DRAFT

PEER REVIEW DRAFT, DO NOT CITE OR QUOTE

United States Office of Chemical Safety and Environmental Protection Agency Pollution Prevention

Risk Evaluation for Methylene Chloride

Systematic Review Supplemental File:

Data Quality Evaluation of Human Health Hazard Studies – Epidemiological Studies

CASRN: 75-09-2

H

H Cl

October, 2019, DRAFT

Cl

DRAFT

Table Listing1 Lash et al. 1991: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . . . 32 Ott et al. 1983: Evaluation of Mortality Outcomes . . . . . . . . . . . . . . . . . . . . 63 Cherry et al. 1983: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . 94 Windham et al. 2006: Evaluation of Neurological/Behavior Outcomes . . . . . . . 145 Siemiatycki 1991: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 186 Cantor et al. 1995: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 217 Heineman et al. 1994: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . 248 Seidler et al. 2007: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 289 Dosemeci et al. 1999: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 3110 Wang et al. 2009: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 3411 Infante-Rivard 2005: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 3812 Miligi et al. 2006: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 4213 Costantini et al. 2008: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . 4514 Radican et al. 2008: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . 4915 Radican et al. 2008: Evaluation of Respiratory Outcomes . . . . . . . . . . . . . . . 5216 Gold et al. 2010: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . 5517 Cocco et al. 1999: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 5818 Barry et al. 2011: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 6219 Bell et al. 1991: Evaluation of Growth (early life) and Development Outcomes . . 6520 Hearne and Pifer 1999: Evaluation of Cancer for Employees in Roll Coating

Division Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6821 Hearne and Pifer 1999: Evaluation of Cancer for All Employees Outcomes . . . . 7222 Hearne and Pifer 1999: Evaluation of Respiratory Outcomes . . . . . . . . . . . . . 7623 Hearne and Pifer 1999: Evaluation of Hematological and Immune Outcomes . . . 8024 Gibbs et al. 1996: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 8425 Lanes et al. 1990: Evaluation of Mortality Outcomes . . . . . . . . . . . . . . . . . . 8726 Lanes et al. 1990: Evaluation of Respiratory Outcomes . . . . . . . . . . . . . . . . . 9027 Lanes et al. 1990: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 9328 Lanes et al. 1990: Evaluation of Cardiovascular Outcomes . . . . . . . . . . . . . . . 9629 Lanes et al. 1993: Evaluation of Respiratory Outcomes . . . . . . . . . . . . . . . . . 9930 Lanes et al. 1993: Evaluation of Cardiovascular Outcomes . . . . . . . . . . . . . . . 10231 Lanes et al. 1993: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 10532 Lanes et al. 1993: Evaluation of Mortality Outcomes . . . . . . . . . . . . . . . . . . 10833 Taskinen et al. 1986: Evaluation of Reproductive Outcomes . . . . . . . . . . . . . . 11134 Soden 1993: Evaluation of Cardiovascular Outcomes . . . . . . . . . . . . . . . . . . . 11635 Soden 1993: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . . . . . . 12036 Soden 1993: Evaluation of Hepatic Outcomes . . . . . . . . . . . . . . . . . . . . . . . 12437 Soden 1993: Evaluation of Hematological and Immune Outcomes . . . . . . . . . . 12838 Kalkbrenner et al. 2010: Evaluation of Neurological/Behavior Outcomes . . . . . 13239 Tomeson 2011: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . . 13640 Tomeson 2011: Evaluation of Cardiovascular Outcomes . . . . . . . . . . . . . . . . . 14141 Roberts et al. 2013: Evaluation of Neurological/Behavior Outcomes . . . . . . . . 14642 Christensen et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . 14943 Neta et al. 2012: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . 15244 Ruder et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 15545 Vizcaya et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 15846 Morales-Suárez-Varela et al. 2013: Evaluation of Cancer Outcomes . . . . . . . . . 16147 von Ehrenstein et al. 2014: Evaluation of Neurological/Behavior Outcomes . . . . 16448 Talibov et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 16749 Mattei et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 17250 Brender et al. 2014: Evaluation of Cardiovascular Outcomes . . . . . . . . . . . . . 17551 Brender et al. 2014: Evaluation of Growth (early life) and Development Outcomes178

1

DRAFT

52 Brender et al. 2014: Evaluation of Neurological/Behavior Outcomes . . . . . . . . 18153 Silver et al. 2014: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . 18454 Silver et al. 2014: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . . 18755 Silver et al. 2014: Evaluation of Hepatic Outcomes . . . . . . . . . . . . . . . . . . . . 19056 Chaigne et al 2015: Evaluation of Hematological and Immune Outcomes . . . . . . 19357 Talbott et al 2015: Evaluation of Neurological/Behavior Outcomes . . . . . . . . . 19658 Garcia et al. 2015: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 20059 Kumagi et al. 2016: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 20360 Carton et al. 2017: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 20761 Purdue et al. 2016: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . 21062 Celanese Fibers, Inc 1987: Evaluation of Hepatic Outcomes . . . . . . . . . . . . . . 21263 General Electric, Co 1990: Evaluation of Hepatic Outcomes . . . . . . . . . . . . . . 21564 General Electric, Co 1990: Evaluation of Neurological/Behavior Outcomes . . . . 21865 Gibbs 1992: Evaluation of Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . . . . 22166 Gibbs 1992: Evaluation of Respiratory Outcomes . . . . . . . . . . . . . . . . . . . . . 22667 Dow Chem, Co 1976: Evaluation of Skin and Connective Tissue Outcomes . . . . 23168 Dow Chem, Co 1972: Evaluation of Skin and Connective Tissue Outcomes . . . . 23469 Ott et al. 1983: Evaluation of Hematological and Immune Outcomes . . . . . . . . 23770 Ott et al. 1983: Evaluation of Hepatic Outcomes . . . . . . . . . . . . . . . . . . . . . 241

2

DRAFT

T abl

e1:

Lash

etal

.19

91:

Eva

luat

ion

ofN

euro

logi

cal/

Beh

avio

rO

utco

mes

Stud

yCita

tion:

Lash,A

A;B

ecker,CE;S

o,Y;S

hore,M

(199

1).Neu

rotoxiceff

ects

ofmethy

lene

chlorid

e:Are

they

long

lastingin

human

s?Occup

ationa

lan

dEnv

ironm

entalM

edicine,

48(6),

418-42

6DataTyp

e:methy

lene

chlorid

e_retir

edworkers_de

layedverbal

mem

ory_

expo

sed-Neu

rological/Beh

avior

HERO

ID:

1350

9

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

Participa

ntswereretiredairlinemecha

nics

who

had

worked

forthesame,

sing

leairlinean

dwho

were

mem

bers

ofthesamelabo

run

ion.

Both

theair-

linean

dtheun

ionprovided

inform

ationab

outthe

stud

ypo

pulation

andhistorical

occu

pation

almethy

-lene

chloride

expo

sures.

