 male from Group 4, 1 female from Group 1, etc.). 22 ) 8.4.2. 2 Neuropatholog

y - Microscopi

c Examination : Th e las t paragrap h o f thi s sectio

n i s replace

dwit h th e following : Base d o n th e result s o f th e qualitative examinatio

n an dth e professiona

l judgmen t o f th e pathologist, selecte

d sites i n th

e nervous syste

man dcellula r component

s ma y b e furthe r evaluate db y th e us e o f additiona l histopath

o logica l method s (a t additiona l cost)
. I f n o neuropathologica

l alteration s ar

e observed

, subsequen

t analysi s wil l no

t b e performed
. 23) Th e followin g sectio n i s adde d t o th e protocol : 8.4.2. 3 Morphometri

c Analysis : Tw o corona

l section s (homologous betwee

n animals ) an

dth e midsagitta

l sectio n o f pons/medullawil l b

e use d fo r morphometry
. Homolog y wil l b e achieve db y step
sectionin g tissu e block s a t 60-micron interval s a

s neede d an dchoosin g th e mos t representativ

e sectio n fo r eac h animal
. Specific level s t o b e analyze dar e Level s 1 , 3 an d5 an dar e defineda

s follow s (Paxino s an

dWatson , 1998)
. Leve l 1 i s acorona

l sectio n obtaine djus t rostra l t o th e gen u o f th e corpus callosu

m an dcontain s th

e followin g major

structures : cerebra

l cortex , corpus callosum , basa l gangli a(caudat

e putamen, nucleus accumbens) , an dlatera l ventricles
. Tw o bilatera l microscopi

c measurement

s ar e obtaine da t thi s level : th

e vertica l heigh t (of th e hemispher

e jus t media l t o th e latera l ventricle , an

dth e vertica l heigh t o f th e cerebra l corte x fro mth e ape x o f th e corpus callosum/cingulu mt o th e dorsa l surfac e o f th e hemisphere
. Level 3 i s acorona

l sectio n obtaine dapproximatel

y a t th e leve l o f th e opti c chiasm, jus t rostra l t o th e pituitary , an

dcontaining th

e followin g majo

r structures : cerebra

lPag e 7 o f 14 WIL-417005

Protocol Attachmen

t 2 cortex , corpus callosum, basa l ganglia , hippocampus/dentat e hilus , thalamus , hypothalamus , an

d latera l an d thir dventricles
. Fou r bilatera l microscopi

c measurement

s ar e take n a t thi s level : th

e radia l thicknes s o f

th e cortex , th

e vertica l heigh t betwee n th e layer s o f th e hippocampa

l pyramida

l neuron s alon g alin e tha

t passe s throug h th e termination o f

th e dorsa l lim b o f th e dentat e hilus , th

e vertica l heigh t o f th e dentat e hilu s measure

d a t th e termination o f

th e ventra l limb , an d th e lengt h o f th e ventra l lim b o f th e dentat e hilu s take

n alon g astraigh t lin e fro mth

e cres t t o th e termination o f

th e ventra l limb
. Leve l 5 i s asagitta

l sectio n o f th e cerebellu

man d medullaoblongata, take n slightly latera l t o th e midline , an

d containin

g th e followin g majo

r structures : cerebellum, medullaoblongat

a(pyramida

l tract , trapezoid body , media l longitudina

l fasciculus) , an d fourt h ventricle
. Singl

e microscopi

c measurement

s o f th e heigh t o f th e cerebellu man d o f th e thicknes s o f

th e bas e o f cerebella r lobule # 9 ar e obtaine d a t thi s level
. Mean s o f paire d measurement

s fo r Level s 1 an

d 3 wil l b

e reporte d an d use d fo r statistica l computations
. Measurement s o n Leve l 5 wil l no

t b e paired
. A tota

l o f 8 microscopi

c measurement

s wil l b e included i n th

e analysis
. 24 ) 1 0 Statistica

l Methods : Th e first sentenc e i n thi s sectio

n i s replace

d wit h th e following : Al l analyse

s wil l b e tw o tailed
. I n addition , th

e followin g i s adde

d t o thi s section : Repeate d measure

s analyses , two-wa

y analysi s o f

varianc e (ANOVA ) models , an

d brai n morphometr

y dat aanalysi s wil l b

e conducte

d b y BioSTAT Consultants , Inc
. A H othe r statistica l analyse s wil l b e conducte

d b y WI L Research
. Th e repeate d measure

s analyse s an d brai n morphometri

c dat aanalyse s performed b

y BioSTAT wil l b

e conducte

d usin g SA S versio n 9. 2 (SA S Institute , Inc. , 2002-2008) , o r higher, software
. 25) 10. 1 In-Lif

e Data : Th e first paragrap h o f thi s sectio

n i s replace

d wit h th e following : Pre-coita l intervals , mea

n estrous cycl

e length , gestatio

n length , forme

r implantation sites , unaccounted-fo

r sites , mea

n day s o f attainmen

t o f developmenta

l landmark

s (balanopreputia

l separatio n an d vagina l patency ) an d th e bod y weigh t o n th e da y o fp . 1 0

