of 83
7/29/2019 Toxicological Review of Ammonia - Draft June 2012
1/83
DRAFT - DO NOT CITE OR QUOTE
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/iris7/29/2019 Toxicological Review of Ammonia - Draft June 2012
2/83
Toxicological Review of Ammonia
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.
ii DRAFTDO NOT CITE OR QUOTE
7/29/2019 Toxicological Review of Ammonia - Draft June 2012
3/83
Toxicological Review of Ammonia
CONTENTS
This document is a draft for review purposes only and does not constitute Agency policy.
iii DRAFTDO NOT CITE OR QUOTE
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
7/29/2019 Toxicological Review of Ammonia - Draft June 2012
4/83
Toxicological Review of Ammonia
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
This document is a draft for review purposes only and does not constitute Agency policy.
iv DRAFTDO NOT CITE OR QUOTE
7/29/2019 Toxicological Review of Ammonia - Draft June 2012
5/83
Toxicological Review of Ammonia
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
This document is a draft for review purposes only and does not constitute Agency policy.
v DRAFTDO NOT CITE OR QUOTE
7/29/2019 Toxicological Review of Ammonia - Draft June 2012
6/83
Toxicological Review of Ammonia
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.
O
U
Nat
.
f
S.
fiic
E
oen
PA
oal Cf Res
eneater
rcfho
ar E
ndn
Dvir
evon
elmo
enpm
tal Aent
Edison, NJ
ssessment
U.S.
NatOffi
icE
oePA
noal Cf Research and Dev
Washingto
e
n,
n
D
ter
C
for Environel
mo
enpm
tal Aent
ssessment
O
fe
a
ll
k
ow
Ridge Institute for Science and Education
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
Production Team
V
M
ic
au
ki S
ree
oto
n Johnson
WNat
U
O
.
f
S.
a
fi
sic
E
o
h
en
PA
i
o
ng
al Cf R
to
ese
n,
nea
D
ter
C
rcfho
ar E
ndn
Dvir
evon
elmo
enpm
tal Aent
ssessment
Ellen F. Lorang, MA
Nat
R
OU
e
.fS.f
s
i
i
c
e
E
o
e
ar
n
PAo
al C
c
f
h
R
T
es
e
r
n
i
ea
an
ter
r
g
c
f
le
h
o
a
P
r E
n
a
d
n
rk,
D
vi
NC
r
ev
on
el
m
o
en
pm
tal
en
A
t
ssessment
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
This document is a draft for review purposes only and does not constitute Agency policy.
vi DRAFTDO NOT CITE OR QUOTE
7/29/2019 Toxicological Review of Ammonia - Draft June 2012
7/83
Toxicological Review of Ammonia
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
This document is a draft for review purposes only and does not constitute Agency policy.
vii DRAFTDO NOT CITE OR QUOTE
7/29/2019 Toxicological Review of Ammonia - Draft June 2012
8/83
Toxicological Review of Ammonia
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.
This document is a draft for review purposes only and does not constitute Agency policy.
viii DRAFTDO NOT CITE OR QUOTE
http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://www.epa.gov/irishttp://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://www.epa.gov/irishttp://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=1921167/29/2019 Toxicological Review of Ammonia - Draft June 2012
9/83
Toxicological Review of Ammonia
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.
This document is a draft for review purposes only and does not constitute Agency policy.