Retireesha

dto

have

worked

aminim

umof

6yearsin

oneor

moreof

14target

jobs

inorde

rto

beeligible.

Med

ical

and

demog

raph

iccriteria

forpa

rticipan

tswere

well-do

cumented

inthe

stud

yrepo

rt.

Follo

w-ups

with

survey

non-

respon

dents/no

n-pa

rticipan

tsrevealed

that

ahigh

erpe

rcentage

ofthem

hadbe

endiag

nosedwithhe

art

disease

and/

orgo

utcompa

red

tosurvey

respon

-de

nts/pa

rticipan

ts,sugg

esting

abias

toward

lower

freque

ncyof

heartdiseasein

thestud

ypo

pulation

.Add

itiona

lly,theau

thorssaythat

retirees

that

had

suffe

red

strokeswereexclud

ed,bu

tTab

le3show

sthat

4pa

rticipan

tsha

dha

dstrokes.

Metric

2:Attrit

ion

Low

×0.4

1.2

Ofthe91

potentialstud

ypa

rticipan

tswho

met

all

themed

ical

andde

mog

raph

iccriteria

andwerein-

vitedto

participatein

thefie

ldstud

y,on

ly46

(25

solvent-expo

sed,

21un

expo

sed)

participated

.The

low

participationrate

isno

texplicitly

explaine

d,al-

thou

ghalogicalassumptionmay

bethat

theseeli-

giblesubjects

electedno

tto

participate.

Metric

3:Com

paris

onGroup

Med

ium

×0.2

0.4

The

unexpo

sed

compa

rison

grou

pconsisted

ofre-

tired

airline

mecha

nics

who

had

worked

inlow-

orno

-solvent-exp

osure

jobs

(jet

engine

assembly

orroutineaircraft

mainten

ance).

The

unexpo

sed

compa

risongrou

pdiffe

redfrom

thesolvent-expo

sed

grou

pin

somede

mog

raph

iccriteria

(e.g.,ethn

icmi-

nority,Eng

lish-speaking

),bu

tmod

elswereno

tad

-justed

accordingly.

Dom

ain2:

Exp

osureCha

racterization

Con

tinu

edon

next

page

...

3

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Lash,A

A;B

ecker,CE;S

o,Y;S

hore,M

(199

1).Neu

rotoxiceff

ects

ofmethy

lene

chlorid

e:Are

they

long

lastingin

human

s?Occup

ationa

lan

dEnv

ironm

entalM

edicine,

48(6),

418-42

6DataTyp

e:methy

lene

chlorid

e_retir

edworkers_de

layedverbal

mem

ory_

expo

sed-Neu

rological/Beh

avior

HERO

ID:

1350

9

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

4:Measurementof

Exp

osure

High

×0.4

0.4

Job-expo

sure

matriceswas

determ

ined

usingoccu

-pa

tion

al/h

istoricalexpo

sure

inform

ationfrom

both

the

airline

and

the

labo

run

ion.

Exp

osure

was

confi

rmed

byindu

strial

hygien

eassessments

(per-

sona

lan

darea

airmon

itoring

from

1975

throug

h19

86),

observation

ofcu

rrentworkp

lace

practices,

andinterviewswithlong

-term

employees.

Add

ition-

ally,thestud

ypo

pulation

consistedof

retirees

who

hadworkedforthesame,

sing

leairlinethroug

hout

theircareers,

andthus

theirfullworkhistorieswere

know

n.Metric

5:Exp

osurelevels

Low

×0.2

0.6

The

stud

yexam

ines

twolevelsof

expo

sure

(solvent-

expo

sedan

dun

expo

sed),b

ased

onoccu

pation

alan

dhistorical

expo

sure

inform

ationprovided

bytheair-

linean

dthelabo

run

ion.

Metric

6:Te

mpo

rality

High

×0.4

0.4

Stud

ypa

rticipan

tsthe

solvent-expo

sed

grou

pworked

inthesejobs

foran

averag

eof

11.6

years

during

thetarget

yearsof

1970

to19

84,an

dfor

anaverag

eof

23.8

yearsin

all.

Formost,

employ

-mentin

thesejobs

was

continuo

us.

Participa

nts

wereassessed

forne

urolog

ical

outcom

esinclud

ing

grip

streng

th,motor

speed,

andmem

ory.

Dom

ain3:

OutcomeAssessm

ent

Metric

7:Outcomemeasurementor

characteriz

ation

Med

ium

×0.66

71.33

Participa

ntsweretested

foranu

mbe

rof

psycho

phys-

ical

andpsycho

logicale

ndpo

ints

(gripstreng

th,sen

-sory

respon

ses,motor

speed,

short-term

visual

mem

-ory,etc.)throug

hseventest

stations

atthefie

ldsite.

Tests

weread

ministeredby

specially

traine

dexam

in-

ers(e.g.,ph

ysicians,p

sycholog

ists,n

urses)

who

were

blindto

thepa

rticipan

ts’expo

sure

grou

p.Metric

8:Rep

ortin

gBias

High

×0.33

30.33

Means

and

stan

dard

deviations

wererepo

rted

for

each

physiologicala

ndpsycho

logicaltest(along

with

pvalues).

Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

Med

ium

×0.5

1The

statisticalan

alyses

weread

justed

only

forag

e.Metric

10:

Covariate

Cha

racterization

High

×0.25

0.25

Que

stionn

aires,

stan

dardized

tests,

and

interviews

bytheresearch

team

and/

orph

ysicians

wereused

tode

term

inepa

rticipationeligibility

andassess

po-

tentialconfou

nders.

Con

tinu

edon

next

page

...

4

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Lash,A

A;B

ecker,CE;S

o,Y;S

hore,M

(199

1).Neu

rotoxiceff

ects

ofmethy

lene

chlorid

e:Are

they

long

lastingin

human

s?Occup

ationa

lan

dEnv

ironm

entalM

edicine,

48(6),

418-42

6DataTyp

e:methy

lene

chlorid

e_retir

edworkers_de

layedverbal

mem

ory_

expo

sed-Neu

rological/Beh

avior

HERO

ID:

1350

9

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

11:

Co-expo

sure

Con

foun

ding

Med

ium

×0.25

0.5

The

issue

ofpo

tentialco-exp

osures

was

notad

-dressed

inthestud

y,bu

tthere’salso

noeviden

cethat

therewereco-exp

osures

that

wereim

prop

erly

adjusted

for.

Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

Asm

alloccu

pation

alcoho

rtof

airlinemecha

nicre-

tirees

with

long

-term

methy

lene

chloride

expo

sure

was

assessed

forne

urolog

ical

outcom

es.

Datapre-

sented

asmeans/stand

ardde

viations

evalua

tedwith

t-tests.

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

The

stud

yha

dlim

ited

samplesize

(25expo

sed,

21un

expo

sed),bu

tshow

edstatistically

sign

ificant

re-

sults.