WIL-417005 Pag e 8 o f 14 Protocol Attachmen t 2 attainment, anogenita

i distanc e (absolut

e an d relative t

o th e cub e root o f bod y weight) , number

s o f nipples/areola, an

d tim e fro mvagina

l patenc y t o first estrus , wil l b e subjecte d t o aparametri

c one-wa y analysi s o f

varianc e (ANOVA ) (Snedeco

r an d Cochran , 1980)
. Dunnett' s tes t (Dunnett, 1964

) wil l b e applie dt o th e dat at o compar e th e treate d group s t o th e contro l grou

p a t th e 0.0 5 significanc e leve

l regardles s o f

th e outcom e o f th e ANOVA
. Foo dan d wate r consumptio

n wil l b e reporte d bu t wil l no t b e statistically analyzed
. In addition , th

e followin g i s adde

d t o thi s section : Bod y weigh t fo r Stud y Days 0 throug

h 9 1 (males ) o

r 2 7 (females) , Gestatio

n Days 0 throug h 2 0 an d Lactatio

n Days 1 t

o 2 1 wil l b

e analyze d separatel

y wit h arepeate

d measure s analysi s o f

varianc e (RANOVA)
. Factor

s i n th e mode l wil l include : fixed effect s treatmen

t grou p (TRT ) an

d da y (TIME) ; an

d interaction ter

mTRT*TIME
. Th e covarianc

e structur e fo r th e RANOV A mode

l wil l b e selecte d b y comparin

g th e correcte d Akaike' s Informatio n Criteri a(AICC)
. Th e Kenward-Roger

s adjustmen

t fo r denominato

r degree s o f freedo mwil l b e applied
. Dunnett' s tes

t wil l b e use d t o mak e pairwis e comparison

s o f eac h individua

l treate d grou p wit h th e control
. I f

th e TRT*TIM E interactio

n i s significant

a t th e 0.0 5 level , Dunnett' s tes

t wil l b e conducte d fo r eac h individua

l day
. I f TRT*TIM E i s no

t significant , Dunnett' s tes t wil l b e conducte

d overal l acros s th e poole d days only
. Bod y weigh t gain s wil l b e reported , bu

t wil l no t b e statisticall

y analyzed
. 26)10. 2 Litte r Data : Th e las t sentenc e o f thi s sectio

n i s removed
. I n addition , th

e followin g i s adde

d t o thi s section : Pre-culling (PN

D 1 an d 4 ) an d post-cullin g (PN

D 4 , 7 , 14 an

d 21 ) pu p bod y weights wil l b e analyze

d separatel

y wit h arepeate

d measure

s analysi s o f

varianc e (RANOVA)
. Factor

s i n th e mode l wil l include : rando

meffect s LITTER ; fixed effect s treatmen

t grou p (TRT) , SE

X an d da y (TIME) ; an

d interaction term

s TRT*SEX , TRT*TIM E an d TRT*SEX*TIME
. Th e first examinatio

n wil l b e whethe r th e TRT*SE

X and/o r TRT*SEX*TIME interaction i s significant
. I f eithe r interaction i s significan t a t th e 0.0 5 level , th

e analysi s wil l b

e conducted, by sex, wit

h aRANOVA
. Factor

s i n th e mode l wil l include : rando

meffec t LITTER ; fixedeffect s TR T an d TIME ; an

d interaction ter

m TRTTIME
. Th

e covarianc

e structur e fo r th e RANOV A mode

l wil l b e selecte d b y comparin g th e correcte

d Akaike' s Informatio n Criteri a(AICC)
. Th e Kenward

-p . 1 1

WIL-417005 Pag e 9 o f 14 Protocol Attachmen t 2 Roger s adjustmen

t fo r denominato

r degree s o f freedo mwil l b e applied
. In th e fina l RANOVA model , Dunnett' s tes t wil l b e use d to mak