ix DRAFTDO NOT CITE OR QUOTE
mailto:[email protected]://hero.epa.gov/index.cfm?action=search.view&reference_id=679766http://hero.epa.gov/index.cfm?action=search.view&reference_id=679766http://hero.epa.gov/index.cfm?action=search.view&reference_id=679766http://hero.epa.gov/index.cfm?action=search.view&reference_id=999438http://hero.epa.gov/index.cfm?action=search.view&reference_id=999438http://hero.epa.gov/index.cfm?action=search.view&reference_id=999438http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=46951http://hero.epa.gov/index.cfm?action=search.view&reference_id=46951http://hero.epa.gov/index.cfm?action=search.view&reference_id=46951http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006149http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006149http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006149http://hero.epa.gov/index.cfm?action=search.view&reference_id=839940http://hero.epa.gov/index.cfm?action=search.view&reference_id=839940http://hero.epa.gov/index.cfm?action=search.view&reference_id=839940http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=999437http://hero.epa.gov/index.cfm?action=search.view&reference_id=999437http://hero.epa.gov/index.cfm?action=search.view&reference_id=999437http://hero.epa.gov/index.cfm?action=search.view&reference_id=994050http://hero.epa.gov/index.cfm?action=search.view&reference_id=994050http://hero.epa.gov/index.cfm?action=search.view&reference_id=994050http://hero.epa.gov/index.cfm?action=search.view&reference_id=37032http://hero.epa.gov/index.cfm?action=search.view&reference_id=37032mailto:[email protected]://hero.epa.gov/index.cfm?action=search.view&reference_id=37032http://hero.epa.gov/index.cfm?action=search.view&reference_id=994050http://hero.epa.gov/index.cfm?action=search.view&reference_id=999437http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=839940http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006149http://hero.epa.gov/index.cfm?action=search.view&reference_id=46951http://hero.epa.gov/index.cfm?action=search.view&reference_id=999434http://hero.epa.gov/index.cfm?action=search.view&reference_id=999438http://hero.epa.gov/index.cfm?action=search.view&reference_id=6797667/29/2019 Toxicological Review of Ammonia - Draft June 2012
10/83
Toxicological Review of Ammonia
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.
This document is a draft for review purposes only and does not constitute Agency policy.
x DRAFTDO NOT CITE OR QUOTE
http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=192116http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006338http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006338http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006338http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006338http://hero.epa.gov/index.cfm?action=search.view&reference_id=1921167/29/2019 Toxicological Review of Ammonia - Draft June 2012
11/83
Toxicological Review of Ammonia
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
This document is a draft for review purposes only and does not constitute Agency policy.
xi DRAFTDO NOT CITE OR QUOTE
http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006151http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006151http://hero.epa.gov/index.cfm?action=search.view&reference_id=1006151http://hero.epa.gov/index.cfm?action=search.view&reference_id=10061517/29/2019 Toxicological Review of Ammonia - Draft June 2012
12/83
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.
agen
E
t t
PA
o id
als
e
o e
To
ntif
xi
xa
y
c
oth
mi
ol
n
o
e
g
e
s
r
i
th
c
cal
h
e
e
to
R
mic
ev
xic
ie
ok
w
in
of
e
A
tic
m
s of
mo
th
nia
e
maass
joressme
mentat i
bolites of the agent)atols (
infcorlu
ede
xaimpn th
lee,
aor
ndd to s
er to moug
r
f
e
adequate information is available, in
modeling.g
fes
ut dlly e
osxp
el
main t
ehtreic
toxics fo
ityr s
ofu
thbs
ee
aqu
geen
ntt
studie
In
s a
ass
r
e
e
s
p
sme
ref
n
e
ts
rre
o
d f
f chemical mixtu
interactions among compor
onth
ee
nir
tsa.bility
re
to r
s, mix
e
ture
search seeks, in decreasing order oTh
fe
plrite
efe
rra
ftule
rcet
(U
.S. EPA, 2000b,1986b):
ence
Studies of the mixture being assessed.
e
S
v
tu
a
di
lu
e
a
s
tin
of
g s
a
imil
su
a
f
r
f
ity
icie
, th
ntl
e
y
a
s
ss
imil
essme
ar mixtu
nt cons
re
ide
. In
thth
erou
algteh
rpatio
titn
r
arof mixtu
s
ioning and trres
ainns
thfor
emaen
tionviro
.nment
3.2. S
th
Stu
ofels
e mix
dies of
tur
in
e, if
div
th
idual chemical components of
uecffic
tinie
gn
ptl
ery s
timil
er
a
e
r
a
m
r
ixtu
e no
re
t a
s.
dequate studies
selecStintudy
g pd
eretinsig
enn
ist
in
epth
ent
e
ep
k
id
ey
em
c
io
on
lo
sid
gic
res
ults of the literature s
ide
ea
mi
rc
ol
h
og
.
ic studiee
sr
s
af
t
tior
u
om
d
n
ies
fth
ore
Cpr
ohov
orid
t se th
tue
distr
eos a
ngenst e
d c
a
pida
ese
miol-con
ogtr
icol s
evidtu
edie
s th
nces,
expos
e
u
y
r
c
es
ol
an
le
d
ct
eff
in
ec
for
ts.
mation about individual
E
g
stc
e
uol
o
dogies)
ic sr
tudies (geographic correlation
evi graphic a
ela
re
te
a.