Statisticalpo

wer

appe

arssufficientto

detect

largeeff

ects.

Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.2

0.4

Results

ofne

urolog

ical

assessments

wererepo

rted

asmeans/stand

ardde

viations.Ana

lysisof

effectesti-

mates

isclearlyde

scribe

d,an

dreprod

ucible.

Metric

15:

Statistic

almod

els

Med

ium

×0.2

0.4

Con

tinu

ousde

pend

entvariab

lesan

alyzed

using

t-tests.

Com

posite

scores

formem

oryan

dattention

testswerestan

dardized

forthepo

oled

grou

pof

sub-

jects.

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

Ov erallQua

lityDetermination‡

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

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;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

5

DRAFT

T abl

e2:

Ott

etal

.19

83:

Eva

luat

ion

ofM

orta

lity

Out

com

es

Stud

yCita

tion:

Ott,MG;Sk

ory,

LK;Holde

r,BB;Bronson

,JM

;W

illiams,

PR

(198

3).

Health

evalua

tion

ofem

ployeesoccu

patio

nally

expo

sed

tomethy

lene

chlorid

eSc

andina

vian

Journa

lofW

ork,

Env

ironm

entan

dHealth

,9(Sup

pl1,Su

ppl1

),1-38

DataTyp

e:DCM_occu

patio

nal_

retrospe

ctivecoho

rt_mortality-Mortality

HERO

ID:

2914

9

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

Participa

ntswereem

ployeesof

acellu

lose

triacetate

andcellu

lose

diacetatefib

erman

ufacturing

plan

tin

South

Carolinawho

had

worked

inprep

arationor

extrusionareasforat

least3mon

thsbe

tween19

54an

d19

77.A

totalo

f127

1em

ployeesfrom

thisplan

twereinclud

edin

themortalitystud

y.Con

trol

grou

ppa

rticipan

ts(948

)weredraw

nfrom

ano

n-DCM-

expo

sure

referenc

eacetatefib

erman

ufacturing

plan

tin

Virginia.

Becau

seworkassign

ments

atthis

plan

tvaried

andda

y-to-day

assign

mentrecordswereno

tkept,em

ployeeswho

workedin

compa

rableareasof

theplan

t(prepa

ration

orextrusionareas)

couldno

tbe

identifie

d.Metric

2:Attrit

ion

Low

×0.4

1.2

Attrition

was

notrepo

rted

/add

ressed

inthisrepo

rt.

Metric

3:Com

paris

onGroup

Med

ium

×0.2

0.4

Becau

seof

anab

senc

eof

workrecordsforem

ployees

ofthereferenc

eplan

t,it

could

notbe

ascertaine

dwhe

ther

participan

tsfrom

this

plan

tworkedin

sim-

ilarareas/op

erations

asthoseof

thepa

rticipan

tsfrom

theDCM-exp

osureplan

t.Add

itiona

lly,d

etails

onpa

rticipan

ts(e.g.,race,sex,

age,

etc.)

werere-

ported

lycolle

cted

,but

notrepo

rted

inthestud

yre-

port.

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

High

×0.4

0.4

Eight-hrTWA

conc

entrations

andpe

akconc

entra-

tion

swerede

term

ined

forbo

thplan

ts.Persona

lair

mon

itoring(>

350samples),area

sampling(170

sam-

ples),

andshort-term

excu

rsionsampling(20sam-

ples)werepe

rformed

over

thecourse

ofa3.5-mon

thsurvey

period

inlate

1977

-early

1978

.Detailsof

the

person

alairsamplingmetho

dsarede

scribe

din

anap

pend

ixto

thestud

yrepo

rt.

Metric

5:Exp

osurelevels

Med

ium

×0.2

0.4

Occup

ationa

lDCM

expo

sure

was

catego

rized

into

threelevels

across

asufficientrang

e.

Con

tinu

edon

next

page

...

6

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Ott,MG;Sk

ory,

LK;Holde

r,BB;Bronson

,JM

;W

illiams,

PR

(198

3).

Health

evalua

tion

ofem

ployeesoccu

patio

nally

expo

sed

tomethy

lene

chlorid

eSc

andina

vian

Journa

lofW

ork,

Env

ironm

entan

dHealth

,9(Sup

pl1,Su

ppl1

),1-38

DataTyp

e:DCM_occu

patio

nal_

retrospe

ctivecoho

rt_mortality-Mortality

HERO

ID:

2914

9

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

6:Te

mpo

rality

Low

×0.4

1.2

The

timefram

ebe

tween

assessed

employee

expo

-suresan

dmortalityis

unclear,

butlik

elyto

bead

e-qu

atesinc

ethisisamortalitystud

y.Cau

sesof

death

werede

term

ined

from

deathcertificates.

Mortality

withintheexpo

sedcoho

rtwas

compa

redwiththat

ofthereferenc

epo

pulation

andthegene

ralU

.S.p

op-

ulation.

Dom

ain3:

OutcomeAssessm

ent

Metric

7:Outcomemeasurementor

characteriz

ation

Med

ium

×0.66

71.33

Cau

seof

death

was

determ

ined

from

copies

death

certificatesof

death

certificatesob

tained

throug

hcompa

nyinsuranc

erecordsor

statevitalstatistics

agen

cies.The

ywere

code

dby

ano

sologist

accordingto

theRevisionof

theInternationa

lClassification

ofDiseasesin

forceat

thetimeof

death.

Mortality

withintheexpo

sedcoho

rtwas

compa

red

with

that

ofbo

ththe

correspo

nding

UnitedStates

popu

lation

andthe

referenc

epo

pulation

.Outcomes

ofapriori

interest

werede

aths

dueto

ischem

iche

art

diseasean

dmaligna

ntne

oplasm

s.Metric

8:Rep

ortin

gBias

Low

×0.33

31.0

Mortality

inform

ation

for

participan

tsis

not

re-

ported

inthis

stud

yrepo

rt.Onlymed

ianexpo

sures

arerepo

rted

.Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

Una

ccep

table×

0.5

0.25

The

reis

nodiscussion

ofcovariatead

justments.

Metric

10:

Covariate

Cha

racterization

Una

ccep

table×

0.25

0.06

The

reis

nodiscussion

ofcovariatecharacterization

.Metric

11:

Co-expo

sure

Con

foun

ding

Low

×0.25

0.75

The

stud

yrepo

rtindicatesthat

expo

sure

toothe

rchem

icals(e.g.,metha

nol,aceton

e)was

possible

attheSo

uthCarolinaplan

t.Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsUna

ccep

table×

0.66

70.44

Statisticala

nalyseswereno

tpresentedin

thisstud

yrepo

rt,an

dthereforeit

isdifficu

ltto

determ

ineac-

ceptab

ility

ontheba

sisof

stud

yde

sign

.Metric

13:

Statistic

alpo

wer

Med

ium

×0.33

30.67

The

stud

yinclud

ed1,27

1expo

sedem

ployeesan

d94

8un

expo

sed

employees,

thus

with

alik

ely

adequa

tesamplesize.

