draft risk evaluation for perchloroethylene (ethene, 1,1,2 ...€¦ · draft risk evaluation for...

United States Office of Chemical Safety and

Environmental Protection Agency Pollution Prevention

Draft Risk Evaluation for Perchloroethylene

(Ethene, 1,1,2,2-Tetrachloro)

CASRN: 127-18-4

Systematic Review Supplemental File:

Data Quality Evaluation of Human Health Hazard Studies –

Epidemiologic Studies

April 2020, DRAFT

PEER REVIEW DRAFT. DO NOT CITE OR QUOTE

Table Listing

1 Stewart et al. 1970: Evaluation of Acute Toxicity/Poisoning Outcomes . . . . . . . 32 Stewart et al. 1977: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . 73 Stewart et al. 1977: Evaluation of Acute Toxicity/Poisoning Outcomes . . . . . . . 114 Mutti et al. 1992: Evaluation of Renal Outcomes . . . . . . . . . . . . . . . . . . . . . 155 Pesch et al. 2000: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 186 Windham et al. 2006: Evaluation of Neurological/Behavior Outcomes . . . . . . . 207 Siemiatycki 1991: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 248 Asal et al. 1988: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . 279 Mandel et al. 1995: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 3010 Heineman et al. 1994: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . 3411 Seidler et al. 2007: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 3812 Stewart et al. 1970: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . 4113 Dosemeci et al. 1999: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 4514 Echeverria et al. 1995: Evaluation of Neurological/Behavior Outcomes . . . . . . . 4815 Cavalleri et al 1994: Evaluation of Ocular and Sensory Outcomes . . . . . . . . . . 5116 Altmann et al. 1990: Evaluation of Neurological/Behavior Outcomes . . . . . . . . 5417 Anderson et al. 1999: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . 5818 Auperin et al. 1994: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 6119 Blair et al. 2003: Evaluation of Mortality Outcomes . . . . . . . . . . . . . . . . . . . 6420 Blair et al. 2003: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 6721 Delahunt et al. 1995: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 7022 Lynge and Thygesen 1990: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . 7423 Stewart et al. 1970: Evaluation of Clinical Chemistry/Biochemical Outcomes . . . 7724 McCredie and Stewart 1993: Evaluation of Cancer Outcomes . . . . . . . . . . . . . 8125 Mellemgaard et al 1994: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . 8426 Miligi et al. 2006: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 8727 Schlehofer et al. 1995: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . 9028 Travier et al 2002: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 9429 Ma et al. 2009: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . . 9830 Lynge et al. 2006: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 10231 Calvert et al. 2010: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 10632 Chang et al. 2003: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 11033 Ji et al. 2005: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . . 11434 Carpenter 1937: Evaluation of Acute Toxicity/Poisoning Outcomes . . . . . . . . . 11735 Sung et al. 2007: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 12036 Wilson et al. 2008: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 12437 Radican et al. 2008: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 12738 Radican et al. 2008: Evaluation of Respiratory Outcomes . . . . . . . . . . . . . . . 13039 Pukkala et al. 2009: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 13340 Seldén and Ahlborg 2011: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . 13841 Brüning et al. 2003: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 14242 Kalkbrenner et al. 2010: Evaluation of Neurological/Behavior Outcomes . . . . . 14443 Forand et al. 2012: Evaluation of Cardiovascular Outcomes . . . . . . . . . . . . . . 14844 Lipworth et al. 2011: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 15145 Carpenter 1937: Evaluation of Clinical Chemistry/Biochemical Outcomes . . . . . 15546 Roberts et al. 2013: Evaluation of Neurological/Behavior Outcomes . . . . . . . . 15847 Aschengrau et al 2011: Evaluation of Neurological/Behavior Outcomes . . . . . . . 16148 Christensen et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . 16549 Goldman et al. 2012: Evaluation of Neurological/Behavior Outcomes . . . . . . . . 16850 Neta et al. 2012: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . 172

1


51 Ruder et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 17552 Vizcaya et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 17853 Vlaanderen et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . 18154 Morales-Suárez-Varela et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . 18555 Ruckart et al. 2013: Evaluation of Growth (early life) and Development Outcomes18856 Rowe et al. 1952: Evaluation of Acute Toxicity/Poisoning Outcomes . . . . . . . . 19157 Ruckart et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 19458 Heck et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 19759 von Ehrenstein et al. 2014: Evaluation of Neurological/Behavior Outcomes . . . . 20160 Bove et al. 2014: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . . 20461 Bove et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 20762 McLean et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 21063 Talibov et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 21364 Mattei et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 21865 Ruckart et al. 2014: Evaluation of Reproductive Outcomes . . . . . . . . . . . . . . 22166 Silver et al. 2014: Evaluation of Renal Outcomes . . . . . . . . . . . . . . . . . . . . . 22567 Stewart et al. 1961: Evaluation of Acute Toxicity/Poisoning Outcomes . . . . . . . 22868 Silver et al. 2014: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . . 23269 Silver et al. 2014: Evaluation of Cancer for testicular cancer outcome Outcomes . 23570 Silver et al. 2014: Evaluation of Cancer for all cancers outcomes other than

testicular cancer Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23871 Bove et al. 2014: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . . 24172 Bove et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 24473 Chaigne et al 2015: Evaluation of Hematological and Immune Outcomes . . . . . . 24774 Aschengrau et al. 2015: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . 25075 Talbott et al 2015: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . 25476 Stingone et al. 2016: Evaluation of Neurological/Behavior Outcomes . . . . . . . . 25877 Bulka et al. 2016: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 26178 Stewart et al. 1961: Evaluation of Cardiovascular Outcomes . . . . . . . . . . . . . . 26479 Carton et al. 2017: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 26880 Purdue et al. 2016: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 27181 Lucas et al. 2015: Evaluation of Other (please specify below) Outcomes . . . . . . 27382 Mahalingaiah et al. 2016: Evaluation of Reproductive Outcomes . . . . . . . . . . . 27783 Ruckart et al. 2015: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 28184 Aschengrau et al. 2016: Evaluation of Neurological/Behavior Outcomes . . . . . . 28485 Aschengrau et al. 2016: Evaluation of Neurological/Behavior Outcomes . . . . . . 28886 Hadkhale et al. 2017: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 29387 Gallagher 2011: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . 29688 Desrosiers et al. 2015: Evaluation of Growth (early life) and Development Outcomes30189 Stewart et al. 1961: Evaluation of Clinical Chemistry/Biochemical Outcomes . . . 30490 Zhao et al. 2016: Evaluation of Hematological and Immune Outcomes . . . . . . . 30891 Dow 1976: Evaluation of Irritation Outcomes . . . . . . . . . . . . . . . . . . . . . . . 31392 Aschengrau et al. 1993: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . 31693 NIOSH 1985: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . . . 322

2


1 Tabl

e1:

Stew

art

etal

.19

70:

Eva

luat

ion

ofA

cute

Tox

icit

y/P

oiso

ning

Out

com

es

Stud

yCita

tion:

R.D

.Stewart,

E.D

.Baretta,H

.C.D

odd,

T.R

.Torkelson

(197

0).Exp

erim

entalh

uman

expo

sure

totetrachloroethylen

eArchivesof

Env

ironm

entalH

ealth

,20(2,2),2

24-229

DataTyp

e:pe

rchloroethylen

e_controlle

d_inha

latio

n_expo

sure_acutetox

-Acu

teTo

xicity/P

oisoning

HERO

ID:

3141

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

Med

ium

×0.4

0.8

Sixteen

healthymalesubjects

wererecruited

from

labo

ratory

person

nel,rang

ingin

agefrom

24to

64yearsof

age.

Forrepe

ated

expo

sures,

malesubjects

wereag

ed36

to64

years.

Participa

ntswereno

tedto

behe

althyfortheprevious

6years.

