Toxicological Review of Ammonia - Draft June 2012

7/29/2019 Toxicological Review of Ammonia - Draft June 2012

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EPA/635/R-11/013A

www.epa.gov/iris

Toxicological Review of Ammonia

(CAS No. 7664-41-7)

In Support of Summary Information on theIntegrated Risk Information System (IRIS)

June 2012

NOTICE

This document is an External Review draft. This information is distributed solely for the purposeof pre-dissemination peer review under applicable information quality guidelines. It has not beenformally disseminated by EPA. It does not represent and should not be construed to represent anyAgency determination or policy. It is being circulated for review of its technical accuracy andscience policy implications.

National Center for Environmental AssessmentOffice of Research and Development

U.S. Environmental Protection AgencyWashington, DC
http://www.epa.gov/irishttp://www.epa.gov/iris


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DISCLAIMER

This document is a preliminary draft for review purposes only. This information is

distributed solely for the purpose of pre-dissemination peer review under applicable

information quality guidelines. It has not been formally disseminated by EPA. It does not

represent and should not be construed to represent any Agency determination or policy.

Mention of trade names or commercial products does not constitute endorsement of

recommendation for use.

This document is a draft for review purposes only and does not constitute Agency policy.

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CONTENTS


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AUTHORS | CONTRIBUTORS | REVIEWERS............................................................................................ vi

PREFACE ............................................................................................................................................... viii

PREAMBLE TO IRIS TOXICOLOGICAL REVIEWS....................................................................................... xi

EXECUTIVE SUMMARY ....................................................................................................................... xxiii

LITERATURE SEARCH STRATEGY | STUDY SELECTION........................................................................ xxvii

1. HAZARD IDENTIFICATION............................................................................................................... 1-1

1.1. Synthesis of Evidence..................................................................................................... 1-1

1.1.1. Respiratory Effects......................................................................................... 1-1

1.1.2. Gastrointestinal Effects................................................................................ 1-12

1.1.3. Reproductive and Developmental Effects ................................................... 1-18

1.1.4. Immune System Effects ............................................................................... 1-19

1.1.5. Other Systemic Effects................................................................................. 1-24

1.1.6. Carcinogenicity............................................................................................. 1-32

1.2. Summary and Evaluation ............................................................................................. 1-35

1.2.1. Effects Other than Cancer............................................................................ 1-35

1.2.2. Carcinogenicity............................................................................................. 1-36

1.2.3. Susceptible Populations and Lifestages ....................................................... 1-36

2. DOSE-RESPONSE ANALYSIS ............................................................................................................ 2-1

2.1. Oral Reference Dose for Effects Other than Cancer ...................................................... 2-1

2.2. Inhalation Reference Concentration for Effects Other than Cancer ............................. 2-2

2.2.1. Identification of Candidate Principal Studies and Critical Effects.................. 2-2

2.2.2. Methods of Analysis....................................................................................... 2-5

2.2.3. Derivation of the Reference Concentration................................................... 2-5

2.2.4. Uncertainties in the Derivation of the Reference Concentration.................. 2-7

2.2.5. Confidence Statement ................................................................................... 2-8

2.2.6. Previous IRIS Assessment: Reference Concentration .................................... 2-8

2.3. Cancer Risk Estimates .................................................................................................... 2-9

REFERENCES........................................................................................................................................ R-1


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TABLES AND FIGURESTable ES-1. Summary of reference concentration (RfC) derivation............................................... xxiv

Table LS-1. Details of the literature search strategy ....................................................................xxviii

Table 1-1. Evidence pertaining to respiratory effects in humans following inhalationexposure....................................................................................................................... 1-6

Table 1-2. Evidence pertaining to respiratory effects in animals following inhalation

exposure....................................................................................................................... 1-9

Table 1-3. Evidence pertaining to gastrointestinal effects in animals following oral exposure..................................................................................................................... 1-15

Table 1-4. Evidence pertaining to reproductive and developmental effects in animalsfollowing inhalation exposure ................................................................................... 1-18

