Air Toxics Hot Spots Program

Risk Assessment Guidelines

Part I

The Determination

of Acute Reference

Exposure Levels for

Airborne Toxicants

March 1999

Secretary for Environmental Protection

California Environmental Protection Agency

Winston H. Hickox

Director

Office of Environmental Health Hazard Assessment

Joan E. Denton, Ph.D.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

i

Determination of Acute Reference Exposure Levels

for Airborne Toxicants

March 1999

CALIFORNIA ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF ENVIRONMENTAL HEALTH HAZARD ASSESSMENT

AIR TOXICOLOGY AND EPIDEMIOLOGY SECTION
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

ii

Prepared by:

George V. Alexeeff, Ph.D.

John D. Budroe, Ph.D.

James F. Collins, Ph.D.

Richard H.F. Lam, Ph.D.

David C. Lewis, Ph.D.

Michael J. Lipsett, M.D., J.D.

Melanie A. Marty, Ph.D.

Thomas R. Parker, M.S.

Air Toxicology and Epidemiology Section

Office of Environmental Health Hazard Assessment

OEHHA also acknowledges the following contributors:

Sharan Campleman, M.S., M.P.H.

Rupali Das, M.D., M.P.H.

Jefferson R. Fowles, Ph.D.

Richard J. Jackson, M.D., M.P.H.

Peggy Lopipero, M.P.H.

Lee Moore, M.P.H.

Renee Paige, B.S.

The authors would like to acknowledge the administrative and clerical support of

Myeast McCauley, Jacqueline V. Grayson, Laurie Bliss, Michelle Johnson, Olivia Rice, and

Joseph S. Coleman.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

iii

Table of Contents

1. Introduction ............................................................................................................................1

1.1 Objective...............................................................................................................................2

1.1.1 Definition of Reference Exposure Level (REL).............................................................2

1.1.2 Legislative Mandate......................................................................................................2

1.1.3 Implementation of Risk Assessment Advisory Committee (RAAC)

Recommendations.......................................................................................................5

1.2 List of Substances Considered ...............................................................................................6

1.2.1 Priority for Evaluation of Chemicals..............................................................................6

1.3 Time Frame of Interest ..........................................................................................................7

1.4 Criteria for Development of Acute Severity Levels................................................................8

1.4.1 Definition of Acute Severity Levels...............................................................................8

1.4.2 Hazard Index Approach................................................................................................9

1.4.3 Relationship of RELs to Severity Levels..................................................................... 12

1.5 Populations of Concern ....................................................................................................... 13

1.6 Exposure Duration and Patterns .......................................................................................... 13

1.6.1 Exposure Concentration Averaging Period.................................................................. 14

1.7 Cumulative Effects of Multiple Chemical Exposures............................................................ 16

1.8 Pre-existing Exposure Guidelines......................................................................................... 16

1.8.1 Description of Existing Guidelines.............................................................................. 17

1.8.1.1 The California Ambient Air Quality Standards (CAAQS) ................................... 17

1.8.1.2 An Emergency Exposure Guidance Level (EEGL) ............................................. 17

1.8.1.3 Emergency Response Planning Guidelines (ERPGs)........................................... 17

1.8.1.3.1 The ERPG-1 ............................................................................................. 17

1.8.1.3.2 The ERPG-2 ............................................................................................. 17

1.8.1.3.3 The ERPG-3 ............................................................................................. 17

1.8.1.4 Immediately Dangerous to Life and Health (IDLH)............................................ 17

1.8.1.5 The Short-term Public Emergency Guidance Level (SPEGL) ............................. 18

1.8.1.6 The Threshold Limit Value-Time Weighted Average

(TLV-TWA) and Short-Term Exposure Limit (STEL)...................................... 18

1.8.1.7 U.S. EPA’s Acute Emergency Guidance Levels (AEGLs) .................................. 18

1.8.1.8 U.S. EPA’s Air Pollution Warning Levels .......................................................... 18

1.8.1.9 U.S. EPA’s Levels of Concern ........................................................................... 18

1.8.2 Priority for Adopting Existing Guidelines.................................................................... 19

2. Hazard Identification............................................................................................................ 20

2.1 Nature of Adverse Effects ................................................................................................... 20

2.2 Definition of Adverse Effect ................................................................................................ 21

2.3 Identification of Adverse Effect ........................................................................................... 24

2.3.1 Weight of Evidence .................................................................................................... 24

2.3.2 Strength of Associated Health Effect .......................................................................... 24

2.3.3 Consistency of Associated Adverse Health Effect........................................................ 24

2.3.4 Specificity of Associated Adverse Health Effect.......................................................... 24

2.3.5 Temporal Association ................................................................................................. 25
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

iv

2.3.6 Coherence of Adverse Health Effect ........................................................................... 25

2.4 Criteria for Studies Utilized to Identify Adverse Health Effects............................................ 25

2.4.1 Selection of Key Studies............................................................................................. 26