ex
T
p
h
o
e
s
y
u
c
res
an p
an
r
d
ovi
ef
de
fec
s
ts
tro
b
ng
y
ebet
dw
eneen
ce igf t
eho
eg
rre aaph
rie lc ar
argeeas
ex, r
poeslatur
ie cvely
onli
tratsttles
p
xp
op
os
ula
u
tion
re v
mig
aria
r
t
a
ion
tion
w
is
ith
lim
in
it
s
ed.
tudy areas, and
l
C
a
a
c
s
k
e r
fexpec
de
e
tedin
por
iti
ts
nuonm
o
of
bef
h
th
ig
r oef
p
h o
cop
r
u
a
la
c
tion
cide
a
n
t
ta
r
l
is
e
k a
xp
n
os
d
u
th
r
e
e
in
re
f
l
o
ev
rma
anc
tio
e of
n abo
na
ouases. They can pr vide
a log
t a
ou
r
s r
ar
e
e
s
e
ults
ffe
in
ct or
anima
ab
l
ou
s.
t the
studieTh
sea
and c
ssaesssm
they suggest
e
e
r
ff
eepnort
tsb
bri
uefly reviews ecologic
3
ep
.3
id
. S
em
el
iol
ec
og
tin
ic
g
s
p
tu
er
die
t
e
in
csts.
e
n
nt ex
ot ide
t rep
n
or
tif
ts
i
d
ed b
etail
y
s
oth
only
e
if
r
for sEexplec
ostin
urge
preourtin
tee
isnt
ae
kxp
eey
p
rde
er
ime
im
snig
en
tan c
l
t
s
a
ontu
l st
sdiid
u
e
d
esr
ies
fartioom
n
th
e results of the literature search.
S
in
tu
vol
di
v
e
e
s
p
of
as
or
sa
a
g
l,
e
in
th
h
r
a
ou
latio
gh a
n,
n
or
a
d
bs
e
or
rma
ption
l exp
ba
os
rr
u
ie
re
r
This document is a draft for review purposes only and does not constitute Agency policy.
xii DRAFTDO NOT CITE OR QUOTE
http://www.epa.gov/irishttp://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=88823http://hero.epa.gov/index.cfm?action=search.view&reference_id=88823http://hero.epa.gov/index.cfm?action=search.view&reference_id=88823http://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://hero.epa.gov/index.cfm?action=search.view&reference_id=752972http://hero.epa.gov/index.cfm?action=search.view&reference_id=752972http://hero.epa.gov/index.cfm?action=search.view&reference_id=752972http://hero.epa.gov/index.cfm?action=search.view&reference_id=194568http://hero.epa.gov/index.cfm?action=search.view&reference_id=194568http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=52150http://hero.epa.gov/index.cfm?action=search.view&reference_id=52150http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http:///reader/full/http://hero.epa.govhttp://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://www.epa.gov/irishttp:///reader/full/http://hero.epa.govhttp://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=52150http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194568http://hero.epa.gov/index.cfm?action=search.view&reference_id=752972http://hero.epa.gov/index.cfm?action=search.view&reference_id=1468http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=1065850http://hero.epa.gov/index.cfm?action=search.view&reference_id=88823http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=862377/29/2019 Toxicological Review of Ammonia - Draft June 2012
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
ere
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
eexp
xposos
uu
rree.
are
Sex
tu e
s
pdi s of
reffec
tudi
os
es
ur
o
e a
f ch
e p
ron
e
i
r
c
titsne
fnt b
romut l
les
essps-rthefer
anr-edch
exposure.
tro
hnian
c
huma
Sh
n
o
s
rt
ma
-dura
information.yRp
tion
rovi
s
de
tu
toxic
dies
ok
in
in
v
e
ol
tic
vin
or
g
e h m
an
e
ima
search involving uman sucbhjaen
ls
is
or
tic
p
con
rinc
side
ipl
r
e
e
s
d on
.
ly if conducted according to eth
cts
ic
is
al
toxic
F
ity
or
,
de
irre
v
v
e
e
lop
rsi
m
bl
e
e
n
e
ta
ff
l toxicity a rep
e n
e
nd
xposur duri g a critic
c
roduct
e a
ts
l
ma
period
y re
of d
sult f
e
r
v
om a
elopm
b
e
r
ive
n
ie
t.