Table 1-5. Evidence pertaining to immune system effects in animals following inhalation

exposure..................................................................................................................... 1-21Table 1-6. Evidence pertaining to other systemic effects in humans following inhalation

exposure..................................................................................................................... 1-26Table 1-7. Evidence pertaining to other systemic effects in animals following oral exposure .. 1-26Table 1-8. Evidence pertaining to other systemic effects in animals following inhalation

exposure..................................................................................................................... 1-27Table 1-9. Evidence pertaining to cancer in animals following oral exposure ........................... 1-34

Figure LS-1. Literature search and study selection strategy for ammonia...................................... xxix

Figure 1-1. Exposure-response array of respiratory effects following inhalation exposure........ 1-11Figure 1-2. Exposure-response array of gastrointestinal effects following oral exposure. ......... 1-16Figure 1-3. Exposure-response array of immune system effects following inhalation

exposure..................................................................................................................... 1-23Figure 1-4. Exposure-response array of systemic effects following inhalation exposure. .......... 1-31Figure 2-1. Exposure-response array of toxicological effects following inhalation exposure. ...... 2-3


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ABBREVIATIONS

ACGIH American Conference of GovernmentalIndustrial Hygienists

ALT alanine aminotransferase

AST aspartate aminotransferaseATSDR Agency for Toxic Substances and Disease

RegistryBCG bacillus Calmette-GurinBMC benchmark concentration

BMD benchmark doseCAC cumulative ammonia concentration

CCRIS Chemical Carcinogenesis ResearchInformation System

CFU colony forming unitEPA Environmental Protection AgencyFDA Food and Drug Administration

FEV1 forced expiratory volume in 1 second

FVC forced vital capacityHERO Health and Environmental Research

OnlineHSDB Hazardous Substances Data Bank

IgE immunoglobulin EIgG immunoglobulin GIRIS Integrated Risk Information System

LC50 50% lethal concentrationLD50 50% lethal doseLOAEL lowest-observed-adverse-effect level

MAO monoamine oxidaseMNNG N-methyl-N-nitro-N-nitrosoguanidine

MRM murine respiratory mycoplasmosis

NCEA National Center for EnvironmentalAssessment

NH3 ammoniaNH4+ ammonium ionNIOSH National Institute for Occupational

Safety and HealthNOAEL no-observed-adverse-effect levelNRC National Research CouncilORD EPAs Office of Research and

Development

PBPK physiologically based pharmacokineticPEF peak expiratory flowPEFR peak expiratory flow ratePOD point of departurePPD purified protein derivativeRD50 50% response doseRfC reference concentrationRfD reference doseRTECS Registry of Toxic Effects of Chemical

Substances

TLV threshold limit valueTSCATS Toxic Substance Control Act Test

Submission DatabaseUF uncertainty factorUFA interspecies uncertainty factorUFH intraspecies uncertainty factorUFL LOAEL to NOAEL uncertainty factorUFS subchronic-to-chronic uncertainty factorUFD database deficiencies uncertainty factorVEh human occupational default minute

volume

VEho human ambient default minute volume


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AUTHORS | CONTRIBUTORS | REVIEWERSAssessment Team

Audrey Galizia, Dr. PH (Chemical Manager)

James Ball, Ph.D.Keith Salazar, Ph.D.Christopher Sheth, Ph.D.Louis DAmico, Ph.D.Christopher Brinkerhoff, Ph.D.

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Scientific Support TeamVincent Cogliano, Ph.D.Samantha Jones, Ph.D.Jamie Strong, Ph.D.Ted Berner, MSJason Fritz, Ph.D.Martin Gehlhaus, MPHJohn Stanek, Ph.D.

U.S. EPAOffice of Research and Development

National Center for Environmental Assessment

Washington, DC

U.S. EPA

Office of Research and Development

National Center for Environmental AssessmentResearch Triangle Park, NC

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Contractor SupportSRC, Inc., Chemical, Biological and Environmental Center, Syracuse, NYAmber Bacom, MSFernando Llados, Ph.D.Julie Stickney, Ph.D.

Executive DirectionVincent Cogliano, Ph.D. U.S. EPALynn Flowers, Ph.D. Office of Research and Development

Samantha Jones, Ph.D. National Center for Environmental Assessment Susan Rieth, MPH Washington, DC


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Internal Review TeamMarian Rutigliano, MDJohn Whalan

Amanda S. Persad, Ph.D.