Furthe

rde

tails

onselectionareno

tprovided

.Metric

2:Attrit

ion

Med

ium

×0.4

0.8

Onlyfiv

eof

thesixteenrecruitedsubjects

werein-

clud

edin

therepe

ated

expo

sure

grou

p.The

reason

fortheuseof

this

sub-samplewas

notde

scribe

d.How

ever,in

therepe

ated

expo

sure

expe

riment,

all

fivesubjects

werefollo

wed

foreach

expo

sure

period

.Metric

3:Com

paris

onGroup

Med

ium

×0.2

0.4

Acontrolg

roup

was

notutilizedin

thisstud

yde

sign

.The

stud

yau

thorsstatethat

they

wereun

able

toconfi

nethesamepa

rticipan

tsin

acontrolexpo

sure

scen

ario,b

utno

othe

rinform

ationisprovided

.Su

b-jectsclinical

chem

istry,

andurinalysis

resultswere

compa

redto

referenc

evalues

obtained

1ho

urprior

toexpo

sure.Cog

nitive

func

tion

test

werepreformed

throug

hout

expo

sure,an

dresultswerecompa

redto

referenc

es(sou

rceno

tclear).

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

High

×0.4

0.4

Purityof

thetest

materialwas

repo

rted

(99.6pe

r-cent)an

dtheinha

lation

cham

berwas

adequa

tely

de-

scribe

d.The

mean,

stan

dard

deviation,

andrang

eof

expo

sure

over

each

expo

sure

period

was

repo

rted

.Con

centration

sof

perchloroethylen

ein

theexpo

sure

cham

berwerede

term

ined

usingbo

thinfrared

spec-

troscopy

andga

schromatog

raph

ywithahy

drog

enfla

mede

tector

(GC-FID

).Metric

5:Exp

osurelevels

Low

×0.2

0.6

Onlyon

elevelof

expo

sure

was

used

forthis

stud

y.The

rewas

noconc

urrent

controla

ndsubjects

could

only

becompa

redto

data

from

priorexam

inations

andreferenc

evalues

forclinical

chem

istryen

dpoints.

Con

tinu

edon

next

page

...

3


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,

E.D

.Baretta,H

.C.D

odd,

T.R

.Torkelson

(197

0).Exp

erim

entalh

uman

expo

sure


eArchivesof

Env

ironm

entalH

ealth

,20(2,2),2

24-229

DataTyp

e:pe

rchloroethylen

e_controlle

d_inha

latio

n_expo

sure_acutetox

-Acu

teTo

xicity/P

oisoning

HERO

ID:

3141

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

6:T e

mpo

rality

High

×0.4

0.4

Each

subjectin

therepe

ated

expo

sure

stud

yha

dbe

enfollo

wed

forsix

yearspriorto

thestud

y.It

isassumed

this

was

performed

asroutineoccu

pa-

tion

almed

ical

exam

inations

andscreen

ings.

Sam-

ples

weretakenjust

priorto

expo

sure,an

deff

ects

weremeasuredafterexpo

sure,establishing

tempo

-ralitybe

tweenexpo

sure

andeff

ects.

Dom

ain3:

OutcomeAssessm

ent

Metric

7:Outcomemeasurementor

characteriz

ation

Med

ium

×0.66

71.33

Aph

ysical

exam

inationwas

performed

priorto

each

expo

sure

period

.A

pre-expo

sure

bloo

dsamplewas

colle

cted

andclinical

chem

istryen

dpointsweremea-

sured.

Eachsubjectalso

prov

ided

urineforurinaly-

sis.

Duringexpo

sure,s

ubjectivemeasuresan

dmea-

suresof

cogn

itivefunc

tion

(Crawford

man

ualde

x-terity,Flann

agan

coordina

tion

,arithm

etic,an

din-

spection

tests,

andamod

ified

Rom

berg

test)were

colle

cted

each

hour.

The

rewas

nocontrolgrou

p,so

investigatorsan

dpa

rticipan

tswou

ldno

tha

vebe

enblinde

dto

expo

sure.

Thisrepresents

amix-

ture

ofmetho

dswith

high

valid

ity(clin

ical

chem

-istry/

urinalysis)an

dmetho

dswithun

certainvalid

-ityan

daconc

ernforlack

ofblinding

(cog

nitive

and

subjective

measures).

Metric

8:Rep

ortin

gBias

Med

ium

×0.33

30.67

Allou

tcom

esou

tlined

intheab

stract,introdu

ction,

andmetho

dswerede

scribe

deither

quan

titatively

orqu

alitativelyin

theresults.

Mostfig

ures

andtables

includ

estan

dard

erroror

stan

dard

deviation.

Dom

ain4:

P otentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

Med

ium

×0.5

1Covariateswereno

tinclud

edin

thean

alysis.

All

subjects

weread

ultmales.

The

subjects

arede

-scribe

dto

beof

thesameoccu

pation

andBMIwas

addressed

byqu

alitativelycompa

ring

expired

con-

centration

sof

perchloroethylen

ean

dsubjectBMI.

Metric

10:

Covariate

Cha

racterization

High

×0.25

0.25

Age,sex,

BMI,

andoccu

pation

altitlewereallpre-

sumab

lyob

tained

byph

ysical

exam

inationan

dem

-ploymentrecords.

Metric

11:

Co-expo

sure

Con

foun

ding

Med

ium

×0.25

0.5

Inha

lation

cham

bers

weremon

itored

byIR

andGC-

FLD

.The

rewas

noindication

ofco-exp

osures.

Dom

ain5:

Ana

lysis

Con

tinu

edon

next

page

...

4


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,

E.D

.Baretta,H

.C.D

odd,

T.R

.Torkelson

(197

0).Exp

erim

entalh

uman

expo

sure


eArchivesof

Env

ironm

entalH

ealth

,20(2,2),2

24-229

DataTyp

e:pe

rchloroethylen

e_controlle

d_inha

latio

n_expo

sure_acutetox

-Acu

teTo

xicity/P

oisoning

HERO

ID:

3141

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

Thisstud

yutilizedacontrolle

dinha

lation

expo

sure

tope

rchloroethylen

e.Noconc

urrent

controlgrou

pwas

employed

and

participan

tsclinical

chem

istry

andcogn

itivefunc

tion

resultswerecompa

redto

ref-

eren

cevalues.

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

Sixteensubjects

wereinclud

edin

thesing

leexpo

sure

expe

rimentwhile

fivesubjects

wereutilizedin

the

repe

ated

expo

sure

expe

riment.

Allfiv

esubjects

were

adultmales.Thisrepresents

asm

allsam

plesize

and

resultsshou

ldbe

interpretedwithcaution.

Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.2

0.4

Results

are

presented

with

numbe

rof

subjects,

rang

esan

dmeans.Ana

lysisarewellde

scribe

dan

dcouldbe

reprod

uced

givenoriginal

data.

Metric

15:

Statistic

almod

els

Low

×0.2

0.6

Results

werecompa

redto

referenc

evalues

andde

-scribe

dqu

alitativelyon

ly.So

noan

alysis

was

pro-

vide

d.Onlytoxicokine

ticda

ta(elim

inationof

per-

chloroethy

lene

via

exha

lation

)was

prov

ided

ina

quan

titative

man

ner.

Dom

ain6:

Other

Con

side

ratio

nsforBiomarkerSe

lectionan

dMeasurement

Metric

16:

Use

ofBiomarkerof

Exp

osure

High

×0.2

0.2

Perchloroethy

lene

was

measuredin

expiredairfrom

expo

sed

subjects,colle

cted

inSa

ran

bags

orglass

pipe

ttes.

This

isa

direct

measurement

ofpe

r-chloroethy

lene

inexpiredair.