Metric

14:

Rep

rodu

cibilityof

analyses

Not

Rated

NA

NA

Details

ofan

alyses

aremissing

from

this

stud

yre-

port.

Con

tinu

edon

next

page

...

7

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Ott,MG;Sk

ory,

LK;Holde

r,BB;Bronson

,JM

;W

illiams,

PR

(198

3).

Health

evalua

tion

ofem

ployeesoccu

patio

nally

expo

sed

tomethy

lene

chlorid

eSc

andina

vian

Journa

lofW

ork,

Env

ironm

entan

dHealth

,9(Sup

pl1,Su

ppl1

),1-38

DataTyp

e:DCM_occu

patio

nal_

retrospe

ctivecoho

rt_mortality-Mortality

HERO

ID:

2914

9

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

15:

Statistic

almod

els

Not

Rated

NA

NA

Details

onstatisticala

nalyseswereno

tpresentedin

this

stud

yrepo

rt.

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

lityDetermination‡

Una

ccep

table?

?2.8

Extracted

No

??Con

sistentwithou

rA

pplic

atio

nof

Syst

emat

icR

evie

win

TSC

AR

isk

Eva

luat

ions

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ment,ifametricforada

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receives

ascoreof

Una

cceptable(score

=4),E

PAwill

determ

inethestud

yto

beun

acceptab

le.In

thiscase,o

neor

moreof

themetrics

wereratedas

unacceptab

le.Assuch,the

stud

yisconsidered

unacceptab

lean

dthescore

ispresentedsolely

toincrease

tran

sparency.

?MW

F=

MetricWeigh

ting

Factor

†High=

1;Med

ium

=2;

Low

=3;

Una

cceptable=

4;N/A

hasno

value.

‡The

overallr

atingis

calculated

asnecessary.

EPA

may

notalwaysprov

ideacommentforametricthat

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.Ifthereview

erdeterm

ines

that

theoverallratingne

edsad

justment,theoriginal

rating

iscrossed

outan

dan

arrow

points

tothenew

rating

.††

Thismetricmet

thecriteria

forhigh

confi

denceas

expe

cted

forthis

type

ofstud

y

8

DRAFT

T abl

e3:

Che

rry

etal

.19

83:

Eva

luat

ion

ofN

euro

logi

cal/

Beh

avio

rO

utco

mes

Stud

yCita

tion:

Che

rry,

N;V

enab

les,

H;W

aldron

,HA

(198

3).The

acutebe

haviou

rale

ffectsof

solventexpo

sure

Occup

ationa

lMed

icine,

33(1),13

-18

DataTyp

e:Coh

ort_

Occup

ationa

l_DCM_Beh

avior-Neu

rological/Beh

avior

HERO

ID:

7458

2

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

Somekeyelem

ents

ofthestud

yde

sign

wereno

tpre-

sented

,but

availableinform

ationindicatesalowrisk

ofselection

bias.

FactoryC

was

thefactorywith

methy

lene

chloride

expo

sure.So

mede

tails

provided

(typ

eof

shift

work,

age).The

rewerethreediffe

r-entshiftsan

dcontrols

wereselected

from

allthree

shifts.

How

ever,p

articipa

tion

ratesan

drecruitm

ent

metho

dswereno

trepo

rted

.Metric

2:Attrit

ion

Una

ccep

table×

0.4

0.16

Tab

leII

indicatesloss

ofover

half

ofthesubjects,

withno

explan

ations.Metho

dsindicatedthat

there

were56

expo

sed

subjects

and

36controlsubjects

from

factoryC,bu

tresultsin

Tab

leII

indicate

asamplesize

of44

.It

was

also

notindicatedif

the

44wereexpo

sed

subjects

only

orif

they

includ

edthecontrolsubjects.In

addition

,althou

ghthey

se-

lected

subjects

from

allthree

shifts,thereisno

infor-

mationto

indicate

that

thoseinclud

edin

theresults

werestill

from

allthreeshifts.

Metric

3:Com

paris

onGroup

Low

×0.2

0.6

Noinform

ationab

outthesimila

rity

betw

eengrou

psno

rwas

thereinform

ationto

indicate

that

controls

werematched

.Altho

ughit

was

notedthat

controls

wereselected

from

each

shift

sothat

they

workedthe

sameshift

patternas

theexpo

sedsubjects.Noothe

rinform

ation

was

provided

includ

ingif

thecontrols

wereallm

enlik

etheexpo

sedworkers.The

meanag

eof

theexpo

sedworkers

was

stated

tobe

43.8

years

old,

butno

agewas

provided

forthe36

controls.

Inad

dition

,on

ly12

ofthecontrols

werefrom

the

areasof

FactoryC

whe

retherewas

nocontactwith

solvents.

The

othe

r24

werefrom

anothe

rfactory

belong

ingto

thesamepa

rent

grou

pon

afilm

mak

ing

processidenticalt

otheexpo

sedmewitho

utsolvent

expo

sure.

Dom

ain2:

Exp

osureCha

racterization

Con

tinu

edon

next

page

...

9

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Che

rry,

N;V

enab

les,

H;W

aldron

,HA

(198

3).The

acutebe

haviou

rale

ffectsof

solventexpo

sure

Occup

ationa

lMed

icine,

33(1),13

-18

DataTyp

e:Coh

ort_

Occup

ationa

l_DCM_Beh

avior-Neu

rological/Beh

avior

HERO

ID:

7458

2

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

4:Measurementof

Exp

osure

Low

×0.4

1.2

Atm

osph

eric

solventconc

entrationwas

measuredon

asub-grou

pof

men

using

individu

alpu

mps

sam-

plingon

tocharcoal

tube

s.The

solventwas

desorbed

incarbon

disulphide

andsolventconc

entrationwas

analyzed

usingga

schromatog

raph

ywitha2m

8%carbow

axcolumn.

Blood

samples

weretaken

and

measuredas

well.

The

reis

noinform

ationprov

ided

onQC

metho

dsor

recovery

ratesforthesemetho

ds.

Metric

5:Exp

osurelevels

Med

ium

×0.2

0.4

The

rang

eof

expo

sure

repo

rted

was

28-173

ppm.

Blood

solventlevelswereno

trepo

rted

.So

meresults

werepresentedas

only

expo

sedvs.un

expo

sed,

but

combine

dtheresultsforthediffe

rent

factoriesan

dcontrolsan

dwereno

tspecificformethy

lene

chloride

expo

sure

(i.e.,Fa

ctoryC)

Metric

6:Te

mpo

rality

Med

ium

×0.4

0.8

Tem

poralityisestablishe

d,bu

titisun

clearwhe

ther

expo

suresfallwithinrelevant

expo

sure

windo

wsfor

theou

tcom

eof

interest.Blood

samples

(usedin

the

analysis)wereob

tained

atthebe

ginn

ingan

den

dof

theshift.