Paul Reinhart, Ph.D.

U.S. EPAOffice of Research and DevelopmentNational Center for Environmental Assessment

Washington, DC

U.S. EPA

Office of Research and DevelopmentNational Center for Environmental AssessmentResearch Triangle Park, NC

Reviewers

This assessment was provided for review to scientists in EPAs Program and Regional Offices.Comments were submitted by:

Office of Policy, Washington, DC

Office of Water, Washington, DCOffice of Childrens Health Protection, Washington, DCOffice of Transportation and Air Quality in the Office of Air and Radiation, Ann Arbor, Michigan

Office of Air Quality and Planning Standards in the Office of Air and Radiation, Washington, DCRegion 2, New York, New York

This assessment was provided for review to other federal agencies and the Executive Office of thePresident. Comments were submitted by:

Agency for Toxic Substances and Disease Registry, Centers for Disease Control andPrevention, Department of Health & Human Services

Council on Environmental Quality, Executive Office of the PresidentFood Safety and Inspection Service, U.S. Department of Agriculture


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PREFACEThis Toxicological Review critically reviews the publicly available studies on ammonia in

order to identify its adverse health effects and to characterize exposure-response relationships.

The assessment covers gaseous ammonia (NH3) and ammonia dissolved in water (ammonium

hydroxide, NH4OH). It was prepared under the auspices of EPAs Integrated Risk Information

System (IRIS) program.

Ammonia and ammonium hydroxide are listed as hazardous substances under the

Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA) and

ammonia is found at about 8% of hazardous waste sites on the National Priorities List (ATSDR,

2004). Ammonia is subject to reporting requirements for the Toxics Release Inventory under the

Emergency Planning and Community Right-to-Know Act of 1986 and to emergency planning

requirements under section 112(r) of the Clean Air Act.

This assessment updates a previous IRIS assessment of ammonia that was developed in

1991. The previous assessment included only an inhalation reference concentration for effects

other than cancer. New information has become available, and this assessment reviews

information on all health effects by all exposure routes.

This assessment was conducted in accordance with EPA guidance, which is cited and

summarized in the Preamble to IRIS Toxicological Reviews. The findings of this assessment and

related documents produced during its development are available on the IRIS website

(http://www.epa.gov/iris/). Appendices for chemical and physical properties, the toxicity ofammonium salts, toxicokinetic information, summaries of toxicity studies and other information

are provided as Supplemental Information to this assessment (see Appendices A to D).

Portions of this Toxicological Review were adapted from the Toxicological Profile for

Ammonia developed by the Agency for Toxic Substances and Disease Registry (ATSDR, 2004) under

a Memorandum of Understanding that encourages interagency collaboration, sharing of scientific

information, and more efficient use of resources.

On December 23, 2011, The Consolidated Appropriations Act, 2012, was signed into law1.

The report language included direction to EPA for the IRIS Program related to recommendations

provided by the National Research Council (NRC) in their review of EPAs draft IRIS assessment offormaldehyde. The NRCs recommendations, provided in Chapter 7 of their review report, offered

suggestions to EPA for improving the development of IRIS assessments. The report language

included the following:

1Pub. L. No. 112-74, Consolidated Appropriations Act, 2012.


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The Agency shall incorporate, as appropriate, based on chemical-specific datasets

and biological effects, the recommendations of Chapter 7 of the National Research

Councils Review of the Environmental Protection Agencys Draft IRIS Assessment of

Formaldehyde into the IRIS processFor draft assessments released in fiscal year

2012, the Agency shall include documentation describing how the Chapter 7

recommendations of the National Academy of Sciences (NAS) have beenimplemented or addressed, including an explanation for why certain

recommendations were not incorporated.

Consistent with the direction provided by Congress, documentation of how the recommendations

from Chapter 7 of the NRC report have been implemented in this assessment is provided in

Appendix E. This documentation also includes an explanation for why certain recommendations

were not incorporated.

For additional information about this assessment or for general questions regarding IRIS,

please contact EPAs IRIS Hotline at 202-566-1676 (phone), 202-566-1749 (fax), [email protected] .