Metric

17:

Effe

ctbiom

arker

Not

Rated

NA

NA

Metric

18:

Metho

dSe

nsitivity

Med

ium

×0.2

0.4

The

limit

ofde

tectionis

notrepo

rted

,ho

wever,re-

ported

data

indicate

that

conc

entrations

wereab

ove

thelim

itof

detectionin

allsub

jectsforthedu

ration

offollo

w-up(16da

yspo

stexpo

sure).

Metric

19:

Biomarkerstab

ility

High

NA

NA

Samplestorag

ewas

describe

d.Sa

mples

colle

cted

inglasspipe

ttes

werean

alyzed

within

16ho

ursan

dsamples

from

Saran

bags

werean

alyzed

within

2ho

ursof

colle

ction.

The

rewas

norepo

rted

loss

ofsamples.

Metric

20:

Samplecontam

ination

Med

ium

×0.2

0.4

The

rewas

nodo

cumentation

inrega

rdto

sample

contam

ination.

Metric

21:

Metho

drequ

irements

Low

×0.2

0.6

Samples

from

Saran

bags

werean

alyzed

usingin-

frared

spectroscopy

andsamples

from

glasspipe

ttes

werean

alyzed

usingga

schromatog

raph

y(assum

edto

beGC-FID

).Metric

22:

Matrix

adjustment

Not

Rated

NA

NA

Matrixad

justmentis

notne

cessaryforsamples

ofbreath.

Con

tinu

edon

next

page

...

5


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,

E.D

.Baretta,H

.C.D

odd,

T.R

.Torkelson

(197

0).Exp

erim

entalh

uman

expo

sure


eArchivesof

Env

ironm

entalH

ealth

,20(2,2),2

24-229

DataTyp

e:pe

rchloroethylen

e_controlle

d_inha

latio

n_expo

sure_acutetox

-Acu

teTo

xicity/P

oisoning

HERO

ID:

3141

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

OverallQua

lityDetermination‡

Med

ium

1.9

Extracted

Yes

?MW

F=

MetricWeigh

ting

Factor

†High=

1;Medium

=2;

Low

=3;

Una

cceptable=

4;N/A

hasno

value.

‡The

overallr

atingis

calculated

asnecessary.

EPA

may

notalwaysprovideacommentforametricthat

hasbe

encategorizedas

High.

Overallrating

=

4ifan

ymetricis

Una

cceptable

⌊ ∑ i(M

etricScore i

×MW

Fi)/

∑ jMW

Fj

⌉ 0.1(rou

ndto

thenearesttenth)

otherw

ise

,

where

High

=≥

1to

<1.

7;Medium

=≥

1.7to

<2.

3;Lo

w=

≥2.

3to

≤3.

0.If

thereview

erdeterm

ines

that

theoverallrating

needsad

justment,

theoriginal

rating

iscrossedou

tan

dan

arrow

points

tothenew

rating

.††

Thismetricmet

thecriteria

forhigh

confi

denc

eas

expe

cted

forthis

type

ofstud

y

6


Tabl

e2:

Stew

art

etal

.19

77:

Eva

luat

ion

ofN

euro

logi

cal/

Beh

avio

rO

utco

mes

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Beh

avior_

Neu

rologicalEffe

cts-Neu

rological/Beh

avior

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

Med

ium

×0.4

0.8

Volun

teer

subjects

wererecruitedfrom

thegene

ral

popu

lation

viaacolle

gene

wsletteran

dde

emed

med

-ically,ph

ysical,an

dne

urolog

ically

healthypriorto

thestartof

theexpe

riment.

Mostsubjects

(9/1

2)wereun

der30

.Ofthoseover

30,on

lyon

ecom-

pleted

thestud

y.W

hile

thesubjectcompo

sition

isexpe

cted

foracontrolle

dexpo

sure

stud

y.Allpa

rtic-

ipan

twereCau

casian

.The

popu

lation

isno

trepre-

sentativeof

thegene

ralp

opulation.

Metric

2:Attrit

ion

Med

ium

×0.4

0.8

Ofthe

12pa

rticipan

tsin

thestud

y,3withd

rewmid-

way

throug

hthestud

yan

don

ewas

adde

d2da

ysinto

the55

daystud

y.Bothmalesubjects

over

30withd

rew

from

thestud

y.The

rewas

noindication

that

withd

rawal

was

associated

withhe

alth

effects

relatedto

thestud

y.Metric

3:Com

paris

onGroup

High

×0.2

0.2

Subjects

unde

rwenthe

alth

evalua

tion

spriorto

en-

rollm

entan

dcompleted

beha

vioral

andne

urolog

ical

analysis

atacontrolle

ddo

seof

0pp

m,thus

serving

astheirow

ncontrols.

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

High

×0.4

0.4

Inthiscontrolle

dexpo

sure

stud

y,subjects

wereex-

posed

tope

rcviainha

lation

atlevels

of0,

25or

100pp

mfor5.5ho

urs/da

yto

simulateoccupa

tion

alexpo

sure

indrycleaning

andindu

strial

degreasing

operationenvironm

ents.Exp

osureoccu

rred

inase-

ries

ofsealed

room

san

dpe

rclevels

weremeasured

continuo

usly

viainfrared

spectrom

etry

andga

schro-

matog

raph

ywithafla

meionization

detector.

Con

tinu

edon

next

page

...

7


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Beh

avior_

Neu

rologicalEffe

cts-Neu

rological/Beh

avior

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

5:Exp

osurelevels

Medium

×0.2

0.4

The

high

estexpo

sure

level(100

ppm)was

theOc-

cupa

tion

alSa

fety

andHealthAgenc

y(O

SHA)stan

-da

rdan

dexpe

cted

torapidlyequilib

rate.

Subject

exercised

mod

erately

during

expo

sure

tosimulate

chan

gesin

inha

lation

ratesthat

may

mim

icoccu

-pa

tion

alexpo

sures.

Subjects

wereexpo

sedfor5.5

hrs/da

y1-2da

ys/w

eek,

with

expo

suressometim

esoccu

rring

onconsecutiveda

ys.

Perchloroethy

lene

levels

werede

term

ined

inbloo

dan

dbreath

andin-

dicate

anexpo

sure

grad

ient.

Baselinevalues

were

provided

,but

bloo

dan

dbreath

levelswereno

teval-

uatedforeveryinstan

ceof

0pp

mexpo

sure.

Metric

6:Te

mpo

rality

High

×0.4

0.4

Beh

avioralan

dne

urolog

ical

evalua

tion

swerecon-

ducted

throug

hout

expo

sure.Testwerecond

ucted

within5-10

minutes

ofthestartan

den

dof

each

ex-

posure

windo

w.

Dom

ain3:

OutcomeAssessm

ent

Metric


characteriz

ation

High

×0.66

70.67

The

follo

wingbe

havioral

andne

urolog

ical

testswere

cond

ucted

during

expo

sure

within

the

controlle

dexpo

sure

cham

ber:

Michiga

neye-ha

ndcoordina

-tion

,rotarypu

rsuit,Flana

gancoordina

tion

,saccade

eyevelocity,du

al-attention

tasks,

andLo

rr-M

cNair

moo

devalua

tion

test.Electroen

ceph

alog

ramswere

taken

during

expo

sure.

Clin

ical

symptom

swere

evalua

ted(heada

che,

fatigu

e,na

usea).

The

rewere

someequipm

entmalfunc

tion

sthroug

hout

thestud

y,which

weregene

rally

resolved

within

afew

days.

The

seevalua

tion

swerecond

ucted

usingstan

dard-

ized

andexplicitprotocolsan

dwereused

toevalua

tearang

eof

outcom

es.

Metric

8:Rep

ortin

gBias

High

×0.33

30.33

Autho

rsrepo

rtthat

testingoccu

rred

indo

uble-blin

dmod

e,indicating

both

subjects

and

assessorswere

blinde

dto

expo

sure

status.It

was

notedthat

sub-

jectscouldsm

ellthepe

rchloroethylen

eat

thehigh

expo

sure

level(100

ppm)bu

tno

tthelow

expo

sure

level(25pp

m).

Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

Low

×0.5

1.5

The

analysis

was

notad

justed

foran

ycovariates.

The

dispropo

rtiona

tewithd

rawal

ofolde

rsubjects

indicatesthat

agecouldbe

anim

portan

tcovariate,

which

was

notaccoun

tedforin

thean

alysis.

Con

tinu

edon

next

page

...

8


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Beh

avior_

Neu

rologicalEffe

cts-Neu

rological/Beh

avior

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

10:

Co variate

Cha

racterization

Med

ium

×0.25

0.5

Subjects

completed

ahe

alth

question

nairean

dex-

tensive

physical

exam

inations

prior

toexpo

sure,

which

indicatedtheselected

subjects

werehe

althy.

Details

onde

mog

raph

icpa

rameters(socioecon

omic

status,race)

areno

tprovided

,but

agean

dsexwere

repo

rted

.Metric

11:

Co-expo

sure

Con

foun

ding

Med

ium

×0.25

0.5

The

stud

ywas

design

edto

prob

einteractions

ofpe

rcwithdiazep

aman

detha

nol.

Subjects

wereexpo

sed

tope

rcviainha

lation

either

alon

eor

conc

urrently

withdo

sagesof

diazep

am(0,6

,10mg/

day)

orvo

dka

(0.0,0

.75,

1.5ml/kg

body

weigh

t).Con

trolsof

perc

only

expo

sure

werealso

used

,which

weretheexclu-

sive

focu

sof

this

stud

yqu

alityevalua

tion

.Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

The

controlle

dexpo

sure

stud

yevalua

tesbe

havioral

and

neurolog

ical

outcom

esin

asm

allgrou

pof

12subjects

withkn

ownpe

rcexpo

sure

of0,

25or

100

ppm.The

design

isap

prop

riatefortheassessmentof

beha

vioral

andne

urolog

ical

effects

associated

with

acuteexpo

sures.

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

The

statisticalpo

wer

was

notexplicitly

stated

.Al-

thou

ghtherewerealownu

mbe

rof

subjects,eachex-

posure

levelw

asevalua

tedin

grou

psof

4-6subjects

6-9times.Results

werepresentedwithastatem

ent

onstatisticalsign

ificanc

e.Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.2

0.4

Ana

lysisarerepo

rted

with

greatde

tail

and

data

isrepo

rted

bysessionan

dsubjectwithmeans

and

stan

dard

deviations.

Metric

15:

Statistic

almod

els

Med

ium

×0.2

0.4

App

ropriate

analysis

was

cond

ucted

foreach

end-

point,

includ

ingregression

mod

elsan

dan

alysis

ofvarian

ce.

Dom

ain6:

Other

Con

side

ratio

nsforBiomarkerSe

lectionan

dMeasurement

Metric

16:

Use

ofBiomarkerof

Exp

osure

High

×0.2

0.2

Perchloroethy

lene

was

determ

ined

inbloo

dan

dbreath

ofsubjects.In

thiscontrolle

dexpo

sure

stud

y,thebiom

arkers

ofexpo

sure

served

asaconfi

rmation

ofexpo

sure,rathe

rthan

theprim

arymetho

dsof

de-

term

iningexpo

sure

levels.

Metric

17:

Effe

ctbiom

arker

Not

Rated

NA

NA

Nobiom

arkers

ofeff

ectwereassessed

.Metric

18:

Metho

dSe

nsitivity

Med

ium

×0.2

0.4

IRspectrom

etry

was

used

tode

term

ine

per-

chloroethy

lene

,which

was

identifie

din

allexpo

sed

subjects.

Con

tinu

edon

next

page

...

9


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Beh

avior_

Neu

rologicalEffe

cts-Neu

rological/Beh

avior

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

19:

Biomark erstab

ility

Low

×0.2

0.6

Storag

ean

dstab

ility

inform

ationno

tprovided

.Metric

20:

Samplecontam

ination

Med

ium

×0.2

0.4

Docum

entation

ofstep

sto

preventsamplecontam

-inationareno

tprovided

,bu

tthereis

noindication

ofcontam

ination.

Metric

21:

Metho

drequ

irements

Low

×0.2

0.6

Perchloroethy

lene

was

quan

tifie

dwith

GC/F

ID,

which

haskn

owninterferan

ts.

Metric

22:

Matrix

adjustment

Not

Rated

NA

NA

Matrixad

justmentis

notne

cessaryforthesematri-

ces(blood

/breath).

OverallQua


Med

ium

1.8

Extracted

Yes

?MW

F=

MetricWeigh

ting

Factor

†High=

1;Medium

=2;

Low

=3;

Una

cceptable=

4;N/A

hasno

value.

‡The

overallr

atingis

calculated

asnecessary.

EPA

may


hasbe

encategorizedas

High.

Overallrating

=

4ifan

ymetricis

Una

cceptable

⌊ ∑ i(M

etricScore i

×MW

Fi)/

∑ jMW

Fj

⌉ 0.1(rou

ndto

thenearesttenth)

otherw

ise

,

where

High

=≥

1to

<1.

7;Medium

=≥

1.7to

<2.

3;Lo

w=

≥2.

3to

≤3.

0.If

thereview

erdeterm

ines

that

theoverallrating

needsad

justment,

theoriginal

rating

iscrossedou

tan

dan

arrow

points

tothenew

rating

.††

Thismetricmet

thecriteria

forhigh

confi

denc

eas

expe

cted

forthis

type

ofstud

y

10


Tabl

e3:

Stew

art

etal

.19

77:

Eva

luat

ion

ofA

cute

Tox

icit

y/P

oiso

ning

Out

com

es

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Acu

teEffe

cts-Acu

teTo

xicity/P

oisoning

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

Med

ium

×0.4

0.8

Volun

teer

subjects

wererecruitedfrom

thegene

ral

popu

lation

viaacolle

gene

wsletteran

dde

emed

med

-ically,ph

ysical,an

dne

urolog

ically

healthypriorto

thestartof

theexpe

riment.

Mostsubjects

(9/1

2)wereun

der30

.Ofthoseover

30,on

lyon

ecom-

pleted

thestud

y.W

hile

thesubjectcompo

sition

isexpe

cted

foracontrolle

dexpo

sure

stud

y.Allpa

rtic-

ipan

twereCau

casian

.The

popu

lation

isno

trepre-

sentativeof

thegene

ralp

opulation.

Metric

2:Attrit

ion

Med

ium

×0.4

0.8

Ofthe

12pa

rticipan

tsin

thestud

y,3withd

rewmid-

way

throug

hthestud

yan

don

ewas

adde

d2da

ysinto

the55

daystud

y.Bothmalesubjects

over

30withd

rew

from

thestud

y.The

rewas

noindication

that

withd

rawal

was

associated

withhe

alth

effects

relatedto

thestud

y.Metric

3:Com

paris

onGroup

High

×0.2

0.2

Subjects

unde

rwenthe

alth

evalua

tion

spriorto

en-

rollm

entan

dcompleted

beha

vioral

andne

urolog

ical

analysis

atacontrolle

ddo

seof

0pp

m,thus

serving

astheirow

ncontrols.

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

High

×0.4

0.4

Inthis

controlle

dexpo

sure

stud

y,subjects

wereex-

posed

tope

rcviainha

lation

atlevels

of0,

25or

100pp

mfor5.5ho

urs/da

yto

simulateoccu

pation

alexpo

sure

indrycleaning

andindu

strial

degreasing

operationenvironm

ents.Exp

osureoccu

rred

inase-

ries

ofsealed

room

san

dpe

rclevels

weremeasured

continuo

usly

viainfrared

spectrom

etry

andga

schro-

matog

raph

ywithafla

meionization

detector.

Con

tinu

edon

next

page

...