The

seap

pear

tobe

thesametimes

that

theou

tcom

ewas

tested

.So

althou

ghthesub-

jectslik

elyworkedarou

ndmethy

lene

chloride

prior

totheou

tcom

es,thereis

noten

ough

inform

ation

provided

onho

wlong

orwhe

nan

dmeasurements

weremad

eat

thesametimeas

theou

tcom

e.How

-ever,thestud

yau

thorsap

pear

tobe

look

ingat

the

acuteeff

ects

indicating

that

thetimingmay

beap

-prop

riate.

Dom

ain3:

OutcomeAssessm

ent

Metric

7:Outcomemeasurementor

characteriz

ation

Med

ium

×0.66

71.33

Three

testswerecompleted

atthebe

ginn

ing

and

theen

dof

shift

(i.e.,

visual

analog

uescales

tore-

flect

moo

d,thedigitsymbo

lsubstitution

test

from

theWescslerAdu

ltIntelligenc

eSc

ale,

andatest

ofsimplereaction

time.

Visua

lana

logu

escales

areself-

repo

rted

rating

scales

that

wereno

tedto

have

been

show

nto

providerelia

blean

dvalid

measure

ofmoo

d.So

mede

tails

wereprovided

ontheothe

rmeasures,

butit

isno

tclearwha

tthecriteria

beingmeasured

were.

Con

tinu

edon

next

page

...

10

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Che

rry,

N;V

enab

les,

H;W

aldron

,HA

(198

3).The

acutebe

haviou

rale

ffectsof

solventexpo

sure

Occup

ationa

lMed

icine,

33(1),13

-18

DataTyp

e:Coh

ort_

Occup

ationa

l_DCM_Beh

avior-Neu

rological/Beh

avior

HERO

ID:

7458

2

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

8:Rep

ortin

gBias

Low

×0.33

31.0

Correlation

swereprov

ided

formethy

lene

chloride

and4moo

dchan

gesno

tedas

part

ofthevisual

ana-

logu

escales.

Noresultswereprovided

forsimple

reaction

timein

methy

lene

chloride

workers.

Al-

thou

ghresultswerestated

tobe

inTab

leIIIa

ndmay

have

evalua

tedmethy

lene

chloride

sepa

rate

from

the

styren

eworkers,therewas

noTab

leIIIin

there-

port

noristhereadiscussion

offin

ding

sforthistest

inmethy

lene

chloride

workers.Digit

symbo

lscores

werejust

notedto

show

nodiffe

renc

e.Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

Low

×0.66

72

All

thesubjects

werepresum

ably

male(not

clear

that

allthe

controls

were

male)

and

subjects

inbo

thexpo

sedan

dcontrolgrou

pwereselected

from

allthreeshifts,

butno

othe

rconfou

ndingvariab

les

werediscussed.

Altho

ughsubjects

wereno

tedin

the

metho

dsto

beselected

from

allthreeshifts,

notall

subjects

appe

arto

have

been

includ

edin

thean

aly-

sisan

ditisno

tclearthat

thiswas

still

accoun

tedfor

intheresults.

Age

was

mention

edfortheexpo

sed

workers,b

utwas

notmention

edforthecontrolsub

-jects.

Metric

10:

Covariate

Cha

racterization

Not

Rated

NA

NA

N/A

becauseno

covariates

werediscussed.

Metric

11:

Co-expo

sure

Con

foun

ding

Low

×0.33

31

Co-expo

sedto

metha

nol(D

CM:m

etha

nol9:1),bu

ttheco-exp

osures

wereno

tad

justed

for.

Thisco-

expo

sure

wou

ldalso

likely

bias

resultsaw

ayfrom

thenu

ll,as

itmight

contribu

teto

effects

seen

.In

addition

,con

trolswereexpo

sedto

othe

run

specified

compo

unds

aspa

rtof

thefilm

mak

ingprocessthat

couldalso

have

contribu

tedto

resultsin

thecontrol

andmay

bias

theresultstowards

thenu

ll.Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

Stud

yde

sign

was

approp

riate.

The

stud

ywas

evalu-

atingacutene

urob

ehavioraleffe

ctsan

dwas

design

edto

test

subjects

before

andafterexpo

sure.

Italso

containe

dcontrols

that

werefrom

thesameplan

tan

dun

expo

sed,

which

wou

ldalso

help

addressif

theexpo

sure

had

achroniceff

ecton

thesubjects

(thu

sloweringtheirinitialscore)

andif

thediffe

r-en

ceswerejust

basedon

working

8ho

ursan

dno

tan

effectof

expo

sure.

Con

tinu

edon

next

page

...

11

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Che

rry,

N;V

enab

les,

H;W

aldron

,HA

(198

3).The

acutebe

haviou

rale

ffectsof

solventexpo

sure

Occup

ationa

lMed

icine,

33(1),13

-18

DataTyp

e:Coh

ort_

Occup

ationa

l_DCM_Beh

avior-Neu

rological/Beh

avior

HERO

ID:

7458

2

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

The

numbe

rof

participan

tsaread

equa

teto

detect

aneff

ectin

the

expo

sed

popu

lation

and/

orsub-

grou

psof

thetotalpo

pulation

.The

initialstud

ygrou

pwas

56expo

sedan

d36

controls.The

results

show

ed44

subjects.

Metric

14:

Rep

rodu

cibilityof

analyses

Low

×0.2

0.6

Itisap

parent

that

theau

thorsmad

eseveralcom

par-

ison

sinclud

ingcorrelations,bu

tthespecificmeth-

odsused

tode

term

inesign

ificanc

eor

correlations

was

notprovided

.The

refore,the

ycouldno

tbe

repli-

cated.

Metric

15:

Statistic

almod

els

Low

×0.2

0.6

Itisap

parent

that

theau

thorsmad

eseveralcom

par-

ison

sinclud

ingcorrelations,bu

tthespecificmeth-

odsused

tode

term

inesign

ificanc

eor

correlations

was

notprovided

.The

refore,the

ycouldno

tbe

repli-

cated.

Dom

ain6:

Other

Con

side

ratio

nsforBiomarkerSe

lectionan

dMeasurement

Metric

16:

Use

ofBiomarkerof

Exp

osure

Low

×0.16

70.5

Methy

lene

chloride

was

repo

rted

tobe

tested

inbloo

dusingahe

adspacean

alyser

and

a2m

8%carbow

axcolumn.

Blood

carboxyh

aemog

lobincon-

centration

was

also

measuredas

notedby

thestud

yau

thorscarbon

mon

oxideis

ametab

oliteof

methy

-lene

chloride

.The

reis

noinform

ationprovided

for

QC

orrecovery

rates.

Nor

istherean

yinform

ation

onho

wthemetab

oliteinform

ationwas

includ

edifat

allintheassessmentof

methy

lene

chloride

expo

sure.