Chemical Properties and Uses

Ammonia is a corrosive gas with a pungent odor. It is highly soluble in water (up to

482 g/L) and is a weak base (Lide, 2008;O'Neil et al., 2006;Eggeman, 2001;Dean, 1985).

Additional information on the chemical and physical properties of ammonia is presented in

Appendix A.

About 80% of commercially produced ammonia is used in agricultural fertilizers. Ammonia

is also used as a corrosion inhibitor, in water purification, as a household cleaner, as anantimicrobial agent in food products, as a refrigerant, as a stabilizer in the rubber industry, as a

source of hydrogen in the hydrogenation of fats and oils, and as a chemical intermediate in the

production of pharmaceuticals, explosives, and other chemicals. Ammonia is also used to reduce

nitrogen oxide emissions from combustion sources such as industrial and municipal boilers, power

generators, and diesel engines (HSDB, 2012;Johnson et al., 2009;Eggeman, 2001).

Ammonia is a component of the global nitrogen cycle and is essential to many biologic

processes. Nitrogen-fixing bacteria convert atmospheric nitrogen to ammonia that is available for

uptake into plants. Organic nitrogen released from biota can be converted to ammonia. Ammonia

in water and soil can be converted to nitrite and nitrate through the process of nitrification.Ammonia is also endogenously produced in humans and other mammals, where it is an essential

metabolite used in nucleic acid and protein synthesis, is necessary for maintaining acid-base

balance, and is an integral part of nitrogen homeostasis (Nelson and Cox, 2008;Socolow, 1999;

Rosswall, 1981). This assessment compares endogenous levels of ammonia in humans to the

toxicity values that it derives.


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Consideration of Ammonium Salts for Inclusion in This Assessment

EPA considered whether to include ammonium salts (e.g., ammonium acetate, chloride, and

sulfate) in this assessment. These salts readily dissolve in water through dissociation into an

ammonium cation (NH4+) and an anion. Oral toxicity studies on ammonium chloride and

ammonium sulfate suggest that these salts may differ in toxicity (see Appendix B for a summary of

subchronic/chronic toxicity information for selected ammonium salts), but it is not clear whetherthis reflects differences between the salts or in the effects that were studied. If the toxicity of the

salts is affected by the anion, then it would not be correct to attribute toxic effects to the ammonium

cation. ATSDR considered this question and concluded, . . . that it would be inappropriate to

extrapolate findings obtained with ammonium chloride (or any ammonium salt) to equivalent

amounts of ammonium, but derived from a different salt (ATSDR, 2004). Similarly, the World

Health Organization considered ammonium chloride-induced kidney hypertrophy and observed

that the extent to which it results from ammonium chloride-induced acidosis or from a direct effect

of the ammonium ion is not clear (IPCS, 1986). Thus, in light of the uncertain influence of the anion

on toxicity, ammonium salts were not used in the identification of effects or in the derivation ofreference values for ammonia and ammonium hydroxide.

Assessments by Other National and International Health Agencies

Toxicity information on ammonia has been evaluated by ATSDR, the National Research

Council, the American Conference of Governmental Industrial Hygienists, the National Institute for

Occupational Safety and Health, and the Food and Drug Administration. The results of these

assessments are presented in Appendix C. It is important to recognize that these earlier

assessments were prepared for different purposes using different methods and could consider only

the studies that were available at the time.


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PREAMBLE TO IRIS TOXICOLOGICAL REVIEWS1. Scope of the IRIS Program

Soon after EPA was established in 1970, it was

at the forefront of developing risk assessment as ascience and applying it in decisions to protecthuman health and the environment. The Clean Air

Act, for example, mandates that EPA provide an

ample margin of safety to protect public health;the Safe Drinking Water Act, that no adverseeffects on the health of persons may reasonably be

anticipated to occur, allowing an adequate marginof safety. Accordingly, EPA uses information onthe adverse effects of chemicals and on exposure

levels below which these effects are not anticipatedto occur.

IRIS assessments critically review the publicly

available studies to identify adverse health effects

from long-term exposure to chemicals and tocharacterize exposure-response relationships. Anassessment may cover a single chemical, a group of

structurally or toxicologically related chemicals, or

a complex mixture. Exceptions are chemicalscurrently used exclusively as pesticides, ionizing

and non-ionizing radiation, and criteria air

pollutants listed under section 108 of the Clean AirAct (carbon monoxide, lead, nitrogen oxides, ozone,

particulate matter, and sulfur oxides; EPAsIntegrated Science Assessments evaluate the effectsfrom these pollutants in ambient air).