11


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Acu

teEffe

cts-Acu

teTo

xicity/P

oisoning

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

5:Exp

osurelevels

Medium

×0.2

0.4

The

high

estexpo

sure

level(100

ppm)was

theOc-

cupa

tion

alSa

fety

andHealthAgenc

y(O

SHA)stan

-da

rdan

dexpe

cted

torapidlyequilib

rate.

Subject

exercised

mod

erately

during

expo

sure

tosimulate

chan

gesin

inha

lation

ratesthat

may

mim

icoccu

-pa

tion

alexpo

sures.

Subjects

wereexpo

sedfor5.5

hrs/da

y1-2da

ys/w

eek,

with

expo

suressometim

esoccu

rring

onconsecutiveda

ys.

Perchloroethy

lene

levels

werede

term

ined

inbloo

dan

dbreath

andin-

dicate

anexpo

sure

grad

ient.

Baselinevalues

were

provided

,but

bloo

dan

dbreath

levelswereno

teval-

uatedforeveryinstan

ceof

0pp

mexpo

sure.

Metric

6:Te

mpo

rality

High

×0.4

0.4

Beh

avioralan

dne

urolog

ical

evalua

tion

swerecon-

ducted

throug

hout

expo

sure.Testwerecond

ucted

within5-10

minutes

ofthestartan

den

dof

each

ex-

posure

windo

w.

Dom

ain3:

OutcomeAssessm

ent

Metric


characteriz

ation

High

×0.66

70.67

The

follo

wingbe

havioral

andne

urolog

ical

testswere

cond

ucted

during

expo

sure

within

the

controlle

dexpo

sure

cham

ber:

Michiga

neye-ha

ndcoordina

-tion

,rotarypu

rsuit,Flana

gancoordina

tion

,saccade

eyevelocity,du

al-attention

tasks,

andLo

rr-M

cNair

moo

devalua

tion

test.Electroen

ceph

alog

ramswere

taken

during

expo

sure.

Clin

ical

symptom

swere

evalua

ted(heada

che,

fatigu

e,na

usea).

The

rewere

someequipm

entmalfunc

tion

sthroug

hout

thestud

y,which

weregene

rally

resolved

within

afew

days.

The

seevalua

tion

swerecond

ucted

usingstan

dard-

ized

andexplicitprotocolsan

dwereused

toevalua

tearang

eof

outcom

es.

Metric

8:Rep

ortin

gBias

High

×0.33

30.33

Autho

rsrepo

rtthat

testingoccu

rred

indo

uble-blin

dmod

e,indicating

both

subjects

and

assessorswere

blinde

dto

expo

sure

status.It

was

notedthat

sub-

jectscouldsm

ellthepe

rchloroethylen

eat

thehigh

expo

sure

level(100

ppm)bu

tno

tthelow

expo

sure

level(25pp

m).

Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

Low

×0.5

1.5

The

analysis

was

notad

justed

foran

ycovariates.

The

dispropo

rtiona

tewithd

rawal

ofolde

rsubjects

indicatesthat

agecouldbe

anim

portan

tcovariate,

which

was

notaccoun

tedforin

thean

alysis.

Con

tinu

edon

next

page

...

12


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Acu

teEffe

cts-Acu

teTo

xicity/P

oisoning

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

10:

Co variate

Cha

racterization

Med

ium

×0.25

0.5

Subjects

completed

ahe

alth

question

nairean

dex-

tensive

physical

exam

inations

prior

toexpo

sure,

which

indicatedtheselected

subjects

werehe

althy.

Details

onde

mog

raph

icpa

rameters(socioecon

omic

status,race)

areno

tprovided

,but

agean

dsexwere

repo

rted

.Metric

11:

Co-expo

sure

Con

foun

ding

Med

ium

×0.25

0.5

The

stud

ywas

design

edto

prob

einteractions

ofpe

rcwithdiazep

aman

detha

nol.

Subjects

wereexpo

sed

tope

rcviainha

lation

either

alon

eor

conc

urrently

withdo

sagesof

diazep

am(0,6

,10mg/

day)

orvo

dka

(0.0,0

.75,

1.5ml/kg

body

weigh

t).Con

trolsof

perc

only

expo

sure

werealso

used

,which

weretheexclu-

sive

focu

sof

this

stud

yqu

alityevalua

tion

.Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

The

controlle

dexpo

sure

stud

yevalua

tesbe

havioral

and

neurolog

ical

outcom

esin

asm

allgrou

pof

12subjects

withkn

ownpe

rcexpo

sure

of0,

25or

100

ppm.The

design

isap

prop

riatefortheassessmentof

beha

vioral

andne

urolog

ical

effects

associated

with

acuteexpo

sures.

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

The

statisticalpo

wer

was

notexplicitly

stated

.Al-

thou

ghtherewerealownu

mbe

rof

subjects,eachex-

posure

levelw

asevalua

tedin

grou

psof

4-6subjects

6-9times.Results

werepresentedwithastatem

ent

onstatisticalsign

ificanc

e.Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.2

0.4

Ana

lysisarerepo

rted

with

greatde

tail

and

data

isrepo

rted

bysessionan

dsubjectwithmeans

and

stan

dard

deviations.

Metric

15:

Statistic

almod

els

Med

ium

×0.2

0.4

App

ropriate

analysis

was

cond

ucted

foreach

end-

point,

includ

ingregression

mod

elsan

dan

alysis

ofvarian

ce.

Dom

ain6:

Other

Con

side

ratio

nsforBiomarkerSe

lectionan

dMeasurement

Metric

16:

Use

ofBiomarkerof

Exp

osure

High

×0.2

0.2

Perchloroethy

lene

was

determ

ined

inbloo

dan

dbreath

ofsubjects.In

thiscontrolle

dexpo

sure

stud

y,thebiom

arkers

ofexpo

sure

served

asaconfi

rmation

ofexpo

sure,rathe

rthan

theprim

arymetho

dsof

de-

term

iningexpo

sure

levels.

Metric

17:

Effe

ctbiom

arker

Not

Rated

NA

NA

Nobiom

arkers

ofeff

ectwereassessed

.Metric

18:

Metho

dSe

nsitivity

Med

ium

×0.2

0.4

IRspectrom

etry

was

used

tode

term

ine

per-

chloroethy

lene

,which

was

identifie

din

allexpo

sed

subjects.

Con

tinu

edon

next

page

...

13


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

R.D

.Stewart,C.L

.Hake,

A.W

u,J.

Kalbfl

eisch,

P.E.N

ewton,

S.K.M

arlow,M

.Vuc

icevic-Salam

a(197

7).Effe

ctsof

perchloroethy-

lene

/druginteractionon

beha

vior

andne

urolog

ical

func

tion

DataTyp

e:Con

trolledE

xposure_

Perc_Acu

teEffe

cts-Acu

teTo

xicity/P

oisoning

HERO

ID:

5821

5

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

19:

Biomark erstab

ility

Low

×0.2

0.6

Storag

ean

dstab

ility

inform

ationno

tprovided

.Metric

20:

Samplecontam

ination

Med

ium

×0.2

0.4

Docum

entation

ofstep

sto

preventsamplecontam

-inationareno

tprovided

,bu

tthereis

noindication

ofcontam

ination.

Metric

21:

Metho

drequ

irements

Low

×0.2

0.6

Perchloroethy

lene

was

quan

tifie

dwith

GC/F

ID,

which

haskn

owninterferan

ts.

Metric

22:

Matrix

adjustment

Not

Rated

NA

NA

Matrixad

justmentis

notne

cessaryforthesematri-

ces(blood

/breath).

OverallQua


Med

ium

1.8

Extracted

Yes

?MW

F=

MetricWeigh

ting

Factor

†High=

1;Medium

=2;

Low

=3;

Una

cceptable=

4;N/A

hasno

value.

‡The

overallr

atingis

calculated

asnecessary.

EPA

may


hasbe

encategorizedas

High.