e pairwis e comparison

s o f eac h individua

l treate d grou p wit h th e control
. I f

th e TRT*TIM E interaction i s significan

t a t th e 0.0 5 level , Dunnett' s tes

t wil l b e conducte

d fo r eac h individua l day
. I f TRT*TIM E i s no

t significant , Dunnett' s tes t wil l b e conducte

d overall acros s th

e poole dday s only
. Pu p bod y weigh t gain s wil l b e reported , bu

t wil l no t b e statisticall

y analyzed
. 27 ) 10. 5 Functiona

l Observationa

l Battery , Locomoto

r Activity , an

d Auditor

y Startle Data : Th e titl e o f thi s sectio

n i s revise d a s indicate d above
. Th e first (only ) sentenc

e i n thi s sectio

n i s remove

d (informatio n move

d t o Sectio n 10)
. 28 ) 10.5. 1 Functiona

l Observationa

l Batter y Data : Th e titl e o f thi s sectio

n i s revise d a s indicate d above , an

d thi s sectio

n i s replace

d wit h th e following : Continuou s Functiona

l Observationa

l Batter y (FOB ) dat

a(includin g th

e averag e o f 3 gri p strengt h trial s an d 3 landin

g foo t spla y trials ) wil l b

e subjecte d t o atwo-wa

y ANOV A (Snedeco

r an d Cochran , 1980

) includin g term

s i n th e mode l fo r treatmen t grou p (TRT) , SEX , an

d TRT*SE

X interaction
. Dunnett' s tes t (1964) wil l b

e use d t o compar e th e contro l an

d treate d groups . I f

TRT*SE X i s significan

t a t th e 0.0 5 level , Dunnett' s tes

t wil l b e conducted, b

y sex, wit

h aone-wa

y ANOVA
. Otherwise , Dunnett' s tes

t wil l b e conducte

d acros s th

e poole d sexes . FO B parameter

s whic h yiel dscala

r an d descriptive dat

awil l b e analyzed , b

y sex, wit h Fisher' s Exac

t Tes t (Stee l an d Torrie , 1980)
. 29 ) 10.5. 2 Locomoto

r Activit y Data : Thi s sectio

n i s replace

d wit h th e following : Ambulator

y activit y count s wil l b e analyzed, b

y session, wit

h arepeate

d measur e analysi s o f

varianc e (RANOVA)
. Factor

s i n th e mode l wil l include : fixedeffect s treatmen t grou p (TRT) , SEX , an

d tim e interva l (TIME) ; interaction term s TRT*SEX , (TRT*TIME) , an

d TRT*SEX*TIME
. Th

e SAS ® procedur

e PRO C MIXE D wil l b

e used , an d th e covarianc

e structur e acros s tim

e wil l b e selecte d b y comparin

g th ep . 1 2

WIL-417005 Pag e 1 0 o f 14 Protocol Attachmen t 2 correcte dAkaike' s Informatio n Criterio n (AICC)
. Th e Kenward-Roger

s adjustmen

t fo r denominato

r degree s o f freedo mwil l b e applied
. Th e first examinatio

n wil l b e whethe r th e TRT*SE

X and/o r TRT*SEX*TIME interaction i s significant
. I f eithe r interaction i s significan

t a t th e 0.0 5 level , th

e analysi s wil l b

e conducted, b

y sex , with aRANOVA
. Factor s i n th e mode l wil l include : fixedeffect s TR

T an dTIME , an

dth e interaction ter

mTRT*TIME
. I n th e fina l RANOVA model , th e monotoni

c dose-respons

e relationshi

p wil l b e evaluate dusin g sequentia

l linea r tren dtest s base d o n ordina l spacin g o f dos e levels
. Th e linea r dos e b y tim e interaction (LinTrt*Time ) wil l b e evaluate dand, i f significan

t a t th e 0.0 5 level , tren

dtest s o n treatmen

t mean s wil l b e performeda

t th e 0.0 5 leve l fo r eac h tim e interval
. I f

th e linea r dos e b y tim e interaction i s no

t significant , th

e tren dtes t wil l b e conducte dacros s th

e poole dtim e interval s o f

th e entir e sessio n only
. Nonmonotoni

c dos e response

s wil l b e evaluate dwheneve

r n o significant

linea r trend s ar e detecte d bu t TR T and/o r TRT*TIM E interaction i s significan t a t th e 0.0 1 level
. Withi n th e framewor

k o f th e RMANOVA , pairwis e comparison s wil l b e mad e fo r eac h individua

l treate dgrou p with th e control grou

p throug h linea r contrasts . I f TRT*TIM E i s significant , th e comparisons wil l b