Periodically, the IRIS Program asks other EPA

programs and regions, other federal agencies, state

government agencies, and the general public tonominate chemicals and mixtures for futureassessment or reassessment. These agents may be

found in air, water, soil, or sediment. Selection isbased on program and regional office priorities andon availability of adequate information to evaluate

the potential for adverse effects. IRIS may assessother agents as an urgent public health need arises.

IRIS also reassesses agents as significant newstudies are published.

2. Process for developing and peer-reviewingIRIS assessments

The process for developing IRIS assessments

(revised in May 2009) involves critical analysis ofthe pertinent studies, opportunities for publicinput, and multiple levels of scientific review. EPA

revises draft assessments after each review, and

external drafts and comments become part of thepublic record (U.S. EPA, 2009).

Step 1. Development of a draft Toxicological

Review (usually about 11-1/2 monthsduration). The draft assessment considers all

pertinent publicly available studies and applies

consistent criteria to evaluate the studies,identify health effects, weigh the evidence ofcausation for each effect, identify mechanistic

events and pathways, and derive toxicityvalues.

Step 2. Internal review by scientists in EPA

programs and regions (2 months). The draftassessment is revised to address commentsfrom within EPA.

Step 3. Interagency science consultation with

other federal agencies and the ExecutiveOffices of the President(1-1/2 months). The

draft assessment is revised to address theinteragency comments. The science

consultation draft, interagency comments, andEPAs response to major comments becomepart of the public record.

Step 4. External peer review, after public

review and comment(3-1/2 months or more,depending on the review process). EPAreleases the draft assessment for public reviewand comment, followed by external peer

review. The peer review meeting is open to the

public and includes time for oral publiccomments. The peer reviewers also receive thewritten public comments. The peer reviewers

assess whether the evidence has beenassembled and evaluated according toguidelines and whether the conclusions are

justified by the evidence. The peer review

draft, peer review report, and written public

comments become part of the public record.

Step 5. Revision of draft Toxicological Review

and development of draft IRIS summary(2 months). The draft assessment is revised toreflect the peer review comments, public

comments, and newly published studies that

are critical to the conclusions of theassessment. The disposition of peer review


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comments and public comments becomes partof the public record.

Step 6. Final EPA review and interagency

science discussion with other federalagencies and the Executive Offices of thePresident (1-1/2 months). The draft

assessment and summary are revised to

address EPA and interagency comments. Thescience discussion draft, written interagencycomments, and EPAs response to major

comments become part of the public record.

Step 7. Completion and posting (1 month). TheToxicological Review and IRIS summary areposted on the IRIS website (http://

www.epa.gov/iris/).

The remainder of this Preamble addresses step1, the development of a draft Toxicological Review.

IRIS assessments follow standard practices of

evidence evaluation and peer review, many ofwhich are discussed in EPA guidelines (U.S. EPA,

2005a, b, 2000b, 1998, 1996, 1991, 1986a, b) andother methods (U.S. EPA, 2011b, 2006a, b, 2002,2000a,1994). Transparent application of scientific

judgment is of paramount importance. To provide aharmonized approach across IRIS assessments, thisPreamble summarizes concepts from these

guidelines and emphasizes principles of general

applicability.

3. Identifying and selecting pertinent studies3.1. Identifying studies

Before beginning an assessment, EPA conductsa comprehensive search of the primary scientificliterature. The literature search follows standard

practices and includes the PubMed and ToxNetdatabases of the National Library of Medicine andother databases listed in EPAs HERO system

(Health and Environmental Research Online,http://hero.epa.gov/). Each assessment specifies

the search strategies, keywords, and cut-off datesof its literature searches. EPA posts the results of

the literature search on the IRIS website andrequests information from the public on additional

studies and ongoing research.EPA also considers studies received throughthe IRIS Submission Desk and studies (typically

unpublished) submitted under the ToxicSubstances Control Act. Material submitted asConfidential Business Information is considered

only if it includes health and safety data that can bepublicly released. If a study that may be critical to

the conclusions of the assessment has not beenpeer-reviewed, EPA will have it peer-reviewed.