2.4.1.1 Human Data....................................................................................................... 26

2.4.1.1.1 Epidemiological Data ................................................................................ 26

2.4.1.1.2 Controlled Human Exposure Studies......................................................... 27

2.4.1.1.3 Case Reports............................................................................................. 27

2.4.1.2 Animal Data....................................................................................................... 27

3. Dose Response Assessment................................................................................................... 28

3.1 Severity of Adverse Effects ................................................................................................. 28

3.2 Levels of Adverse Effects.................................................................................................... 29

3.2.1 Level Protective Against Mild Effects......................................................................... 29

3.2.1.1 Lower Airway Responsiveness........................................................................... 30

3.2.2 Level Protective Against Severe Adverse Effects........................................................ 31

3.2.3 Level Protective Against Life-threatening Effects........................................................ 33

3.3 Estimation of Threshold or Low Response Concentrations .................................................. 33

3.3.1 Benchmark Concentration........................................................................................... 34

3.3.1.1 Selection of Appropriate Benchmark Concentration Criteria............................... 34

3.3.2 Use of No-Observed-Adverse-Effect-Levels (NOAEL)............................................... 40

3.3.2.1 Derivation of Acute Reference Exposure Levels Using NOAELs ....................... 42

3.3.3 Use of Lowest-Observed-Adverse-Effect-Levels (LOAEL)......................................... 42

3.3.4 Accounting for Uncertainties in the Database.............................................................. 44

3.3.4.1 Differences Between Human and Animal Susceptibility ...................................... 47

3.3.4.2 Increased Susceptibility of Sensitive Individuals ................................................. 48

3.4 Effects of Exposure Duration .............................................................................................. 50

3.4.1 Time Extrapolation..................................................................................................... 51

4.0 Supporting Data .................................................................................................................. 56

5.0 Areas for Further Research.................................................................................................. 57

Appendix A. Acute Reference Exposure Levels (RELs), Averaging Times, and Toxicologic

Endpoints; Hazard Index Target Organs

Appendix B. Substances for which Emissions Must Be Quantified

Appendix C. Acute Toxicity Summaries

Appendix D. Categorical Regression Analysis

Appendix E. Glossary of Acronyms

Appendix F. Modified LOAEL to NOAEL Uncertainty Factor
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

1

1. Introduction

Hazardous substances are routinely released into the environment as a result of predictable

continuous or short-term emissions from facilities and predictable process upsets or leaks. As a

result, the public living or working in communities surrounding industrial facilities is at risk of

being exposed to airborne toxicants.

Local air pollution control officers, industrial facility operators, and others have a need for clear

guidance regarding the acute health effects of hazardous substances. Currently there are

numerous sources of acute exposure levels developed by various committees for application

primarily to occupational and military settings. However, values for acute exposure of the general

public are of limited number and uneven quality, and focus on industrial accidents instead of

predictable, routine, short-term emissions. While some methods relate toxicological information

from human data and animal experiments to acute chemical exposure, they may be based upon

flawed or inconsistent algorithms or are not designed for the special case of predictable exposure

of the public to airborne toxicants (Robinson and Paxman, 1992). Furthermore, there often exist

several different acute exposure levels for a single compound, each developed by a different

organization. These values may differ by more than 100-fold, which confounds prudent decisions.

Consequently, there are few existing guidelines that reflect sound science, clearly take into

account issues such as appropriate endpoints and uncertainties about toxicity, and focus on

routine or predictable acute air releases.

The National Academy of Sciences (NAS)1 recommends that the United States Environmental

Protection Agency (U.S.EPA) more clearly define, and in some cases change, the methods and

assumptions used to estimate the risk of cancer and other health problems from hazardous air

pollutants (NRC, 1994). Specifically, NAS has endorsed the development of biologically based

quantitative methods for assessing the effects of exposure to a chemical. This includes

incorporating information on mechanisms of action and variability among populations and

between individuals that might affect susceptibility to toxic insults, such as age, lifestyle, genetic

background, sex, and ethnicity. NAS recognized the continued need to use default options to

address the uncertainties of underlying mechanisms in risk assessment for populations. NAS has

recommended that U.S.EPA (1) explicitly identify each use of a default option in risk assessment;

(2) clearly state the scientific and policy basis for each default option; and (3) articulate criteria for

allowing departure from default options. NAS has also recommended that U.S.EPA screen the

hazardous air pollutants identified in the 1990 Clean Air Act Amendments to establish priorities

for setting standards, identifying data gaps, and developing incentives to expedite the generation

of data by other governmental agencies.