Thisis

prob

ably

notavery

accu

rate

metho

d.Metric

17:

Effe

ctbiom

arker

Not

Rated

NA

NA

Nobiom

arkerof

effectwas

measured..

Metric

18:

Metho

dSe

nsitivity

Low

×0.16

70.5

LOD/L

OQ

values

areno

tstated

Metric

19:

Biomarkerstab

ility

Low

×0.16

70.5

The

reis

noinform

ationon

thestorag

eor

stab

ility

ofthesamples

norwas

thereinform

ationprovided

onwhe

nthesamples

weretested

incompa

risonto

whe

nthey

werecolle

cted

.Metric

20:

Samplecontam

ination

Low

×0.16

70.5

The

reis

noinform

ation

abou

tthecolle

ction

and

storag

eof

thesamplein

rega

rdsto

contam

ination.

Metric

21:

Metho

drequ

irements

Low

×0.16

70.5

Sigm

aH6he

adspacean

alyser

was

used

.Metric

22:

Matrix

adjustment

Low

×0.16

70.5

The

rewas

noinform

ation

abou

tad

justments

(or

not)

forthematrix.

The

reareno

unitsprovided

soit

cann

otbe

determ

ined

iftherewas

anyad

just-

ments

orho

wtheexpo

sure

was

presented.

OverallQua

lityDetermination‡

Una

ccep

table?

?2.7

Extracted

No

Con

tinu

edon

next

page

...

12

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Che

rry,

N;V

enab

les,

H;W

aldron

,HA

(198

3).The

acutebe

haviou

rale

ffectsof

solventexpo

sure

Occup

ationa

lMed

icine,

33(1),13

-18

DataTyp

e:Coh

ort_

Occup

ationa

l_DCM_Beh

avior-Neu

rological/Beh

avior

HERO

ID:

7458

2

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

??Con

sistentwithou

rA

pplic

atio

nof

Syst

emat

icR

evie

win

TSC

AR

isk

Eva

luat

ions

docu

ment,ifametricforada

tasource

receives

ascoreof

Una

cceptable(score

=4),E

PAwill

determ

inethestud

yto

beun

acceptab

le.In

thiscase,o

neor

moreof

themetrics

wereratedas

unacceptab

le.Assuch,the

stud

yisconsidered

unacceptab

lean

dthescore

ispresentedsolely

toincrease

tran

sparency.

?MW

F=

MetricWeigh

ting

Factor

†High=

1;Med

ium

=2;

Low

=3;

Una

cceptable=

4;N/A

hasno

value.

‡The

overallr

atingis

calculated

asnecessary.

EPA

may

notalwaysprov

ideacommentforametricthat

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.Ifthereview

erdeterm

ines

that

theoverallratingne

edsad

justment,theoriginal

rating

iscrossed

outan

dan

arrow

points

tothenew

rating

.††

Thismetricmet

thecriteria

forhigh

confi

denceas

expe

cted

forthis

type

ofstud

y

13

DRAFT

T abl

e4:

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_DCM_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

...

14

DRAFT

. ..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_DCM_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:

OutcomeAssessm

ent

Metric

7:Outcomemeasurementor

characteriz

ation

High

×0.66

70.67

Cases

wereidentifie

dby

CADDRE

active

surveil-

lanc

eof

Califo

rnia

Dep

artm

entof

Develop

mental

Services

andKaiserPerman

ente

records.

Identifie

dcaseswereconfi

rmed

bytheprincipa

linv

estiga

torby

diag

nosisfrom

aqu

alified

med

ical

profession

al,q

ual-

ification

forspecialed

ucationun

deran

autism

ex-

ceptiona

lity,

orau

tistic

beha

viorsap

pearingto

meet

DSM

-IV

criteria

forASD

.Thisrepresents

awell-

establishe

dmetho

dof

determ

iningan

autism

diag

-no

sis.

Metric

8:Rep

ortin

gBias

Med

ium

×0.33

30.67

Allou

tcom

esou

tlined

intheab

stract,introdu

ction,

andmetho

dswereprov

ided

intheresults.

The

num-

berof

casesan

dcontrolswas

detaile

dforsomean

al-

yses,bu

tno

tforchem

ical-spe

cific

analyses

which

wou

ldno

tallowed

forde

taile

dextraction

ofthenu

m-

berof

cases/controls.Thisis

notexpe

cted

toha

vean

appreciableim

pact

ontheresults.

Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Con

tinu

edon

next

page

...

15

DRAFT

. ..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_DCM_OR_Q4-Neu

rological/Beh

avior

HERO

ID:

1035

22

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

9:Covariate

Adjustm

ent

High

×0.5

0.5

Potential

confou

ndersinclud

edmaterna

lag

e,race,

and

educ

ation,

parity,pa

ternal

race

and

age,

low

birthweigh

t,preterm

deliv

ery,

andchild

race.The

final

mod

elsinclud

echild

race,materna

lag

e,an

dmaterna

led

ucation.

Cases

andcontrols

werebirth

mon

th-an

dsex-matched

.The

authorsstated

they

didno

tinclud

ethesetw

ovariab

lesin

thefin

almod

elas

itmad

elittlediffe

renc

e.Metric

10:

Covariate

Cha

racterization

High

×0.25

0.25

Forcontrols,d

emog

raph

icda

tawerestated

tobe

ab-

stracted

from

thebirthcertificate.Dem

ograph

icin-

form

ationforcaseswas

draw

nfrom

med

ical

orDDS

records.

The

searebo

threlia

blemetho

dsof

obtain-

ingcovariateinform

ation.

Metric

11:

Co-expo

sure

Con

foun

ding

Med

ium

×0.25

0.5

App

roximately30

hazardou

sairpo

llutants(H

APs)

wereconsidered

inthis

stud

y.The

chlorina

tedsol-

vents(P

erc,

TCE,D

CM,a

ndviny

lchloride)

tend

edto

becorrelated

witheach

othe

r.TCE

was

noted

tobe

high

lycorrelated

tometals.

Che

mical-spe

cific

analyses

didno

tcontrolfor

expo

sure

toothe

rHAPs.

Altho

ugh,

therewas

noeviden

ceof

unba

lanced

co-

expo

suresby

case

status.

Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

Acase-con

trol

stud

yde

sign

was

used

toassess

re-

lation

shipsbe

tweenexpo

sure

toHAPsdu

ring

preg-

nanc

y/earlychild

hood

andthepresen

ceof

ASD

di-

agno

sisat

age9.

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

The

rewerea

sufficientnu

mbe

rof

casesan

dcon-

trolsto

detect

aneff

ect.:28

4cases,

657controls.

The

stud

yau

thorsexplicitly

stated

they

kept

birth

mon

th-an

dsex-matched

controls

who

sematched

casesdidno

tmeetthestud

y’sdiag

nostic

criteria

inorde

rto

maintainalarger

samplesize.

Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.2

0.4

The

descriptionof

thean

alysis

was

sufficient.