Overallrating

=

4ifan

ymetricis

Una

cceptable

⌊ ∑ i(M

etricScore i

×MW

Fi)/

∑ jMW

Fj

⌉ 0.1(rou

ndto

thenearesttenth)

otherw

ise

,

where

High

=≥

1to

<1.

7;Medium

=≥

1.7to

<2.

3;Lo

w=

≥2.

3to

≤3.

0.If

thereview

erdeterm

ines

that

theoverallrating

needsad

justment,

theoriginal

rating

iscrossedou

tan

dan

arrow

points

tothenew

rating

.††

Thismetricmet

thecriteria

forhigh

confi

denc

eas

expe

cted

forthis

type

ofstud

y

14


Tabl

e4:

Mut

tiet

al.

1992

:E

valu

atio

nof

Ren

alO

utco

mes

Stud

yCita

tion:

Mutti,

A;A

linovi,R;B

erga

maschi,E;B

iagini,C

;Cavazzini,S

;Franchini,I;L

auwerys,R

R;B

erna

rd,A

M;R

oels,H

;Gelpi,E

;Rosello,

J;Ram

is,I

;Pric

e,RG;T

aylor,

SA;d

eBroe,

M;N

uyts,G

D;S

tolte

,H;F

els,

LM;H

erbo

rt,C

(199

2).Nep

hrop

athies

andexpo

sure

tope

rchloroethylen

ein

dry-cleane

rsThe

Lanc

et,3

30(881

3),1

89-193

DataTyp

e:Pe

rc-nep

hrotox

icity

markers-R

enal

HERO

ID:

5834

8

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

Low

×0.4

1.2

Alm

ostno

inform

ationis

prov

ided

onho

wthesub-

jectswereselected

.Nometho

dof

recruitm

entwas

provided

.Limited

inform

ationprovided

onsetting

(i.e.,drycleaning

shop

s)an

dexclusioncriteria.

Metric

2:Attrit

ion

Low

×0.4

1.2

Num

bers

ofindividu

alswereno

trepo

rted

atim

por-

tant

stag

esof

stud

y(e.g.,nu

mbe

rsof

eligiblepa

rtici-

pantsinclud

edin

thestud

yor

analysissample,

com-

pletingfollo

w-up,

and

analyzed

).It

ison

lyno

ted

that

therewere50

expo

sedan

d50

unexpo

sedsub-

jects

Metric

3:Com

paris

onGroup

Med

ium

×0.2

0.4

Con

trolswerematched

bysexan

dag

e.Other

base-

linecharacteristicsweresimila

r,bu

tthereweresome

slight

diffe

renc

es.

The

sediffe

renc

esareno

tlik

ely

enou

ghto

sign

ificantly

bias

theresults.

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

Low

×0.4

1.2

Exp

osed

subjects

worked

ina

dry-cleaning

shop

.Con

trolswerebloo

ddo

nors.

Exp

osurewas

mea-

suredin

thebloo

dan

dairof

workers,b

uton

lyasin-

glelevelwas

provided

withno

JEM,this

levelwas

also

notused

inthean

alysis.

Levels

inthework-

ersan

dairweremeasuredusingga

schromatog

ra-

phywithmassselectivede

tector

withlevelsrang

ing

from

traceam

ountsto

85pp

m.Med

ianPCE

inair

was

14.8

ppm

andin

bloo

dwas

143ug

/L.N

obloo

dlevels

weremeasuredin

thecontrols.The

refore,e

x-po

sure

foran

alysis

isba

sed

only

onworking

ina

dry-cleaning

shop

orno

t.Metric

5:Exp

osurelevels

Low

×0.2

0.6

Onlyexpo

sedan

dun

expo

sed.

Metric

6:Te

mpo

rality

Med

ium

×0.4

0.8

Tem

poralityisestablishe

d,bu

titisun

clearwhe

ther

expo

suresfallwithinrelevant

expo

sure

windo

wsfor

the

outcom

eof

interest.

Exp

osed

subjects

were

noted

toha

veworked

inadry-cleaning

shop

and

expo

sedto

Percfor10

yearson

averag

e.How

ever,

thereis

noinform

ationprovided

onwhe

ntheexpo

-sure

stop

pedor

how

long

itwou

ldtake

toeff

ectthe

rena

lbiom

arkers.

Con

tinu

edon

next

page

...

15


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Mutti,

A;A

linovi,R;B

erga

maschi,E;B

iagini,C

;Cavazzini,S

;Franchini,I;L

auwerys,R

R;B

erna

rd,A

M;R

oels,H

;Gelpi,E

;Rosello,

J;Ram

is,I

;Pric

e,RG;T

aylor,

SA;d

eBroe,

M;N

uyts,G

D;S

tolte

,H;F

els,

LM;H

erbo

rt,C

(199

2).Nep

hrop

athies

andexpo

sure

tope

rchloroethylen

ein

dry-cleane

rsThe

Lanc

et,3

30(881

3),1

89-193

DataTyp

e:Pe

rc-nep

hrotox

icity

markers-R

enal

HERO

ID:

5834

8

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain3:

OutcomeAssessm

ent

Metric


characteriz

ation

Med

ium

×0.66

71.33

Metho

dsap

pear

tobe

stan

dard

metho

dswithcita-

tion

s,bu

tit

isun

clearif

thesearethego

ldstan

-da

rds.

The

rewas

nomention

ofstan

dard

kitassays

beingused

.How

ever,metho

dsareacceptab

le.

Metric

8:Rep

ortin

gBias

High

×0.33

30.33

Allinform

ationis

provided

insufficientde

tail.

Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

High

×0.5

0.5

Subjects

werematched

byag

ean

dsex.

Subjects

were

simila

rin

characteristicsrepo

rted

includ

ing

height,weigh

t,BMI,

and

smok

ing

status.

The

rewere

more

controls

who

dran

kalcoho

l,bu

tthe

amou

ntconsum

edwas

notthat

diffe

rent.Exp

osed

subjects

hadmoredrug

consum

ption.

The

stud

yau

-thorsdidno

tconsider

thereto

beadistingu

isha

ble

diffe

renc

e.It

isno

tclearifSE

Swou

ldbe

apo

tential

confou

nder

asit

isn’tclearwhe

rethebloo

ddo

nors

wereob

tained

orifSE

Swou

ldbe

aconfou

nder

for

thebiom

arkers

measured.

Metric

10:

Covariate

Cha

racterization

Med

ium

×0.25

0.5

Astan

dardized

question

naire(not

stated

tobe

val-

idate)

was

used

.Metric

11:

Co-expo

sure

Con

foun

ding

Med

ium

×0.25

0.5

Altho

ugh

thereis

potentialforexpo

sure

toothe

rchem

icalsin

drycleaning

,Percis

likelythehigh

-estexpo

sure

andthereis

noeviden

cethat

expo

sure

toothe

rchem

icalswou

ldha

veoccu

rred

atasimila

rrate

intheexpo

sedsubjects.

Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.5

1App

ropriate

design

(i.e.,

cross-sectiona

lde

sign

for

assessmentof

rena

ldiseasein

relation

tope

rcex-

posure)an

dstatisticalmetho

ds(i.e.,

compa

risons

betw

eengrou

pmeans

wereba

sedon

thettest

for

inde

pend

entsamples,correlations

amon

gvariab

les

assessed

byPearson

’scoeffi

cients)wereem

ployed

toan

alyzeda

ta.

Metric

13:

Statistic

alpo

wer

Med

ium

×0.25

0.5

The

rewere50

expo

sedan

d50

unexpo

sed.

Thiswas

enou

ghfortheou

tcom

emeasuredan

dstatisticalre-

sultswereob

tained

.Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.25

0.5

Description

ofthean

alyses

issufficientto

unde

r-stan

dwha

tha

sbe

endo

nean

dto

bereprod

ucible

withaccess

totheda

ta.