The Office of Environmental Health Hazard Assessment (OEHHA) has followed the NAS

recommendations by establishing uniform, science-based guidelines to be used in the derivation of

acute severity levels applicable to the general public exposed routinely to hazardous substances

released into the environment. By investigating existing exposure values developed by other

organizations (described below), OEHHA has been able to identify some of the data gaps and

 

1

 Appendix E contains a glossary of the principal acronyms used in this document.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

2

inconsistencies contained in the existing guidelines. The results of this investigation have allowed

the development of a more rigorous and resource-intensive scientific methodology which has been

used to calculate acute exposure levels for prioritized chemicals. The use of benchmark dose

methodology, described later in this document, is an example of departure from default options as

recommended by NAS. Better human dose-response data, for example, from improved

workplace monitoring correlated with symptoms and more extensive epidemiologic studies, are

needed before the departure from default approaches can be expanded to more substances.

1.1 Objective

The objective of this document is to present a method for deriving acute (one-hour) inhalation

Reference Exposure Levels (RELs) for hazardous airborne substances. The acute REL is an

exposure that is not likely to cause adverse effects in a human population, including sensitive

subgroups, exposed to that concentration for one hour on an intermittent basis. These healthbased acute RELs are applicable to risk characterization of air releases, defined in Health and

Safety Code Section 44303, as:

“including actual or potential spilling, leaking, pumping, pouring, emitting, emptying,

discharging, injecting, escaping, leaching, dumping, or disposing of a substance into the

ambient air and that results from routine operation of a facility or that is predictable,

including, but not limited to continuous and intermittent releases and predictable process

upsets or leaks.”

1.1.1 Definition of Reference Exposure Level (REL)

The concentration level at or below which no adverse health effects are anticipated for a specified

exposure duration is termed the reference exposure level (REL). RELs are based on the most

sensitive, relevant, adverse health effect reported in the medical and toxicological literature.

RELs are designed to protect the most sensitive individuals in the population by the inclusion of

margins of safety. Since margins of safety are incorporated to address data gaps and

uncertainties, exceeding the REL does not automatically indicate an adverse health impact.

Figure 1 depicts the steps involved in developing RELs. While we conduct a complete literature

search for each chemical, in the chemical summaries in Appendix C we only describe the key

studies used in the acute REL development.

1.1.2 Legislative Mandate

As defined under the Air Toxics “Hot Spots” Information and Assessment Act of 1987 (“AB

2588” [Chapter 1252, Statutes of 1987], California Health and Safety Code Section 44300 et

seq., as amended), a risk assessment includes a comprehensive analysis of the dispersion of

hazardous substances in the environment, and the potential for human exposure and a quantitative

assessment of both individual and population-wide health risks associated with those levels of

exposure. This document establishes a standardized procedure for generating the health based

values (acute reference exposure levels) used for assessing acute, noncancer risks within the risk

assessment process.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

3

In preparing this document, OEHHA is responding to state legislation enacted in 1992. Senate

Bill (SB) 1731 (Stats. 1992, Ch. 1162) requires OEHHA to develop risk assessment guidelines

for implementing the “Hot Spots” Act. Assembly Bill (AB) 2728 (Statutes of 1992, Chapter

1161; California Health and Safety Code Section 39660) added a mandate to the Toxic Air

Contaminants Program that all Federal Hazardous Air Pollutants be identified as Toxic Air

Contaminants. The Health and Safety Code also requires OEHHA to use a margin of safety when

estimating levels of exposure that may cause adverse health effects. This margin of safety must

account for heterogeneity within human populations and uncertainty related to the applicability

and completeness of the available data. To help meet the requirements of AB 2728 and SB 1731,

OEHHA described and evaluated methodology to estimate acute RELs and derived such levels

for specific chemicals. The acute RELs are designed for use in the Air Toxics “Hot Spots”

Program.

Figure 1. REL development process

Prioritize chemicals to be evaluated

(select from list of substances in Appendix A)

⇓

conduct literature search

 ⇓

identify & evaluate existing standards ⇒ if appropriate, adopt as REL

⇓

appropriate standards do not exist

⇓

choose best study, emphasizing human data

⇓

identify critical biological endpoint

⇓

estimate threshold for effect (NOAEL)

⇓

temporal/dosimetric adjustments (time extrapolation, HEC)

⇓

account for uncertainties in data

(applying animal to human data, occupational studies to sensitive subgroups)

⇓

Reference Exposure Level (REL)

(listed in Appendix B)
Figure 2

Public and Peer Review Process for Establishing Reference Exposure Levels

Prioritization of 

Compounds

Selection of Candidate 

Compound

Request for Health 

Information from Public

Development of "Technical Support 

Document for the Determination of 

Acute Reference Exposure Levels"

Consultation with California Air 

Pollution Control Officers Association 

(CAPCOA)

Draft Document for 

Public Comment

Public Workshop

Review by Scientific Review 

Panel on Toxic Air 

Contaminants

Adoption of 

 "Technical Support 

Document for the 

Determination of Acute 

Reference Exposure Levels"
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

5

OEHHA and the Air Resources Board (ARB) have set up a procedure to facilitate the extensive

public comment and peer review necessary for implementation of AB 2728 and SB 1731 (Figure

2). This process includes internal OEHHA and Cal/EPA review, consultation with the California

Air Pollution Control Officers Association (CAPCOA), a public comment period, and public

workshops. In addition, this document has been reviewed by the Scientific Review Panel onToxic

Air Contaminants administered by the ARB. A draft of this document was released for public

comment in January 1995. We have responded to public comment and updated and revised the

chemical-specific information. The State’s Scientific Review Panel on Toxic Air Contaminants

reviewed this document and provided comments which were incorporated into this final draft.