f
Ath
ccordingly, specialized study designs are
4.ese
E
e
va
ff
l
e
u
c
a
ts
tin
(U
g
.S
t
. E
he
P
qu
A, 20
alit
0
y o
6b,
f i
1
n
9
d
9
ivid
8,19
u
9
a
6
l s
,u19
s9ed
.
tud
1f
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
eigh
v
t g
alu
iv
at
en
io
to e
n (U
ac
.S
h
. E
ep
P
i
A
de
, 2
mi
0
ol
0
ogic stu
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
lea
ste
To
izd e
e
xi
aff
c
e
o
nc
l
d sts
o
.
gi
ta
cal
tistic
Re
a
v
l p
iew
ow
o
e
f
r
A
to d
mmo
et
nia
ect
P
for
ar
s
tic
el
ip
ec
a
tio
tio
n
n
b
r
ia
a
s
te
.
s and the resulting potential
bP
deiaote
s antia
re idel con
ntiffou
iend a
dinn
gd a
addrnd oth
esseed in
r sthou
erc
setus of
dy
fror
sign
c
or
ons
i
id
n
er
th
atio
e a
n
naly
of c
sis of
on
r
f
e
ou
su
n
lts. The basis
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
R
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
This document is a draft for review purposes only and does not constitute Agency policy.
xiii DRAFTDO NOT CITE OR QUOTE
http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=1945677/29/2019 Toxicological Review of Ammonia - Draft June 2012
14/83
Toxicological Review of Ammonia
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.
This document is a draft for review purposes only and does not constitute Agency policy.
xiv DRAFTDO NOT CITE OR QUOTE
http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=86599http://hero.epa.gov/index.cfm?action=search.view&reference_id=86599http://hero.epa.gov/index.cfm?action=search.view&reference_id=86599http://hero.epa.gov/index.cfm?action=search.view&reference_id=86599http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86599http://hero.epa.gov/index.cfm?action=search.view&reference_id=86599http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=862377/29/2019 Toxicological Review of Ammonia - Draft June 2012
15/83
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
cw
rhitic
ethal
esr thites
eada
To
ndta
xi
eb
c
faf
o
esc
l
e
o
tsis
g
.a
ic
de
al
q
R
u
e
a
v
te
ie
to
w
e
o
v
f
a
A
lu
m
ate
m
oth
onia
er
In evaluating evidence of genotoxicity:
c
D
h
e
r
mo
omos
nstr
om
ati
e
on
aberr
of
ations,
ge
or
ne
aneu
mu
ploidy
tations,
in vi
ivo
n
p
hu
ro
ma
vid
n
es
s
t
or
he s
e
t
x
r
p
o
e
n
r
g
im
es
e
t
n
ev
ta
i
l
d
ma
ence.
mmals ( )
orTh
gisa
isnis
fms
ol ow e
g
l d by pos
other eor i
e itiv results in
netic evn
ecnutsltu.
red cells (
Negative results carry less w
in
e
v
ig
it
h
r
t
ol
) o
owr for
er
beca
, partly
effecuts
sien
thoth
eye
cr
atisnn
sotues
exc(IA
luRdCe, 2
th0
e0
p6)
os.
sibility of
cate
For germ-cell muta
resugltsor
ofies of
he
umavi
nde
gnc
ee
g
, r
enic
an
ity
gin
, E
g f
PA
r
h
om p
as d
os
ef
i
i
tiv
ned
e
1ne
3
ga
rm-ce
5
9
.
8
. C
6tiva
h
).e
a
r
ra
e
c
su
ter
lts
iz
f
in
or
g
a
m
ll e
o
f
d
fe
e
c
s
ts
o
o
ll
f
mu
conc
ta
ern
gen
(U
ic
.