Con

tinu

edon

next

page

...

16


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Mutti,

A;A

linovi,R;B

erga

maschi,E;B

iagini,C

;Cavazzini,S

;Franchini,I;L

auwerys,R

R;B

erna

rd,A

M;R

oels,H

;Gelpi,E

;Rosello,

J;Ram

is,I

;Pric

e,RG;T

aylor,

SA;d

eBroe,

M;N

uyts,G

D;S

tolte

,H;F

els,

LM;H

erbo

rt,C

(199

2).Nep

hrop

athies

andexpo

sure

tope

rchloroethylen

ein

dry-cleane

rsThe

Lanc

et,3

30(881

3),1

89-193

DataTyp

e:Pe

rc-nep

hrotox

icity

markers-R

enal

HERO

ID:

5834

8

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

15:

Statistic

almod

els

Not

Rated

NA

NA

Norisk

estimates

werede

rived.

Meanvalues

were

compa

redusingt-testsan

dfreque

ncyof

abno

rmal

results.

Dom

ain6:

Other

Con

side

ratio

nsforBiomarkerSe

lectionan

dMeasurement

Metric

16:

Use

ofBiomarkerof

Exp

osure

Medium

×0.14

30.29

Perclevels

weremeasured

inthebloo

dwith

gas

chromatog

raph

ywith

amass

selective

detector.

LODswereno

tprovided

.Metric

17:

Effe

ctbiom

arker

High

×0.14

30.14

Biomarkers

aregene

rally

accepted

asbe

ingrelated

tokidn

eyfunc

tion

andindicate

keyevents

inAOP.

Asno

tedby

theau

thors‘T

hebioche

mical

andim

-mun

oche

mical

abno

rmalitiessugg

esteddiffu

sestruc-

turalan

dfunc

tion

alchan

geswithinthekidn

ey’.

Metric

18:

Metho

dSe

nsitivity

Low

×0.14

30.43

NoLO

Dwas

provided

.Metric

19:

Biomarkerstab

ility

Med

ium

×0.14

30.29

Limited

inform

ationon

storag

ehistory(justthat

itwas

stored

at-20de

greesC),an

dno

inform

ationon

stab

ility.

Metric

20:

Samplecontam

ination

Med

ium

×0.14

30.29

The

reis

incomplete

docu

mentation

ofthe

step

staken

toprovidethene

cessaryassuranc

ethat

the

stud

yda

taarerelia

ble.

Metric

21:

Metho

drequ

irements

Med

ium

×0.14

30.29

Instrumentation

was

employed

that

allowsforiden

-tific

ationof

thebiom

arkerwithahigh

degree

ofcon-

fiden

cean

dtherequ

ired

sensitivity(i.e.,Perclevels

weremeasuredin

thebloo

dwithga

schromatog

ra-

phywithamassselectivede

tector;ren

albiom

arkers

measuredwithcitedassaymetho

ds).

Metric

22:

Matrix

adjustment

Med

ium

×0.14

30.29

App

licab

leforthebiom

arkerun

derconsideration,

however,thestud

yon

lyprov

ides

resultsusingon

emetho

d(nomatrixad

justmentis

discussed).

OverallQua


Med

ium

2.1

Extracted

Yes

?MW

F=

MetricWeigh

ting

Factor

†High=

1;Medium

=2;

Low

=3;

Una

cceptable=

4;N/A

hasno

value.

‡The

overallr

atingis

calculated

asnecessary.

EPA

may


hasbe

encategorizedas

High.

Overallrating

=

4ifan

ymetricis

Una

cceptable

⌊ ∑ i(M

etricScore i

×MW

Fi)/

∑ jMW

Fj

⌉ 0.1(rou

ndto

thenearesttenth)

otherw

ise

,

where

High

=≥

1to

<1.

7;Medium

=≥

1.7to

<2.

3;Lo

w=

≥2.

3to

≤3.

0.If

thereview

erdeterm

ines

that

theoverallrating

needsad

justment,

theoriginal

rating

iscrossedou

tan

dan

arrow

points

tothenew

rating

.††

Thismetricmet

thecriteria

forhigh

confi

denc

eas

expe

cted

forthis

type

ofstud

y

17


Tabl

e5:

Pes

chet

al.

2000

:E

valu

atio

nof

Can

cer

Out

com

es

Stud

yCita

tion:

Pesch,

B;Haerting,

J;Ran

ft,U;Klim

pel,

A;Oelschläg

el,B;Schill,

W(200

0).

Occup

ationa

lris

kfactorsforrena

lcellcarcinom

a:Agent-spe

cific

results

from

acase-con

trol

stud

yin

German

yInternationa

lJou

rnal

ofEpide

miology,2

9(6),1

014-10

24DataTyp

e:Case-controls

tudy

ofrena

lcellc

ancerexcess

risk-Pe

rcfemales

med

ium

exp.-C

ancer

HERO

ID:

8597

3

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

High

×0.4

0.4

Setting,

respon

serate,inclusionan

dexclusioncri-

teria,

metho

dsof

case

ascertainm

entan

dcontrol

matchingweredescribe

dan

dfoun

dacceptab

le.

Metric

2:Attrit

ion

Med

ium

×0.4

0.8

Respo

nserateswere88

%forcasesan

d71

%forcon-

trols.

Metric

3:Com

paris

onGroup

High

×0.2

0.2

Con

trolswerefrequenc

y-matched

tocases(1

case

to4controls)by

geog

raph

ical

region

,sexan

dag

e(5-yearag

egrou

p).

Differen

cesbe

tween

case

and

controlag

edistribu

tion

weresaid

tobe

aresult

ofsharingthecontrolgrou

pwitholde

rcanc

ercases.

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

Low

×0.4

1.2

Exp

osurecatego

ries

estimated

byJE

Man

dJE

TM

wereba

sed

onjob

titles

and

job

tasksfrom

ques-

tion

naires

andinterviews(not

employmentrecords).

Specified

chem

ical

agentexpo

sureswereestimated

basedon

prob

ability

andintensityof

expo

sure

asso-

ciated

withthejobtitles

andtask.

Metric

5:Exp

osurelevels

Medium

×0.2

0.4

Med

ium,high

orsubstantialexpo

sure

rating

swere

used

.Metric

6:Te

mpo

rality

Med

ium

×0.4

0.8

88.5%

ofRCC

caseswereinterviewed

inthefirst

2mon

thsafterdiag

nosis.

Tem

poralityof

expo

sure

isestablishe

d,bu

tit

isun

clearwhe

ther

expo

suresfall

withinrelevant

expo

sure

windo

wsfortheou

tcom

eof

interest.

Dom

ain3:

OutcomeAssessm

ent

Metric


characteriz

ation

High

×0.66

70.67

Diagn

osis

was

confi

rmed

histolog

ically

(95%

)an

dsono

grap

hy(5%).

Metric

8:Rep

ortin

gBias

High

×0.33

30.33

ORswithCIs

wereused

andap

prop

riate.

Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

High

×0.5

0.5

Adjustedforag

e,stud

ycenter

andsm

oking.

Metric

10:

Covariate

Cha

racterization

High

×0.25

0.25

Assessedby

valid

andrelia

blequ

estion

naires.

Metric

11:

Co-expo

sure

Con

foun

ding

Low

×0.25

0.75

Other

chem

ical

agentworkerexpo

sureswereno

tap

-prop

riatingad

justed

forwhich

couldresultin

biased

expo

sure-outcomeassociation.

Dom

ain5:

Ana

lysis

Con

tinu

edon

next

page

...

18


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Pesch,

B;Haerting,

J;Ran

ft,U;Klim

pel,

A;Oelschläg

el,B;Schill,

W(200

0).