1.1.3 Implementation of Risk Assessment Advisory Committee (RAAC) Recommendations

The California Environmental Protection Agency (Cal/EPA) Risk Assessment Advisory

Committee (RAAC) was a panel of scientists convened under Chapter 418, Statutes of 1993,

Health and Safety Code, Section 57004, to review the health risk assessment practices within

Cal/EPA. The RAAC issued a report on its findings (Risk Assessment Advisory Committee,

1996). In the completion of the acute REL document, the RAAC recommendations were

carefully considered (Table 1).

Table 1. Implementation of RAAC Recommendations

RAAC

Recommendation

Implementation

Formalized peer review

program

This document was reviewed by an advisory committee of non-governmental

scientists: the Scientific Review Panel on Toxic Air Contaminants, prior to

adoption.

Input from risk

managers and from

external stakeholders

This document has been reviewed by risk assessors and managers of the Cal/EPA

Boards and Departments. The document has also been reviewed by representatives

of the Air Quality Management and Air Pollution Control Districts, as part of the

California Air Pollution Control Officers Association review. The early draft of

this document was distributed for comment to others, including external

stakeholders. Two public workshops were held, one in Northern California and

one in Southern California to solicit stakeholder input. Many changes were made

in response to the input.

Balance level of effort

with importance

The selection of chemicals for intensive review in this document was based in part

on the importance of the chemical within California. Emphasis was placed on

developing health levels for those substances with high emissions or of concern to

risk managers. The project incorporated all available risk assessment information

from U.S.EPA, NAS, and other authoritative bodies.

Coordinate effort with

U.S.EPA

The project made use of all available risk assessment information. At the time of

preparation of this document, no final U.S.EPA documents were available. A draft

U.S.EPA report for consideration of accidental exposures to 12 chemicals was

released in 1997 (CFR 62 No. 210; Oct 30, 1997). These were reviewed, but since

they are subject to change, were not incorporated into the OEHHA document. The

draft was sent to U.S.EPA’s ORD for review and technical issues were discussed

with U.S.EPA staff.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

6

RAAC

Recommendation

Implementation

Incorporate

consideration of effect

severity

Concerns that severely adverse and high incidence effects should be addressed

differently from mild and/or rarely encountered effects were addressed by

incorporation of intermediate LOAEL uncertainty factors. In addition, the data are

presented based on a classification scheme of severity. Adverse effects were

classified as mild, severe, and life-threatening. Information was also provided,

when available, on the effects that could result from doses above the REL.

Additional research will be needed to use more sophisticated approaches to this

problem.

In general, the committee recommendations were well addressed. Complete implementation of all

committee recommendations will require additional efforts and research beyond the scope of the

current project. In particular, developing alternative approaches to some areas of uncertainty now

addressed with default assumptions will require extensive data collection and analyses.

1.2 List of Substances Considered

All substances compiled by the ARB for the Air Toxics “Hot Spots” list of substances were

considered for evaluation and inclusion in this guidance. The substances included on the Air

Toxics “Hot Spots” Program List are those substances found on lists developed by the

International Agency for Research on Cancer (IARC), the U.S. Environmental Protection Agency

(U.S.EPA), the U.S. National Toxicology Program, the ARB (list used in the Toxic Air

Contaminant Program), the Hazard Evaluation System and Information Service (State of

California), or on the Proposition 65 list of carcinogens and reproductive toxicants (State of

California). The complete list of substances whose emissions must be quantified is contained in

Appendix B.

Several exposure guidelines as well as published toxicological and epidemiologic literature serve

as sources of information for chemicals for which acute RELs are being developed. These are:

California Ambient Air Quality Standards (CAAQS) developed by the State of California;

Emergency Exposure Guidance Levels (EEGLs) and Short-term Public Emergency Guidance

Levels (SPEGLs) developed by the NAS; Emergency Response Planning Guidelines (ERPGs)

developed by the American Industrial Hygiene Association (AIHA); and Immediately Dangerous

to Life and Health (IDLH) levels developed by the National Institute of Occupational Safety and

Health (NIOSH).