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rcet

(U

.S. EPA, 2000b,1986b):

ence

Studies of the mixture being assessed.

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r


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13/83

aenv

nd airo

rnme c

eontns

aidl e

exrped m

osureos

.t pertinent to human

I

c

n

o

je

ns

c

i

ti

d

on

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or

d

im

less

p

p

la

e

n

r

ta

tin

tio

en

n

t

s

b

tu

ut

die

ma

s a

y

re often

vin

aflouramable

tiotoxic

n. Theoky a

inelstico ma

ory b

me

provide

identifying effects in animals if de

e uscehfuan

l fistic

or

apbarstorcption is

o

i s andle ibp

position r

f errosb).lematic (for example, for

cons

E os

studie

ide

xp

ratio

ure du

s.

n for s

ra

e

tio

lec

n

ti

is

ng p

a

er

l

tin

so a

ent e

k

xp

ey

erim

des

en

i

ta

gn

l

mosStudi

t pes

eof

rtineefnfet to

ctsl

fif

reom ctime h

huron

maicn

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are

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search involving uman sucbhjaen

ls

is

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ly if conducted according to eth

cts

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ity

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ccordingly, specialized study designs are

4.ese

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e

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(U

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he

P

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d

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ivid

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u

9

a

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.

tud

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ies

)or

4.1. E

T

v

he as

aluatin

se

g

s

the qustudies

smen

ts th

t

alit

at c

ev

y of epidemiologic

a

alu

n in

at

c

e

r

s

e

d

ase o

es

r

i

d

gn

e

an

creas

d

e

o

meth

v

eth

9e

wodologic aspec

1

9rall e

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v

t g

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iv

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en

io

to e

n (U

ac

.S

h

. E

ep

P

i

A

de

, 2

mi

0

ol

0

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5

in

4,1991):a, 199

dy

8, 19

th

96

e

,

p

D

op

oc

u

u

l

me

ation

nta

c

tio

ha

n

r

of

acte

s

ris

tu

tic

dy

s, an

de

d r

s

e

ig

s

n

u

,

l

m

ts.

ethods,

Dcomp

efinitioaris

no

an p

nod spula

etionlecti

son.

of the study and

A

for

sc

mis

erta

c

in

la

me

ssif

n

ic

t of

ation

ex

.

posure and the potential

pA

otesce

nrta

tiainl f

meor

nmist of

cld

assisif

eicaastione or

.effect and the

Dad

uera

effeq

tion

cts

ua, icny

off a

e e and follow-up an

luodinr

xposur d

c g lsseate

ssint

negffec

thtse o.

ccurrence of

Characterization of exposure during critical

periods.

Sa

an

mpticip

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ste

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izd e

e

xi

aff

c

e

o

nc

l

d sts

o

.

gi

ta

cal

tistic

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a

v

l p

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ow

o

e

f

r

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to d

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for

ar

s

tic

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ec

a

tio

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b

r

ia

a

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s and the resulting potential

bP

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ntiffou

iend a

dinn

gd a

addrnd oth

esseed in

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setus of

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i

id

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er

th

atio

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naly

of c

sis of

on

r

f

e

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su

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peraesvonalen

abtle

inexpectation that the con

dinfou

g is a

ee p

nd

both x osuret

ah

er is

p nd ouop

tculat

omeion

.and is related to

toxicFityor

, nedeur

votoelop

xicm

ityen

, atal

ndtoxiccance

ityr th

,erreep

isro

fduur

cthtiv

ee

gep

uidida

emnc

iole

ogonic s

the nuances of evaluating

r

2

4

0

.2

stu

0

. E

5a

v

,1

a

9

lu

9

a

8

t

,

in

19

g

9tu

t

6

h

die,

e

1

qu

9s

dies

9of1)

t.