Cut-

points

forqu

artilesof

expo

sure

andtheproced

ure

forinclusion/

exclusionof

potentialc

onfoun

ders

was

describe

d.Metric

15:

Statistic

almod

els

Med

ium

×0.2

0.4

Odd

sratios

werecalculated

forthetw

ohigh

estqu

ar-

tilesof

expo

sure

usinglogistic

regression

.The

mod

-elsan

dde

cision

son

catego

ries

ofexpo

sure

werede

-scribe

din

detailin

themetho

ds.

Dom

ain6:

Other

Con

side

ratio

nsforBiomarkerSe

lectionan

dMeasurement

Metric

16:

Use

ofBiomarkerof

Exp

osure

NA

NA

Con

tinu

edon

next

page

...

16

DRAFT

. ..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_DCM_OR_Q4-Neu

rological/Beh

avior

HERO

ID:

1035

22

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

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

Ov erallQua

lityDetermination‡

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

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;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

17

DRAFT

T abl

e5:

Siem

iaty

cki

1991

:E

valu

atio

nof

Can

cer

Out

com

es

Stud

yCita

tion:

Siem

iatycki,J(199

1).Riskfactorsforcanc

erin

theworkp

lace

#journa

l#,#

volume#

(#issue#

),#Pa

ges#

DataTyp

e:DCM_workeran

yexpo

sure_rectal

canc

er-C

ancer

HERO

ID:

1579

54

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

High

×0.4

0.4

Of

4576

eligible

male

cases

from

the

Mon

treal

metropo

litan

area

wereascertaine

dbe

tween

1979

-19

85,3

730completed

aninterviewdu

ring

thisstud

y(initiated

in19

79as

acase-con

trol

design

).Each

canc

erwas

code

dby

theInternationa

lClassification

ofDisease

forOnc

olog

y.Of54

1eligible

popu

la-

tion

malecontrols,3

75wereinterviewed

andselected

from

rand

omdigitcalling

,the

provincial

election

of19

81,wereno

ncan

cerpa

tients

hospitalized

inthe

sameinstitutions

asthosewithcanc

er-asubg

roup

ofcontrolc

ancercasesun

relatedto

occu

pation

alex-

posure

orwith

canc

erat

anothe

rsite

deem

edno

toccu

pation

ally

relevant

was

also

interviewed

Metric

2:Attrit

ion

High

×0.4

0.4

81.5%

ofeligible

casescompleted

interviews.

72%

ofcontrols.Non

respon

sesdu

eto

refusal,de

ath,

none

xtof

kinfoun

d,pa

tientdischa

rged

,no

valid

ad-

dress,

psychiatriccases,

notran

slator,or

physician

refusal

Metric

3:Com

paris

onGroup

High

×0.2

0.2

Baselinecharacteristicswerecolle

cted

from

partic-

ipan

tsan

dad

justed

for;

casesan

dcontrols

were

simila

rin

that

they

wereselected

from

Mon

treal,

Can

ada,

betw

een35

-70yearsold,

malean

drecruited

from

1979

-198

5.Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

Low

×0.4

1.2

Exp

osurede

term

ined

byqu

estion

naire,

nooccu

pa-

tion

alrecords.

Che

mist-hy

gien

ists

interview

consul-

tantsto

better

grasptheworking

sof

particular

in-

dustries,o

ccup

ations

wereselected

andcode

das

low

med

ium

orhigh

conc

entrations

ofexpo

sure

toaho

stof

chem

icalsba

sedon

jobtitle

Metric

5:Exp

osurelevels

Medium

×0.2

0.4

Any

orsubstantialexpo

sure

was

assign

edto

each

job

titlean

dpa

tients

wereassign

edto

oneof

the

twocatego

ries

foran

alysis.Assignm

ents

mad

eby

achem

ist-hy

gien

ist

Metric

6:Te

mpo

rality

Low

×0.4

1.2

Cases

aged

35-70,

timesinc

efirst

expo

sure

notes-

timated

;study

was

initiatedin

1979

withexpo

sures

occu

rringbe

fore

orbe

tween19

45-197

5.Dom

ain3:

OutcomeAssessm

ent

Con

tinu

edon

next

page

...

18

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Siem

iatycki,J(199

1).Riskfactorsforcanc

erin

theworkp

lace

#journa

l#,#

volume#

(#issue#

),#Pa

ges#

DataTyp

e:DCM_workeran

yexpo

sure_rectal

canc

er-C

ancer

HERO

ID:

1579

54

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

7:Outcomemeasurementor

characteriz

ation

High

×0.66

70.67

Histologicalor

autopsyconfi

rmationof

prim

arytu-

mor

site.

Metric

8:Rep

ortin

gBias

High

×0.33

30.33

ORswith90

%CIs.

Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

High

×0.5

0.5

Foreach

associationbe

tweenoccu

pation

alexpo

sure

and

cancer

type

adjustments

weremad

einclud

edag

e,he

ight,placeof

birth,

andrace

Metric

10:

Covariate

Cha

racterization

Med

ium

×0.25

0.5

Con

foun

ders

basedon

literaturean

dqu

estion

naire

data.

Metric

11:

Co-expo

sure

Con

foun

ding

Med

ium

×0.25

0.5

Adjustm

ents

forothe

roccu

pation

alexpo

sure

type

s,sm

oking,

andalcoho

lintake

weremad

e.Dom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

Thisis

acase-con

trol

stud

ythat

colle

cted

canc

ertype

andlifetim

eoccu

pation

alhistoryfrom

canc

erpa

tients

tode

term

ineifoccu

pation

alhistoryeff

ected

canc

errisk

Metric

13:

Statistic

alpo

wer

Med

ium

×0.2

0.4

DCM

was

notinclud

edin

Tab

le1results,

which

in-

clud

edalla

ssociation

swhe

repo

wer

was

adequa

teto

detect

a2-fold

risk

(based

on#

participan

tsan

dat

least2%

expo

sure).

DCM

was

includ

edin

Ta-

ble2which

show

selevated

ORson

ly(irrespe

ctiveof

power

tode

tect

excess

risk).

Metric

14:

Rep

rodu

cibilityof

analyses

Med

ium

×0.2

0.4

Ana

lysiswas

fully

describe

daMan

tel-Haenszela

nal-

ysis

was

performed

toan

alyzeod

dsratios

forthe

data.

Metric

15:

Statistic

almod

els

Med

ium

×0.2

0.4

Metho

dwas

tran

sparent.

AMan

tel-Haenszela

naly-

siswas

performed

toan

alyzeod

dsratios

fortheda

ta.

p-values

werecompu

tedby

theMan

tel-Haenszelchi-

squa

retest

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

lityDetermination‡

Med

ium

1.7

Extracted

Yes

Con

tinu

edon

next

page

...