1.2.1 Priority For Evaluation Of Chemicals

Substances were prioritized for the development of acute RELs on the basis of several criteria

(Table 2). All 32 chemicals for which acute noncancer RELs appeared in the Air Toxics “Hot

Spots” Program Revised 1992 Risk Assessment Guidelines (California Air Pollution Control

Officers Association, 1993) were considered for evaluation. This was done to maintain

consistency in the Hot Spots program and, by using existing information as much as possible, to

conserve resources. Additional substances were chosen from the ARB’s Air Toxics “Hot Spots”
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

7

emissions inventory based on: (1) the availability of California ambient air quality standards, (2)

the magnitude of emissions in California, or (3) known toxic properties. The list of 51 substances

that have been evaluated with the methods delineated in this Technical Support Document is

contained in Appendix A.

Table 2. Prioritization Process for Acute Toxicity Exposure Levels

Listed in CAPCOA (1993) Document

1. Acrolein

2. Ammonia

3. Arsine

4. Benzyl chloride

5. Carbon tetrachloride

6. Chlorine

7. Copper and compounds

8. 1,4-Dioxane

9. Ethylene glycol monobutyl ether

10. Ethylene glycol monoethyl ether acetate

11. Ethylene glycol ethyl ether

12. Ethylene glycol methyl ether

13. Formaldehyde

14. Hydrochloric acid

15. Hydrogen cyanide

16. Hydrogen fluoride

17. Hydrogen sulfide

18. Mercury (inorganic)

19. Methyl chloroform

20. Methylene chloride

21. Nickel and compounds

22. Nitrogen dioxide

23. Ozone

24. Perchloroethylene

25. Phosgene

26. Propylene oxide

27. Selenium and compounds

28. Sodium hydroxide

29. Sulfates

30. Sulfur dioxide

31. Xylenes

California Ambient Air Quality Standard

(not already listed by CAPCOA)

1. Carbon monoxide

High Emissions

(High on ATEDS emissions inventory)

1. Arsenic and compounds

2. Benzene

3. Chloroform

4. Chloropicrin

5. Copper and compounds

6. Epichlorohydrin

7. Isopropyl alcohol

8. Methanol

9. Methyl bromide

10. Nitric acid

11. Phenol

12. Styrene

13. Sulfuric acid

14. Toluene

15. Vanadium pentoxide

16. Vinyl chloride

Other known toxic compounds

1. Acrylic acid

2. Carbon disulfide (CEPRC list)

3. Triethylamine

1.3 Time Frame of Interest

In the Air Toxics Hot Spots program, routine industrial emissions are evaluated for potential

public health impacts. Chronic exposure is evaluated using ambient air concentrations of emitted

chemicals averaged over a year. The annualized average air concentration forms the basis for

both chronic noncancer and cancer risk evaluation. In reality, exposure over a 24-hour period

does not occur at a continuous level. Facility emissions may fluctuate considerably, with daily and
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

8

hourly maximum and minimum concentrations. The commonly used air dispersion models

account for only some of this variation as they can only accommodate emissions data entered as a

single value in pounds emitted per hour or per year. However, the models can calculate

concentrations hour by hour throughout a year, giving an indication of the one-hour maximum

exposure concentrations. The hourly fluctuations are a reflection of the changing meteorological

conditions that are included in the model.

In general, the one-hour modeled maximum concentrations in the Air Toxics Hot Spots program

are used in a hazard index approach in order to evaluate “acute” exposures and potential public

health impacts from such exposure. Modeled concentrations of several hours are used for some

reproductive/developmental toxicants (see section 1.6.1). The hazard index is the ratio of the

modeled concentration to the acute reference exposure level. If the ratio exceeds one, then the

risk manager needs to consider whether risk reduction is appropriate. An exceedance of one does

not mean adverse effects will occur. Rather, it is an indication of the erosion of the margin of

safety for exposure to that chemical.

1.4 Criteria for Development of Acute Severity Levels

Acute severity levels are concentration levels at or below which specified health effects are not

expected to occur. Toxicological responses to acute exposures follow a graded response,

dependent on the exposure dose (determined by concentration and time). Dividing this graded

response into several categories facilitates the development of graded acute severity levels for

each chemical, based on the severity of effect. OEHHA has chosen to follow the NAS guidelines

(NRC, 1993) to divide these responses into three severity levels, as detailed below.

The Air Toxics Hot Spots Program uses the reference exposure levels, derived from the most

sensitive endpoint of toxicity, for the risk assessment process. Designation of the effects of

exposure to increasing doses into severity categories will likely be helpful to risk assessors

evaluating exceedances by helping them to better understand the practical implications of the

endpoint of concern. Furthermore, the proximity of the REL to the next severity level may help

risk managers in making decisions on appropriate actions. In a brief review of approximately 300

risk assessments submitted by facilities complying with the Air Toxics Hot Spots Program,

OEHHA found 20% of the facilities with exceedances of the acute reference exposure levels,

ranging from 2-fold to as high as 500-fold.