Occup

ationa

lris

kfactorsforrena

lcellcarcinom

a:Agent-spe

cific

results

from

acase-con

trol

stud

yin

German

yInternationa

lJou

rnal

ofEpide

miology,2

9(6),1

014-10

24DataTyp

e:Case-controls

tudy

ofrena

lcellc

ancerexcess

risk-Pe

rcfemales

med

ium

exp.-C

ancer

HERO

ID:

8597

3

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

The

stud

yde

sign

usingcase-con

trol

andcond

itiona

llogistic

regression

was

approp

riateto

evalua

terare

diseasewithassociated

expo

sures.

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

The

reis

asm

allgrou

pof

substantially

expo

sed

workers

inthegene

ralp

opulationlim

itingthepo

wer

tode

tect

dose-respo

nserelation

ships.

Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.2

0.4

The

description

ofthean

alysis

issufficientto

un-

derstand

precisely

wha

tha

sbe

endo

nean

dto

bereprod

ucible.

Metric

15:

Statistic

almod

els

Med

ium

×0.2

0.4

Mod

elwas

wellde

scribe

d.Dom

ain6:

Other

Con

side

ratio

nsforBiomarkerSe

lectionan

dMeasurement

Metric

16:

Use

ofBiomarkerof

Exp

osure

NA

NA

Metric

17:

Effe

ctbiom

arker

NA

NA

Metric

18:

Metho

dSe

nsitivity

NA

NA

Metric

19:

Biomarkerstab

ility

NA

NA

Metric

20:

Samplecontam

ination

NA

NA

Metric

21:

Metho

drequ

irements

NA

NA

Metric

22:

Matrix

adjustment

NA

NA

OverallQua


Med

ium

1.7

Extracted

Yes

?MW

F=

MetricWeigh

ting

Factor

†High=

1;Medium

=2;

Low

=3;

Una

cceptable=

4;N/A

hasno

value.

‡The

overallr

atingis

calculated

asnecessary.

EPA

may


hasbe

encategorizedas

High.

Overallrating

=

4ifan

ymetricis

Una

cceptable

⌊ ∑ i(M

etricScore i

×MW

Fi)/

∑ jMW

Fj

⌉ 0.1(rou

ndto

thenearesttenth)

otherw

ise

,

where

High

=≥

1to

<1.

7;Med

ium

=≥

1.7to

<2.

3;Lo

w=

≥2.

3to

≤3.

0.If

thereview

erdeterm

ines

that

theoverallr

atingneedsad

justment,

theoriginal

rating

iscrossedou

tan

dan

arrow

points

tothenew

rating

.††

Thismetricmet

thecriteria

forhigh

confi

denc

eas

expe

cted

forthis

type

ofstud

y

19


Tabl

e6:

Win

dham

etal

.20

06:

Eva

luat

ion

ofN

euro

logi

cal/

Beh

avio

rO

utco

mes

Stud

yCita

tion:

Windh

am,G

C;Z

hang

,L;G

unier,R;C

roen

,LA;G

rether,J

K(200

6).Autism

spectrum

disordersinrelatio

nto

distrib

utionof

hazardou

sairpo

llutantsin

theSa

nFran

ciscoBay

area

Env

ironm

entalH

ealth

Perspe

ctives,1

14(9,9),

1438

-144

4DataTyp

e:Califo

rnia_case_control_

autis

m_Pe

rc_OR_Q4-Neu

rological/Beh

avior

HERO

ID:

1035

22

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

Med

ium

×0.4

0.8

Cases

wereidentifie

dfrom

theCalifo

rnia

Centers

forAutism

andDevelop

mentalD

isab

ilities

Research

andEpide

miology

(CADDRE)which

draw

sinform

a-tion

onASD

byactive

surveilla

nceof

Califo

rnia

De-

partmentof

Develop

mentalSe

rvices

(DDS)

andthe

KaiserPerman

ente

Med

ical

CareProgram

.Autho

rsestimated

that

thesemetho

dscaptured

75-80%

ofcasesliv

ingin

thearea

(Croen

etal.20

02);

authors

note

that

extrem

een

dsof

thesocioecono

mic

status

werelik

elyno

twellcovered.

Cases

wereinclud

edif

they

werebo

rnin

1994

andreside

din

oneof

sixSa

nFran

ciscoBay

area

coun

ties.Con

trolswereidenti-

fiedfrom

aCalifo

rnia

1994

linkedbirth-infant

death

certificate

databa

seusingthesameinclusioncrite-

ria.

Con

trolswererand

omly

selected

andmatched

onbirthmon

than

dsex(2

to1).

Metric

2:Attrit

ion

High

×0.4

0.4

Ofthecasesidentifie

din

theda

taba

ses,

expe

rtre-

view

bythePIconfi

rmed

83.3%

ASD

diag

noses,

us-

ingthesamecriteria

forallexclusion/

inclusionby

expe

rtreview

.Exclusion

from

thecontrolpo

pula-

tion

was

minim

al(n=18

)an

dwas

sufficiently

ex-

plaine

d.Metric

3:Com

paris

onGroup

High

×0.2

0.2

The

reis

someeviden

ceof

diffe

renc

esbe

tween

the

controlsan

dcases;ho

wever,p

arentala

ndchild

char-

acteristicssuch

asrace/ethnicity,materna

led

uca-

tion

,an

dpa

rity

wereconsidered

aspo

tentialcon-

foun

ders

inthestatisticalan

alysis.

Dem

ograph

icde

tails

provided

inTab

le2.

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

Med

ium

×0.4

0.8

Ann

uala

verage

conc

entrationestimates

weredraw

nfrom

EPA

’sNationa

lAir

Toxics

Assessm

ent

(U.S.EPA

;41

5230

3).Con

centration

estimates

were

availableby

census

tractfor19

96that

matched

the

geocod

edad

dressesfrom

birth

certificates.

Esti-

mates

werecalculated

bysummingconc

entrations

across

variou

ssources

(mob

ile,

point,

and

area

sources).Thisrepresents

awell-establishe

dmetho

dof

determ

iningexpo

sure

toHAPsan

dwas

assessed

consistently

across

grou

ps.

Con

tinu

edon

next

page

...

20


... c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Windh

am,G

C;Z

hang

,L;G

unier,R;C

roen

,LA;G

rether,J

K(200

6).Autism

spectrum

disordersinrelatio

nto

distrib

utionof

hazardou

sairpo

llutantsin

theSa

nFran

ciscoBay

area

Env

ironm

entalH

ealth

Perspe

ctives,1

14(9,9),

1438

-144

4DataTyp

e:Califo

rnia_case_control_

autis

m_Pe

rc_OR_Q4-Neu

rological/Beh

avior

HERO

ID:

1035

22

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

5:Exp

osurelevels

Medium

×0.2

0.4

Forchem

ical

specifican

alyses,q

uartile

sof

expo

sure

wereused

.The

sewerede

term

ined

byexpo

sure

dis-

tributionqu

artilesin

controls.Thisrepresents

more

than

twolevels

ofexpo

sure.Meanexpo

sureswere

0.64

-0.68

ug/m

3(D

CM),

0.60

-0.61

ug/m

3(P

erc),

and0.17

-0.19ug

/m3(T

CE).

Metric

6:Te

mpo

rality

Low

×0.4

1.2

Cases

werediag

nosed

with

Autism

Spectrum

Dis-

orde

rby

age

9(suffi

cientwindo

wfordiag

nosis).

Cases

and

controls

weredraw

nfrom

apo

pulation

ofchild

renbo

rnin

1994

;how

ever,e

xposurewas

de-

term

ined

from

census

tract-levelexpo

sure

data

for

birthad

dressfrom

1996

expo

sure

estimates

(other

option

was

1994

).It

isun

clearho

wstab

lethesees-

timates

may

befrom

year

toyear.Using

expo

sure

data

from

1996

may

notaccu

rately

capturetheex-

posure

that

occu

rred

during

gestation,

butinstead

refle

ctan

earlychild

hood

developm

entalwindo

w.

Dom

ain3:

Outco

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