19

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Siem

iatycki,J(199

1).Riskfactorsforcanc

erin

theworkp

lace

#journa

l#,#

volume#

(#issue#

),#Pa

ges#

DataTyp

e:DCM_workeran

yexpo

sure_rectal

canc

er-C

ancer

HERO

ID:

1579

54

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

?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;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

20

DRAFT

T abl

e6:

Can

tor

etal

.19

95:

Eva

luat

ion

ofC

ance

rO

utco

mes

Stud

yCita

tion:

Can

tor,KP;S

tewart,PA

;Brin

ton,

LA;D

osem

eci,M

(199

5).Occup

ationa

lexp

osures

andfemalebreast

canc

ermortalityin

theUnited

States

Journa

lofO

ccup

ationa

land

Env

ironm

entalM

edicine,

37(3,3),33

6-34

8DataTyp

e:DCM_breast

canc

er_occu

patio

nal_

case-con

trol_OR_black2

-Can

cer

HERO

ID:

1941

30

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Dom

ain1:

Stud

yPa

rticipation

Metric

1:Pa

rticipan

tselection

High

×0.4

0.4

Cases

werewom

enwho

sede

ath

certificateslisted

breast

canc

eras

thecauseof

death(across24

U.S.

states).

Con

trolswererand

omly

selected

from

non-

canc

erde

aths,an

dfreque

ncy-matched

forag

e,gen-

der,an

drace

(fou

rcontrols

percase).

Records

were

from

years19

84to

1989

,from

ada

taba

sesupp

orted

bytheNationa

lCan

cerInstitute,

NIO

SH,an

dthe

Nationa

lCenterforHealth

Statistics.

Cases

for

which

’hom

emaker’was

thede

sign

ated

occu

pation

wereexclud

ed,leaving29

,397

white

wom

encases,

102,95

5white

wom

encontrols,4,11

2blackwom

encases,

and14

,839

blackwom

encontrols.

Metric

2:Attrit

ion

High

×0.4

0.4

Only

casesforwhich

’hom

emaker’was

thede

sig-

nated

occu

pation

were

exclud

ed(45.1%

ofwhite

wom

encases,

31.1%

ofblackwom

encases;

51.7%

ofwhite

wom

encontrols,37

.9%

ofblackwom

encon-

trols).

Metric

3:Com

paris

onGroup

High

×0.2

0.2

Con

trolswererecruitedfrom

recordsfrom

thesame

databa

sean

dforthesametimepe

riod

ascases,an

dwerefreque

ncy-matched

forag

e,gend

er,an

drace.

Dom

ain2:

Exp

osureCha

racterization

Metric

4:Measurementof

Exp

osure

Med

ium

×0.4

0.8

Exp

osurewas

estimated

usingajobexpo

sure

ma-

trix,ba

sedon

theassign

edoccu

pation

alcode

s,an

dde

velope

daccordingto

profession

aljudg

ementof

anindu

strial

hygien

ist,

inform

ationin

thegene

rallit-

eratureon

occu

pation

alexpo

sure,an

dNIO

SHan

dOSH

Aoccu

pation

alexpo

sure

databa

ses.

Exp

osure

prob

ability

andlevelwas

estimated

for31

occu

pa-

tion

alexpo

sure

catego

ries,of

which

DCM

expo

sure

was

one.

Scores

wereassign

edforprob

ability

and

levelof

expo

sure.The

rewereno

detaile

dem

ploy-

mentrecordsused

.Metric

5:Exp

osurelevels

Low

×0.2

0.6

Four

levels

ofexpo

sure

arepresented,

includ

ingno

expo

sure.Detailedrang

esforexpo

sure

areno

tin-

clud

edin

thepresentreferenc

e,bu

tmorede

tails

may

beavailablein

HERO

ID’s

7079

12an

d11

88.

Con

tinu

edon

next

page

...

21

DRAFT

. ..c

onti

nued

from

prev

ious

page

Stud

yCita

tion:

Can

tor,KP;S

tewart,PA

;Brin

ton,

LA;D

osem

eci,M

(199

5).Occup

ationa

lexp

osures

andfemalebreast

canc

ermortalityin

theUnited

States

Journa

lofO

ccup

ationa

land

Env

ironm

entalM

edicine,

37(3,3),33

6-34

8DataTyp

e:DCM_breast

canc

er_occu

patio

nal_

case-con

trol_OR_black2

-Can

cer

HERO

ID:

1941

30

Dom

ain

Metric

Rating†

MW

F?

Score

Com

ments

††

Metric

6:Te

mpo

rality

Med

ium

×0.4

0.8

Exp

osureislik

elyto

have

occu

rred

priorto

theou

t-come,

buttheexacttimelineof

occu

pation

alexpo

-suresin

relation

toou

tcom

eisn’tclear.

Dom

ain3:

OutcomeAssessm

ent

Metric

7:Outcomemeasurementor

characteriz

ation

High

×0.66

70.67

Outcomewas

assessed

from

causes

ofde

ath

listed

onoffi

cial

deathcertificates.

Mortalityfrom

breast

canc

erwas

determ

ined

usingtheun

derlying

causeof

death(ICD-9,code

174)

listedon

thede

athcertifi-

cate.

Metric

8:Rep

ortin

gBias

High

×0.33

30.33

One

outcom

e(breastcanc

er)was

assessed

,an

dis

approp

riately

identifie

din

thestud

yrepo

rt.

The

numbe

rsof

casesan

dcontrols

includ

edin

theas-

sessmentarealso

repo

rted

.Dom

ain4:

PotentialC

ounfou

nding/

Varia

bleCon

trol

Metric

9:Covariate

Adjustm

ent

High

×0.5

0.5

Ana

lysesweread

justed

forag

eat

timeof

death,

and/

orsocioecono

mic

class.

Results

werestratifie

dby

race.

Metric

10:

Covariate

Cha

racterization

Med

ium

×0.25

0.5

The

assign

mentof

SESwas

describe

din

thecu

rrent

referenc

eas

theSE

Sstatus

implied

bytheusua

loccu

pation

listed

foran

individu

al.

Thisis

nota

well-establishe

dmetho

d,bu

tthereisno

eviden

ceto

sugg

estthat

itis

notavalid

metho

d.Metric

11:

Co-expo

sure

Con

foun

ding

Low

×0.25

0.75

The

stud

yau

thorsdiscusspo

tentialfor

"overlap

ping

expo

sures"

and

statethis

asa

limitation.

ofthe

stud

yDom

ain5:

Ana

lysis Metric

12:

Stud

yDesignan

dMetho

dsMed

ium

×0.4

0.8

Thiscase-con

trol

stud

ycalculates

odds

ratios

and

95%

confi

denc

eintervalsforprob

ability

andlevelo

fexpo

sure

toDCM

amon

gbreast

canc

erdeaths

across

24states,from

1984

to19

89.The

design

isap

pro-

priate

forinvestigatingtheeff

ects

ofDCM

onbreast

canc

ermortality.

Metric

13:

Statistic

alpo

w