1.4.1 Definition of Acute Severity Levels

This methods document is focused on the development of three categories of acute severity levels

in accordance with criteria established by NRC (1993): the level protective against mild adverse

effects, the level protective against severe adverse effects, and the level protective against lifethreatening effects (see Figure 3). Each of these three acute exposure levels is determined for a

one-hour exposure duration. While NAS established these categories for the evaluation of

accidental chemical releases, the toxicological principles validating the three severity levels are

applicable to any acute exposures. However, the major focus of this document is in developing

acute RELs for the preparation of risk assessments for non-emergency routine releases. Thus, the
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

9

RELs used in the risk assessment are generally levels protective against mild adverse effects; a

few are based on severe effects (e.g., reproductive/developmental).

A central assumption in the development of acute noncancer toxicity levels is that all toxicologic

endpoints included under these levels are considered to have a threshold for adverse effects.

However, the threshold may not be observable and, in some cases, may only be estimated. Areas

of uncertainty in estimating effects among a diverse human population are addressed using

extrapolation and uncertainty factors (UFs).

Protection against carcinogenicity and against the adverse health effects of chronic exposures are

not considered in these guidelines. For this reason, chemicals should be evaluated separately for

their carcinogenicity and for any additional chronic health effects that may occur. Methods for

these evaluations are provided in the related OEHHA documents entitled Technical Support

Document for Describing Available Cancer Potency Factors and Technical Support Document

for the Determination of Noncancer Chronic Reference Exposure Levels.

1.4.2 Hazard Index Approach

RELs are used by the Air Toxics “Hot Spots” Program as indicators of the potential adverse

health effects of chemicals. A “hazard index” approach is used to estimate potential health effects

resulting from hazardous substances by comparing measured exposure levels to calculated RELs.

This approach assumes that multiple sub-threshold exposures to chemicals acting on the same

target organ could result in an overall risk of developing an adverse health effect.

For many facilities a large number of chemicals may be emitted or may be present in the air at the

location of the receptor or exposed population. To assess the cumulative impact of several

chemicals present at the same time, it is important to consider the interaction of effects of the

toxicants. Unless specific information is available to the contrary, the interaction of two or more

chemicals is assumed to be additive for a given toxicological endpoint. This may underestimate

the effect in the cases in which interactions are synergistic or overestimate it if the effects are not

additive or are antagonistic.

An underlying issue in chemical interactions and additivity is the concept of a threshold.

Exposure to a single chemical in the air may not result in a toxic response if it is below the

threshold necessary to elicit a response. However, simultaneous exposure to two similar

chemicals at sub-threshold levels may result in a toxic response. This is taken into account by

adding the individual ratios of modeled concentrations to acute RELs for chemicals that impact
Level protective against life-threatening effects: Any exposure 

above this level is potentially lethal to sensitive individuals, and as 

exposure duration increases, death becomes a high probability for 

all exposed persons. Exposure for specified time duration can lead 

to complete incapacitation. Depending on the chemical, severe, 

irreversible injury can occur to any organ system.

Level protective against mild adverse effects: The level at or 

below which no adverse effects are expected. Exposure above this 

level may produce mild irritation of the eyes, nose, or throat, or 

may result in other mild adverse physiological changes (see text or 

Table 5). For most individuals, the irritation and other adverse 

physiological changes do not persist after exposure ceases. As 

exposure concentration and duration increases, however, adverse 

health effects of short duration may be observed in an increasing 

number of persons. This level is generally used as the Reference 

Exposure Level (REL).

Level protective against severe adverse effects: Exposure above 

this level and time duration may lead individuals to seek 

assistance. Effects may be disabling by causing impaired 

judgement or by adversely affecting one's ability to take protective 

actions or to escape. Effects of exposure may be long-lasting or 

permanent and may include effects on the outcome of an existing 

or subsequent pregnancy. This level is sometimes used as the 

Reference Exposure Level (REL) (e.g., for 

reproductive/developmental effects).

Persons may detect exposure by odors, sights, taste, or smell. 

There are no adverse effects of exposure on health.

Figure 3. Acute Severity Exposure Levels for 1-hour Durations
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

11

the same target organ or system (Appendix A lists RELs and toxicologic endpoints). For a

particular target organ or system, the HI is calculated as follows:

HI = C1 / REL1 + C2 / REL2 + . . . + Ci / RELi

where for i substances with the same toxicological endpoint,

HI = hazard index

Ci = 1-hour maximum concentration for the i

th substance

RELi = acute REL for the i

th substance

Target organs or systems considered for hazard index calculations are general categories that may

include varied effects (Table 3). For example, the target system, “Respiratory System,” includes

upper airway irritation as well as lower airway effects, such as bronchoconstriction. This

approach assumes additive interactions, as explained above. Because the precise relative

contributions of exposure to multiple substances that principally affect different areas of the same

physiologic system (in the previous example, the respiratory system) are unknown, this approach

may under- or over-estimate the effects of chemical interactions in certain cases. However, in

most cases this approach provides an appropriate health protective assumption. We have

indicated in Appendix A, Table A-1 which toxicological endpoints are relevant to the specific

REL for each chemical. While the REL is based on the most sensitive endpoint, some

toxicological endpoints are manifested at exposures close to that which induces the toxicological

endpoint that serves as the basis for the REL. Therefore, some chemicals should be evaluated for

impacts on multiple target organs or systems. In addition, predisposing conditions are known to

increase susceptibility to some chemicals. The target organs for those predisposing conditions

should also be included in the hazard index approach. The target organs to be evaluated for

hazard index are presented in Table A-2 in Appendix A, and in each chemical summary in

Appendix C.