hese effects (U.S. EPA,

methTohdole aogicsseassment

alit

ev

y

a

o

lu

f

a

ex

te

p

s d

erim

e

e

si

n

g

t

n

al

and

thov

e weight give

s

n

p

to

ects

ea

th

ch

a

e

t c

xp

an

er

in

im

c

e

re

n

a

ta

s

l

e

s

o

tu

r d

dy

e

i

cr

n

e

th

as

e

e

1

9

e9r4all e,199

v1alu):

ation (U.S. EPA, 2005a, 1998, 1996,

D umen tion f stu

rstu

oc ta o

esudy

lts.population, meth

dy

o

d

ds

e

,

s

b

ig

a

n

s

,

ic

an

da

ima

ta,

ls

a

or

nd

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ex

e

p

le

er

van

im

c

en

e t

ta

o

l

h

m

u

et

m

h

an

od

s

s

o

.

f the animal model and

impChar

uarcitieter

siz

aatio e

a e h

nn

dminister e

d cof th

mical

o

or

ntana

d c mi

minture and extent of

xtu

a

r

n

e

ts

.

of the

C(in

hacrlua

dincter

gizaagtioe a

nt

oexp

f dososu

e and dosing regimen

to elicit adverse effects, in

re

c

)

lu

an

din

d t

g l

h

a

e

t

i

e

r ad

nt e

eq

ffe

u

c

ac

ts

y

.

Sdos

ampe-r

leel

sat

ized

esd

aif

nfer

d sen

taces

tisotic

r tarl pen

owds.

er to detect

o

A

r

sc

ef

e

f

r

ec

ta

t

in

s,

me

an

n

d

t

ca

of s

use o

urv

f d

iv

ea

al,

th

v

.

ital signs, disease

th

Con

e oc

trol

cu

of

rr

oth

ence

e

of

r v

e

ar

ffe

iab

cts

le

.

s that could influence

evalThe assessment uses statistical tests to

c

sig

ha

n

nucaete. T

wh

he

esth

tae

nr th

dared f

obosrervations may be du

ificance of a response

de

is

te

a

rmin

tr

in

e

g

n

s

d te

tatistice t

aol

ca

ompgains

at thrison

osofe

ouof c

tcoom

nceusr

i

situation ,

rn th

st or

s examination of

ent ce

histor

onetrxp

oloss.

eId g

n srou

ical control da

omp

es

fsrtuom th

dy mae s

yaimpme l

raov

boe th

ratore a

yna

wlyith

sin a few years of th

ta

nis. For an uncommoe

effect that is not statistically significant compared

with concurrent controls, historical controls may


xiii DRAFTDO NOT CITE OR QUOTE
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show that the effect is unlikely to be due to chance.For a response that appears significant against aconcurrent control response that is unusual,

historical controls may offer a differentinterpretation (U.S. EPA, 2005a).

For developmental toxicity, reproductive

toxicity, neurotoxicity, and cancer there is furtherguidance on the nuances of evaluating

experimental studies of these effects (U.S. EPA,2005a, 1998, 1996, 1991). In multi-generation

studies, agents that produce developmental effectsat doses that are not toxic to the maternal animalare of special concern. Effects that occur at doses

associated with mild maternal toxicity are notassumed to result only from maternal toxicity.Moreover, maternal effects may be reversible,

while effects on the offspring may be permanent

(U.S. EPA, 1998,1991).

4.3. Reporting study results

The assessment uses evidence tables to

summarize details of the design and key results ofpertinent studies. There may be separate tables foreach site of toxicity or type of study.

If a large number of studies observe the same

effect, the assessment considers the studycharacteristics in this section to identify thestrongest studies or types of study. The tables

report details from these studies, and the

assessment explains the reasons for not reportingdetails of other studies or groups of studies that donot add new information. Supplemental material

provides references to all studies considered,including those not summarized in the tables.

The assessment discusses strengths andlimitations that affect the interpretation of eachstudy. If the interpretation of a study in the

assessment differs from that of the study authors,the assessment discusses the basis for thedifference.

As a check on the selection and evaluation ofpertinent studies, EPA asks peer reviewers to

identify studies that were not adequatelyconsidered.

5. Weighing the overall evidence of each effect

5.1. Weighing epidemiologic evidenceFor each effect, the assessment evaluates the

evidence from the epidemiologic studies as a wholeto determine the extent to which any observedassociations may be causal. Positive, negative, and

null results are given weight according to studyquality. This evaluation considers aspects of an

association that suggest causality, discussed byHill(1965) and elaborated byRothman and Greenland

(1998)(U.S. EPA, 2005a;CDC, 2004;U.S. EPA, 2002,1994).