e conducte

dfo r eac h tim e interval
. I f onl y th e TR T effec t i s significant , th

e comparison

s wil l b e conducte

dacros s th

e poole dtim e interval s o f

th e entir e session
. Thes

e nonmonotoni

c dos e respons e comparison

s wil l b e conducte da t th e 0.0 1 significanc e level
. 30 ) 10.5. 3 Auditor

y Startl e Respons e Data : Thi s sectio

n i s replace

dwit h th e following : Mea n respons e amplitud

e (o n eac h block o f 1 0 trials ) wil l b

e analyzed , b

y sessio n wit h aRANOVA
. Factor

s i n th e mode l wil l includ

e fixedeffects : treatmen

t grou p (TRT) , SE

X an dTRIA L block ; interaction term s TRT*SEX , TRT*TRIAL , an d TRT*SEX*TRIAL
. Th

e SAS ® procedur

e PRO C MIXE D wil l b

e selecte d b y comparin g th e correcte dAkaike' s Informatio n Criterio n (AICC)
. Th e Kenward

Roger s adjustmen

t fo r denominato

r degree s o f freedo mwil l b e applied
. Th e first examinatio

n wil l b e whethe r th e TRT*SE

X and/o r TRT * SEX*TRIA

L interaction i s significant
. I f eithe r interaction i s significan

t a t th e 0.0 5 level , th

e analysi s wil l b

e conducted, b

y sex , wit

h aRANOVA
. Factor

s i n th e mode l wil l include : fixedeffect s TR

T an dTRIAL ; an

dth e interaction ter

mTRT*TRIAL
. In th

e final RANOVA , th

e monotoni

c dose-respons

e relationshi

p wil l b e evaluate dusin g sequentia l linea r tren dtest s base d o n ordina l spacin g o f dos e levels
. Th

e linea r dos e b y tria l interaction (LinTrt*Trial ) wil l b e evaluate dand, i f significant

a t th e 0.0 5 level , tren dtest s o n treatmen t mean s wil l b e performe d a

t th e 0.0 5 leve l fo r eac h tria lp . 1 3

WIL-417005 Pag e 1 1 o f 14 Protocol Attachmen t 2 block
. I f th e linea r dos e b y tria l interaction i s no

t significant , th

e tren d test wil l b e conducte d acros s th

e poole dtrial block

s o f th e entir e sessio n only
. Nonmonotoni

c dos e response

s wil l b e evaluate d wheneve

r n o significan

t linea r trends ar e detecte d bu t TR T and/o r TRT*TRIAL interaction i s significant a t th e 0.0 1 level
. Withi n th e framewor

k o f th e RANOVA , pairwis e comparison s wil l b e mad e fo r eac h individua l treate d grou p wit h th e contro l grou

p throug h linea r contrasts . I f TRT*TRIAL i s significant , th e comparisons wil l b

e conducte

d fo r eac h tria l block
. I f onl y th e TR T effec t i s significant , th

e comparison

s wil l b e conducte

d acros s th

e poole d tria l block

s o f th e entir e session
. Thes

e nonmonotoni

c dos e respons e comparison

s wil l b e conducte d a t th e 0.0 1 significanc e level
. Latenc y t o maximu mrespons e (TMAX ) wil l b

e reporte d bu t no t statisticall

y analyzed
. 31 ) 10. 6 Brai n Morphometri

c Dat a (Cohor t2A) : Thi s sectio

n wil l b e revise d i n afollowin g protoco l attachment
. 32 ) 1 1 Qualit

y Assurance : Th e las t paragrap h o f thi s sectio

n i s replace

d wit h th e following : Dat aanalysi s performed b

y BioSTAT Consultants , Inc
. wil l follo w th e curren t procedura l guideline s o f

BioSTAT Consultants , Inc
. BioSTAT Consultants , Inc
. wil l provid e astatistica

l analysi s report, whic h wil l b e include d a s a n appendi x t o th e fina l report . Qualit

y Assuranc

e auditing o f

th e statistica

l repor t (fo r interna l consistenc

y an d consistenc

y wit h th e stud y report ) wil l b e conducte

d unde r th e directio n o f

th e WI L Researc

h Qualit y Assuranc

e Department
. 33 ) 1 7 References : Th e followin g i s adde

d t o thi s section : Paxinos , G . an d Watson , C . Th e Ra tBrai n i n Stereotaxi