Table 3. Target organs or systems used in acute hazard index calculations

Hazard Index Targets Health Effects Included Among the 51 RELs

Hematologic System Hemolysis; anemia; platelet abnormalities; effects on

hematopoietic stem cells

Cardiovascular System Aggravation of angina

Nervous System Electroencephalograph (EEG) results; performance on

neurobehavioral or neuropsychological tests; clinical

neurological exam; headache, lightheadedness, dizziness

Eyes Irritation of eyes; histological changes to eye tissue
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

12

Alimentary Tract Hepatotoxicity; nausea, vomiting

Immune System Lymphocyte proliferation; host resistance to infection

Reproductive/Developmental Fetotoxicity; teratogenicity; intrauterine growth

retardation; preimplantation loss; altered behavior in

offspring

Respiratory System Irritation of nose and throat; increased mucus

production; histological changes in nasal epithelium;

histologic changes in lung tissue; lung function following

inhalation challenge (see Table 8)

Skin Irritation of skin

Physiological Response to Odors Headache; nausea

1.4.3 Relationship of RELs to Severity Levels

OEHHA has defined the lowest available acute severity level as the REL. It is important to note

that the level protective against the lowest severity level for a given chemical may be associated

with a severe, rather than a mild, toxic effect for the following reason. Adverse health effects that

are minor and reversible are classified as mild effects (U.S.EPA effect severity level 5 or less, see

Table 5). However, the most sensitive detectable adverse effect of a chemical may be a severe

effect (U.S.EPA effect severity level 5-9, see Table 5). For chemicals with three severity levels,

the level protective against mild adverse effects is considered the REL; for chemicals for which

such a level is not appropriate (i.e., does not exist), the level protective against severe adverse

effects is the REL. For example, the most sensitive endpoint found in the literature for arsenic

and related compounds was reproductive toxicity, a severe effect (Acute Toxicity Summary for

Arsenic, Appendix C); thus, for arsenic, the REL is a level protective against severe adverse

effects.

For most compounds there are three identifiable severity levels. However, as stated above, there

are some chemicals for which all severity level criteria do not apply. Those chemicals for which a

severe toxicologic effect may occur below the level at which mild adverse effects occur will have

fewer severity levels described. For example, there would be no level protective against mild

adverse effects for a chemical if reproductive toxicity, considered a severe adverse effect, was the

most sensitive endpoint, as is the case for carbon disulfide. Additionally, the toxicology data for

some chemicals may be lacking and thereby not permit the establishment of a particular level. The

amount of data and the quality of the information will ultimately determine which acute exposure

levels are identified. As more data become available, either in the toxicologic literature or from

guideline committees, such as U.S.EPA or the NAS, the acute exposure levels may be updated.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

13

1.5 Populations of Concern

Acute RELs are intended to protect the individuals who live or work in the vicinity of emissions

of these substances. The general population consists of individuals with a wide range of

susceptibility. The susceptibility may be transitory or chronic. Individuals in the general

population who may be at greater risk for developing adverse effects following chemical exposure

include those with increased exposure (e.g., children, adults engaged in physical activity), those

undergoing physiological change (e.g., children, pregnant women and their fetuses), individuals

with impaired physiological conditions (e.g., elderly persons, persons with existing diseases such

as lung, heart or liver disease), and individuals with lower levels of protective biological

mechanisms due to genetic variability within the population (U.S.EPA, 1994a). Less susceptible

individuals are healthy adults without any genetic or biological predisposition that may increase

sensitivity to the chemical of concern.

Acute RELs are intended to protect both individuals at low risk for chemical injury as well as

identifiable sensitive subpopulations (highly susceptible or sensitive individuals) from adverse

health effects in the event of exposure. However, they may not protect hypersensitive individuals

(those exhibiting idiosyncratic responses that cannot be predicted from studying the health effects

of the substance).