Strength of association: The finding of a large

relative risk with narrow confidence intervals

strongly suggests that an association is not dueto chance, bias, or other factors. Modestrelative risks, however, may reflect a small

range of exposures, an agent of low potency, anincrease in an effect that is common, exposuremisclassification, or other sources of bias.

Consistency of association: An inference of

causality is strengthened if elevated risks areobserved in independent studies of differentpopulations and exposure scenarios.

Reproducibility of findings constitutes one ofthe strongest arguments for causality.

Discordant results sometimes reflectdifferences in study design, exposure, or

confounding factors.

Specificity of association: As originally intended,this refers to one cause associated with oneeffect. Current understanding that many agentscause multiple effects and many effects have

multiple causes make this a less informativeaspect of causality, unless the effect is rare orunlikely to have multiple causes.

Temporal relationship: A causal interpretation

requires that exposure precede development of

the effect.

Biologic gradient (exposure-response relation-

ship): Exposure-response relationships

strongly suggest causality. A monotonicincrease is not the only pattern consistent withcausality. The presence of an exposure-

response gradient also weighs against bias andconfounding as the source of an association.

Biologic plausibility: An inference of causality isstrengthened by data demonstrating plausiblebiologic mechanisms, if available.

Coherence: An inference of causality is

strengthened by supportive results fromanimal experiments, toxicokinetic studies, andshort-term tests. Coherence may also be found

in other lines of evidence, such as changingdisease patterns in the population.

Natural experiments: A change in exposure thatbrings about a change in disease frequency

provides strong evidence of causality, forexample, an intervention to reduce exposure inthe workplace or environment that is followed

by a reduction of an adverse effect.


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Analogy: Information on structural analogues oron chemicals that induce similar mechanisticevents can provide insight into causality.

These considerations are consistent with

guidelines for systematic reviews that evaluate thequality and weight of evidence. Confidence is

increased if the magnitude of effect is large, if there

is evidence of an exposure-response relationship,or if an association was observed and the plausiblebiases would tend to decrease the magnitude of the

reported effect. Confidence is decreased for study

limitations, inconsistency of results, indirectness ofevidence, imprecision, or reporting bias (Guyatt et

al., 2008a;Guyatt et al., 2008b).

To make clear how much the epidemiologicevidence contributes to the overall weight of the

evidence, the assessment may choose a descriptor

such as sufficient evidence, suggestive evidence,

inadequate evidence, or evidence suggestive of nocausal relationship to characterize the

epidemiologic evidence of each effect(CDC, 2004).5.2. Weighing experimental animal evidence

For each effect, the assessment evaluates theevidence from the animal experiments as a whole

to determine the extent to which they indicate apotential for effects in humans. Consistent resultsacross various species and strains increase

confidence that similar results would occur in

humans. Several concepts discussed byHill (1965)are pertinent to the weight of experimental results:

consistency of response, dose-response

relationships, strength of response, biologic

plausibility, and coherence (U.S. EPA, 2005a,2002,1994).

In weighing evidence from multipleexperiments, (U.S. EPA, 2005a) distinguishes

Conflicting evidence (that is, mixed positive andnegative results in the same sex and strainusing a similar study protocol) from

Differing results (that is, positive results and

negative results are in different sexes or strainsor use different study protocols).

Negative or null results do not invalidate positive

results in a different experimental system. EPA

regards all as valid observations and looks tomethodological differences or, if available,

mechanistic information to reconcile differing

results.It is well established that there are critical

periods for some developmental and reproductive

effects. Accordingly, the assessment determines

whether critical periods have been adequatelyinvestigated (U.S. EPA, 2006b, 2005a, b, 1998,

1996,1991). Similarly, the assessment determines

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etween the test animals andhumans. Site concordance is not assumed


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between animals and humans, though it mayhold for certain effects or modes of action.Information suggesting quantitative

differences in doses where effects would occurin animals or humans is considered in thedose-response analysis but is not us

Toxicological Review of Ammonia - Draft June 2012

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