c Coordinate

s 4t h edition . Academi c Press , Sa n Diego , CA , 1998

. Stanton , A . A n Analytica

l Metho d Validatio

n an d Stabilit y Stud y o f Ethylen e Dichlorid e i n Aqueou s Formulations

. WIL Research

, Ashland , OH , DRAFT .p . 1 4

WIL-417005 Pag e 1 2 o f 1 4 Protocol Attachmen t 2 34 ) Appendi

x A Stud y Design : References t

o weekl y DetailedClinica

l Observations fo r

th e F o an d F i generations ar

e remove d fro mthi s section
. Reason s fo r Protoco l Modification : 1 ) T o clarif y tha t animals wil l no

t b e paire d mor e tha n once , an

d tha t asecon d generatio n ma y b e warrante d base d o n th e result s obtaine d fro mth e F Q animals
. 2 ) T o includ e th e Contributing Scientist

(Statistica

l Analysis)
. 3 ) T o updat e th e stud y schedule
. 4-5 ) Th e tes t substanc e interact s with plastic
. Therefore , thes e modification s updat

e th e type o f bottle s t o b e use d fo r administration o f

th e tes t substance
. 6 ) T o allo w fo r

mor e frequen t preparatio

n o f th e tes t substanc e formulations
. 7 ) T o indicat e tha t roo mtemperatur

e storag e stabilit y wa s include d i n aconcurren

t study
. 8 ) T o remov e th e requiremen

t fo r homogeneit

y assessment

. 9 ) T o clarif y tha t same-se x littermate s wil l no

t b e assigne d t o th e sam e Cohort
. 10-17 ) Give

n tha t formulation s ma

y nee d t o b e prepare d mor e frequently tha

n onc e pe r week , thes e modification s updat

e th e schedul e fo r bod y weight , foo dconsumptio n an d wate r consumptio

n t o twice-weekl

y t o accommodat

e th e mor e frequen t tes t substanc e formulation
. 18 ) T o exten d th e counterbalancin

g procedures fo r

behaviora

l testin g t o includ e cage, sex, an d treatmen

t grou p i n addition t

o testin g time s 19 ) Give n tha t formulation s ma

y nee d t o b e prepare d mor e frequently tha

n onc e pe r week , thes e modification s updat

e th e schedul e fo r bod y weight , foo dconsumptio n an d wate r consumptio

n t o twice-weekl

y t o accommodat

e th e mor e frequen t tes t substanc e formulation
. 20) T o chang e 100-p. mcannul ato 100-u mchambe r slide , an d t o updat e th e version o f

th e Hamilton-Thorn

e HTM-IVO S system. 21 ) Counterbalancin

g o f perfusion s acros s day , sex, an d treatmen

t grou p i s added
.p . 1 5

WIL-417005 Pag e 1 3 o f 14 Protocol Attachmen t 2
22) T o clarif y wha t ma y occu r i f th e pathologis t

recommend

s furthe r analysi s o f

specifi c sites withi n th

e nervou s system . 23 ) T o includ e detail s fo r

th e morphometri

c analysis
. 24-31 ) T o revis e th e statistica

l analyse s t o b e performed
. 32 ) T o includ e Qualit y Assuranc

e responsibilitie s fo r

al l statistica

l analyse s performed b

y BioSTAT Consultants , Inc
. 33 ) Additiona

l reference s included
. 34 ) Weekl y detaile d clinica l observations wer

e remove d fro mth e protocol vi aProtocol Amendmen

t 1
.Pag e 14 o f 1 4 WIL-41700 5

Protocol Attachmen

t 2 Approval : Sponsors approval

was obtained

via f^mrv^l

on J^Jtfl&u 2tiJ3-- Dal * WI L Researc

h

Stud

y Directo r HA P Tas k

Forc e Meliss aJ
. Beck , Ph D Dait J

"PcterE
. Voyt^k , Ph

D Dat e / Sponso r Representativep . 1 7

CURRICULUM

VITAE October 1,2012

Forma l Education : 200 8 200 0

199 5

1993
Professional

Experience:

04/24/1 0 - Presen

t 

## PRAGATISAWHNE Y CODE R Developmental

and Reproductive Toxicology
Diplomate , America

n Boar do f Toxicolog y India n Institut e o f Technology-Bomba

y (IITB ) Biotechnology Centr

e Powai , Bombay , Indi a Ph D Molecula

r Biolog y JamiaMilli aUniversit

y Centr e fo r Bio Sciences Ne w Delhi , Indi a M S Bi o Sciences JamiaMilli aUniversit