ity
S. E
t
PA
o
,
avail
F
a
or
bl
e
e in
ach
for
e
ma
ffect, the ss
as d
tion o
(
n
a
sociate
its
esf
men
m
sactio
odes of ac
s
n cu
ti
ss
on
key events key event
t dis es th
and
e
o
m
b
a
s
r
e
k
rv
er
a
s o
ble
f su
, n
c
e
h
ce
st
ss
e
a
p
ry
s;
p
m
re
ode
cursor s
ofop
kerat
eyi
eonal an
ventsd
iannv
atolovmin
icg
cih
o
nante
f a
gre
ct
b
io
teienp
g mpir
b
s oe
ein
r b
g a
i
s
oilcoally
er
g
ies
ic
. P
sca
disease)
,tionan
n
d rwes
ithult
cin
eglilsn,
a
fr
r
om
e s
s
tr
tu
uc
di
tu
e
e
s
r
o
ti
f
n
m
en
e
t in
tabol
for
ite
m
s
a
or
tion may also come
mechanismsra
. Ill
ny
fso
imilrma
atior o
nrotnh
modat a
of
c
c
t th
omp
rou
ou
gh
n
s
ds
imil
tha
r
e of actionar
t
e
is not
relat
quire
Tedh
t
d
ao
f
ean
or a
ag
c
e
on
nt
c
(
lus
ssessmentU
a.S
ion
EP
t
d. A
h
sse,
a
2
t a
dre00
n
5
e
a)
f
.
fect is causally
about each hypothesized mode
s se
of a
v
c
e
tio
ral q
200
5
Is t
a).
he hypothesized mode o
n
f a
(U
u
.
e
S.
stions
(1) c
E
ti
PA
on
,
su
to aStro
fficng
mod
iensu
tplypo
ertsu
fofop
r aa
pokr
c
tetio
edy e
nv
c
ien tnt
abn c
eseing
t
omenaenc
f
imess
aalrys?
ex
mode
peri
of
m
a
en
c
t
tion
al c
,
h
in
all
w
en
h
g
ic
er
s
to
tudie
the hypoth
p
es
p
i
r
zom
s that su e
ed
ss
aS
kup
epyor
etve
fornt
h
strengthene
oba mo
serdeve s
ofup
apcrtionession
isof
d b
mthe
on
aninefg
fe u
ec
y c
f llty.
ere
xppl
eicrimate
eenta
xple
modrime
els nt r
n,iste esults in diffe
tss mu
in thch
emorsa
e so thanrebnyt
c
Is t
a
a
ss
u
e
h
s
s
a
e h
s
lity
me
yp
in
n
o
t ma
a
th
ddr
es
y
iz
e
c
s
ed
s
on
in
m
g
sid
t
o
h
e
d
is
r
e
q
v
o
u
a
f a
e
r
s
ioume model T
ti
s a. he
spects of
on.
(2)
dif
teove
f
h
e
n
r
uts to id
Tehnetif
ays
cses
rsiticme
anl s
t rimilevct
iioewa
n
riti
rs
el
eth
s
ev
ae k
a
neyn
d
t
e
man
es
s
nc b
?
etween the test animals andhumans. Site concordance is not assumed
This document is a draft for review purposes only and does not constitute Agency policy.
xv DRAFTDO NOT CITE OR QUOTE
http://hero.epa.gov/index.cfm?action=search.view&reference_id=783306http://hero.epa.gov/index.cfm?action=search.view&reference_id=783306http://hero.epa.gov/index.cfm?action=search.view&reference_id=783306http://hero.epa.gov/index.cfm?action=search.view&reference_id=783306http://hero.epa.gov/index.cfm?action=search.view&reference_id=783307http://hero.epa.gov/index.cfm?action=search.view&reference_id=783307http://hero.epa.gov/index.cfm?action=search.view&reference_id=783307http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=88823http://hero.epa.gov/index.cfm?action=search.view&reference_id=88823http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=1466http://hero.epa.gov/index.cfm?action=search.view&reference_id=93206http://hero.epa.gov/index.cfm?action=search.view&reference_id=8567http://hero.epa.gov/index.cfm?action=search.view&reference_id=30019http://hero.epa.gov/index.cfm?action=search.view&reference_id=30021http://hero.epa.gov/index.cfm?action=search.view&reference_id=88823http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=194567http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=6488http://hero.epa.gov/index.cfm?action=search.view&reference_id=88824http://hero.epa.gov/index.cfm?action=search.view&reference_id=86237http://hero.epa.gov/index.cfm?action=search.view&reference_id=71664http://hero.epa.gov/index.cfm?action=search.view&reference_id=56384http://hero.epa.gov/index.cfm?action=search.view&reference_id=783307http://hero.epa.gov/index.cfm?action=search.view&reference_id=783306http://hero.epa.gov/index.cfm?action=search.view&reference_id=7833067/29/2019 Toxicological Review of Ammonia - Draft June 2012
16/83
Toxicological Review of Ammonia
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