y Centr e fo r Bi o Sciences B S Bi o Sciences

WI L Researc

h Ashland , O H Position : Senio

r Toxicologis t Developmenta

l an d Reproductive Toxicolog y Stud y Directo r

fo r developmental , reproductiv e an d neurotoxicit

y studies
. Responsibl

e fo r the planning , conduc

t an d successfu

l reportin g o f

assigne d studies
. Review departmenta

l toxicolog y reports fo r interpretatio n an

d presentation o f

stud y findings
. Provide senio r leve l interpretatio n o f

dat agenerate d b y toxicolog y studies
. Consul t wit h Stud

y Director s an

d other s t o provid e advic e fo r appropriat

e analysis , presentation an d descriptio n o f

stud y findings
. Mentor

an d advis e junio r

leve l Stud

y Director s regarding scientifi c aspect s o f stud y design an

d dat aanalysi s an d interpretation
. Confe

r wit h client s and/o

r othe r externa l scientists to provid e advic e a s appropriate
. Prepar

e technica

l papers , publication s an d report s a

s directed
. Maintai n competenc

y a s asenio r toxicologis t

b y researchin

g scientifi cp. 1 8 Pragati Sawhney Coder CURRICULUM VITAE Pag e 2 Professional

Experience (Continued)

literature , attending seminars , scientifi c meeting s an d othe r venues fo r

continuin g education
. Serv e a s aprimar

y scientifi c contac t fo r key client s an

d provide on-sit

e suppor t fo r their programs . Develo

p ne w capabilitie s fo r

WI L Research
. 01/16/0 6 - 04/23/1 0 Position : Staf f Toxicologis t Developmenta

l an d Reproductive Toxicolog y Stud y Director

fo r developmental , reproductive an d neurotoxicit

y studies
. Responsibl

e fo r th e planning , conduc

t an d successfu l reportin g o f

assigne d studies
. Participat

e i n repor

t review an

d generatio

n process . Develo

p ne w capabilitie s fo r WI L Research
. Communicat e wit h Sponsor

s a s required
. Th e Universit

y o f Texa s a t Austi n College o f Pharmacy , Divisio n o f

Pharmacolog

y an d Toxicolog y Austin , T X 200 2 - 200 5 Position : Postdoctora l Researc h Associat

e Laborator y o f Dr
. Joh n H
. Richbur

g Conducte d an d supervise

d toxicologica

l researc h i n th e lab
. Performed overal l maintenanc e o f th e laborator

y includin g complianc e with environmenta l healt h an d radiatio n safety
. Solel y responsibl

e fo r th e developmen

t o f mous e exposur

e mode l fo r th e evaluation o f

cisplatin-induce dtesticula r toxicity
. 200 0 - 2002 Position : Postdoctora l Fello w Laborator y o f Dr
. Joh n H
. Richbur

g Scientific Trainine: 2000-200 5 Developmenta l Stagin g o f Roden tSpermatogenesi

s Worke dunde

r th e direct tutelage o f

leading expert

s i n th e fiel d o f roden t testicula r histopathology an

d spermatogenesi s staging , Prof
. Re x Hes s (Veterinar

y Biosciences , Universit

y o f Illinois , Universit y o f Illinoi s a t Urbana-Champaign

) an d Prof
. Marvi n Meistrich , (Experimenta l Radiatio n Oncology , Universit y o f Texa s M D Anderso n Cance

r Center)
. Traine d graduat e student s an d ne w appointee s i n th

e laborator

y o f Dr
. Joh n Richburg , a

s neede d durin g thi s period
.Pragat i Sawhne y Coder Pag e 3 Awards: WI L Researc

h Compan

y Scientifi c Publicatio n Award
. 2011
. Continuing Education: Ste mCell s i n Toxicology
. 51 s t Annua l Meeting , Societ

y o f Toxicology , Sa

n Francisco , CA , Marc h 11 , 2012
. MicroRNA s i n Biolog y an dToxicology
. 51 s t

Annua l Meeting , Societ

y o f Toxicology , Sa

n Francisco , CA , March 11 , 2012
. Preclinica l Developmenta

l Toxicit y Studies
. 51 s t

Annua l Meeting o f

th e Teratology Society , Sa n Diego , CA , Jun

e 25,2011
. Postmarketin

g Sirveillanc e Studies an dCommunication o f

Risk
. 51 s t

Annua l Meeting o f

th e Teratology Society , Sa

n Diego , CA , Jun

e 25,2011
. Th e Biolog y an

dToxicolog y o f

Peri

- an dPost-Nata

l Development
. 50 t hAnnua l Meeting , Societ y o f Toxicology , Washington , DC , Marc h 6 , 2011
. Reproductive an

dDevelopmenta

l Toxicolog y fo r

Industria l an dRegulator

y Scientists , Noblis , Inc
. Sponsore

d b y Teratology Society , Fall s Church , VA
. Octobe r 25-28 , 2010
. CN S Functiona

l Teratology
. 48 t hAnnua l Meeting o f

th e Teratology Society , Monterey , CA , Jun e 28 , 2008
. Nanoparticles
. 48 t hAnnua l Meeting o f

th e Teratology Society , Monterey , CA , Jun e 28 , 2008
. Th e Biolog y an

dToxicolog y o f

Peri

- an dPost-Nata

l Development
. 46 t hAnnua l Meeting o f

th e Societ y o f Toxicology , Charlotte , NC , Marc h 25 , 2007
. Vertebrat e Embryology
. 46 t hAnnua l Meeting o f

th e Teratology Society , Tucson , AZ , Jun e 25

- 26 , 2006
. Articles: Hovey , R.C. ; Coder, P.S. ; Wolf , J.C. ; Sielken , R.L
. Jr. ; Tisdel , M.O. ; Breckenridge , C.B
. Quantitativ e Assessmen

t o f Mammar

y GlandDevelopmen

t i n Femal

e Lon g Evans Ra

t Followin g i n uter

o Exposur

e t o Atrazine
. Toxicological Sciences 2011,119(2) , 380-390
. Yao , P. ; Lin , Y. ; Sawhney , P. ; Richburg , J.H
. Transcriptiona l regulatio n o f

Fas L expression an dparticipatio n o f

sTNF- ai n response to Sertol i cel l injury
. Journa l o f Biologica l Chemistr y 2007 , 282(8) , 5420-5431
. p . 1 9 CURRICULUM

VITAEp . 2 0

Pragati Sawhney Coder CURRICULUM VITAE Pag e 4 Article s (Continued) : Sawhney , P. ; Giammona , C.J. ; Meistric h M.L. ; Richburg , J.H
. Cisplatin-Induce d long-ter m failur e o f spermatogenesi s i n adul

t C57/B1/6 J mice
. Journa l ofAndrolog y 2005 , 26(1) , 139

- 145
. Seaman, F.C. ; Sawhney , P. ; Giammona , C.J. ; Richburg , J.H
. Cisplatin-induce d puls e o f ger mcel l apoptosi s precedes lon g ter melevated apoptoti c rate s i n C57/BL/ 6 mous e testis
. Apoptosi s 2003 , 8 , 101-108
. Giammona , C.J. ; Sawhney , P. ; Chandrasekara n Y. ; Richburg , J.H
. Deat h recepto r signalin g i n roden t testi s after

MEHP exposure . Toxicology an d Applie dPharmacology 2002 , 185 , 119-127
. Book Chapters: Stump , D.G. ; Nemec

, M.D. ; Parker

, G.A. ; Sawhne

y Coder , P. ; Sloter

, E.D. ; Varsho , B.J . Significance , Reliability , an d Interpretatio

n o f Developmenta

l an d Reproductiv

e Toxicit y Stud y Findings . I

n Developmenta

l an d Reproductiv

e Toxicology : A Practical Approach, 3 r d Edition ; Inform

a Healthcar

e Books , 2011 . Sawhne y Coder , P. ; Sloter

, E.D. ; Bowman

, C.J. ; Stump

, D.G. ; Nemec

, M.D . Evaluatio

n o f a Mal e Reproductiv

e Toxicant

. I n Comprehensiv

e Toxicology

, 2 n dEdition ; Elsevie r Ltd. : Oxford , UK , 2010 . Abstracts: Lewis , K.M. ; Ferguson , J. ; Gleason , T. ; Sawhne y Coder , P
. Effect s o f

intraoperativel

y applied cosea l o n embryo/feta

l developmen

t i n rats . Th

e Toxicologis t

2010,11 4 (l),9 l (Supplement)
. Sawhne y Coder,P. ; Carpenter, T.M. ; Kopp , C.A. ; Clevidence , K.J. ; Fleeman , T.L. ; Stump , D.G.;Nemec , M.D
. Evaluatio n O f A Shortene

d Skeleta l Stainin g (Alizari n Re

d S ) Metho d Fo r Roden t An dRabbit

Fetuses
. Birt h Defect s Research , Part A 2009 , 85 , 341
. Sawhne y Coder, P. ; Barrett , R.M. ; Varsho , B.J. ; Stump , D.G. ; Nemec , M.D. ; Holson , J.F
. Comparison o f

feta l malformatio n an d developmenta

l variatio n rate s betwee n Hra:(NZW)SP

F rabbit s obtained fro mth e Denve r o r Kalamazo o facilitie s o f Covance Researc h Products
. Birt h Defect s Researc h Par t A 2008 , 82 , 353
. Sawhne y Coder, P. ; Stump , D.G. ; Nemec , M.D. ; Lampert , B.M. ; Trost , L.C
. Developmenta l toxicit y studie s i n rats an d rabbits with CMX001 : abroa d spectru mora l anti-vira l agent. Birt h Defect s Researc

h Part A 2008 , 82 , 379
.p . 2 1

Pragati Sawhney Coder CURRICULUM VLTAE Pag e 5
Abstracts (Continued): Sawhney , P. ; Birchmeier , P.A. ; Varsho , B.J. ; Stump , D.G. ; Nemec , M.D. ; Holson , J.F
. A comparison o f

materna

l growt h curve s an

d reproductiv e parameter s betwee

n HRA:(NZW)SPF Rabbits obtained fro mth e Denve r o r Kalamazo o facilitie s o f Covance Researc h Products
. Birt h Defect s Researc h Par t A 2007 , 79 , 415
. Nemec, M.D.; Kirkpatrick, D.T.; Sawhney Coder, P.; Knapp, J.F.; Sherman, J.; Tanchevski, E.; Donahue, D.A.; Petruzzi, E.E.; Farr, C.H. A Two-Generation Reproductive Toxicity and Lactational

Inhalation-Phase Exposure Study of Dimethyl Disulfide in Rats. The Toxicologist 2007, 96(1), 312. Sawhney, P.; Richburg, J.H. The XVIII thtestis workshop: Testicular cell dynamics and endocrine signaling. Journal of Andrology 2005, 26(6). Sawhney , P. ; Richburg , J.H
. Testicula r Sertol i cell s surviv e despit e Cisplatin-induce d injur y du e to th e expression o f

inhibito r o f Apoptosi s Protein s tha

t disrup t Mitochondrial-mediate d apoptoti c signaling , Th

e Toxicologis t

2004 , 78(S1) , 401
. Sawhney , P. ; Giammona , C.J. ; Seaman, F.C. ; Ye , Y. ; Richburg , J.H
. Trai l an d deat h recepto r response i n roden

t testi s afte r

cisplati n exposure . Th

e Toxicologis t

2003 , 72(S1) , 360
. Ye , Y. ; Giammona , C.J. ; Sawhney , P. ; Richburg , J.H
. Th e expression o f

TNF-Relate d Apoptosi s inducin g Ligan d (TRAIL ) i n roden t Sertol i cells
. Th

e Toxicologis t

2003 , 72(81) , 357
. Sawhney , P. ; Seaman, F.C. ; Giammona , C.J. ; Castro , C ; Richburg , J.H
. Establishmen t o f a mous e model fo r

assessin g th e mechanism

s o f sustaine d testicula

r damag e after Cisplati n exposure . Th

e XVII t hTesti s Workshop : Functional Genomic s o f Mal e Reproductio n 2003 , Abstrac t 69
. Sawhney , P. ; Giammona , C.J. ; Seaman, F.C. ; Richburg , J.H
. Correllatio n o f ger mcel l deat

h an d Apoptoto c signallin g i n testes o f C5 7 mic e expose

d to Cisplatin
. Proceeding s o f th e 93 r d Annual Meeting , Vo l 42
. America n Associatio n fo r

Cance r Researc h 2002 , Abstrac t

2625
. Professional

Affiliations: Societ y o f Teratology , USA , 2006 - presen t Societ y o f Toxicology , USA , 2002 - presen t America n Societ y o f Andrology , 2002 - 201 1 America n Associatio n fo r

Cance r Research , USA , 200 1 - 200 5 Gul f Coas t Chapter, Societ

y o f Toxicology , USA , 2000 - 200 6 Symbiotek , India

n Institut e o f Technology , India , 1995 - presen t India n Societ y o f Cel l Biology , Studen

t Membe r 199 5 - 200 0Pragat i Sawhne y Coder Pag e 6 p . 2 2 CURRICULUM

VITAE

Seminars: Cisplatin , Coppe

r an d Spermatogenesis
. Departmen t o f Urology , Weil l Medical Colleg e o f Cornel l Universit

y an d Ne w Yor k Presbyteria

n Hospital , 2005
. Th e Altruisti c Sertol i cell
. Cente r fo r Researc h i n Reproductiv e Physiology , Th e Universit

y o f Pittsburgh Schoo l o f

Medicine , 2005
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.

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