While OEHHA has attempted to identify specific sensitive subgroups for each substance from the

literature, it has not been possible to identify all conditions predisposing toward adverse health

effects following exposure to toxic substances. Because RELs pertain to inhalation exposures,

the lungs are often the major target organ of toxicity, and asthmatics are frequently identified as a

sensitive group. For most compounds, the range of intraindividual variability is poorly

characterized. An exception is sulfur dioxide, which has been extensively studied in both normal

as well as asthmatic individuals. In a study of asthmatic subjects, Horstman et al. (1986) found

that there was a 7-fold distribution in the range of sulfur dioxide concentrations required to

produce bronchoconstriction. Thus, it is reasonable to conclude that asthmatics may be at least

seven times as sensitive to the effects of sulfur dioxide as normal individuals.

An analysis of human variability in threshold responses in pharmacodynamic and toxicologic

studies by Hattis (1996) has shown that human variability in response can often be well modeled

by a log-normal distribution and that the magnitude of the variability depends greatly on the

endpoint and slope of the dose-response curve. In their analysis, some human threshold responses

ranged over more than 3 orders of magnitude. Because the range of variability within the human

population for most responses is unknown, there may be a proportion of the population for whom

the acute RELs will not be protective. It is OEHHA’s intent that, to the maximal extent possible,

the levels will protect nearly all individuals. As more susceptible groups are defined, it is our

intent to adjust the levels as necessary to protect such individuals.

1.6 Exposure Duration and Patterns

As indicated in Section 1.3, the focus of acute RELs is generally a one-hour exposure. While

shorter and longer durations may also provide useful information, the one-hour increment is
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

14

consistent with hour-by-hour monitoring or modeling that is generally conducted for facilities

under the Hot Spots program. The exceptions in this document include RELs based on several

hours exposure for reproductive/developmental endpoints (see Section 1.6.1). The acute REL

may be adjustable to other exposure durations. Sometimes it is necessary to extrapolate from

other experimental exposure durations to a one-hour exposure duration. This is described in

Section 3.4.

The distribution and concentration of a chemical following predictable continuous or intermittent

emissions will be influenced by meteorological conditions and topography. The most useful

descriptors of exposure are the duration and the concentration to which people were exposed

during the time period involved. Several acute exposure guidelines, for example, EEGLs and

ERPGs, are expressed in terms of a 1-hour duration. In order to maintain a practical and standard

time frame, a 1-hour exposure duration was chosen for the determination of the acute RELs.

However, as mentioned previously, health effects of concern may occur hours to days after

exposure ceases. For example, the onset of pulmonary edema may be delayed for up to 24 hours

following exposure to phosgene at doses several fold higher than the REL.

1.6.1 Exposure Concentration Averaging Period

The acute REL is a concentration that is not likely to cause adverse effects in a human population,

including sensitive subgroups, exposed on an intermittent basis to that concentration for one hour

(or in the case of reproductive/developmental endpoints several hours as indicated in individual

toxicity summaries). Intermittent exposure is difficult to define. U.S.EPA views intermittent

exposure as that lasting less than 24 hours and occurring no more frequently than monthly

(U.S.EPA, 1994b). This is in part based on an assumption that an acute exposure concentration is

at least 10-fold higher than the monthly average, and the presumption that individual exposures

are independent of one another. U.S.EPA (1994b) points out that very few chemicals will have

sufficient data to determine safe “periodicity” of an acute exposure. Thus, U.S.EPA (1994b) has

identified three issues to be addressed: length of acute exposure, periodicity of exposures, and the

relationship between the acute exposure and the chronic background. These will be discussed

below.

In acute toxicology experiments, the study design usually involves exposures of short duration to

an otherwise unexposed animal. However, real world “acute” exposures occur intermittently,

rather than as rare events in a lifetime. Thus, the typical ambient exposure scenario is not

reflected in the standard acute toxicology experimental design. The possibility of cumulative

effects from intermittent ambient exposure cannot be addressed in acute REL development.

Hence, acute environmental exposures are considered by U.S.EPA to occur no more frequently

than monthly. U.S.EPA also recommends that longer interexposure periods be established for

chemicals with long clearance times or with evidence of cumulative or sensitizing effects.2

 

2

 In April 1998 U.S.EPA updated its planned approach to the Acute Reference Exposure

(U.S.EPA, 1998, an external review draft). U.S.EPA defines the Acute Reference Exposure

(ARE) as “the exposure (concentration and duration), with an uncertainty spanning an order of

magnitude, that is not likely to cause adverse effects in a human population, including sensitive
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

15

A related exposure issue is the fact that peak exposures are superimposed on lower long-term

exposures to the same compound. This is also not reflected in the standard acute toxicology

design. For some compounds this will result in an increased body burden relative to the typical

toxicology experimental design and in a potential lowering of the acute exposure needed to

produce an adverse effect. U.S.EPA’s approach is to assume that the peak exposures are at least

10 times the monthly average so that the acute exposure can be considered relatively independent

of the longer-term chronic exposure to the same substance (U.S.EPA, 1994b).

Despite the inability to mimic typical human exposures in the laboratory, it is imperative to

examine whether short-term exposures to peak concentrations might result in adverse public

health impacts. OEHHA’s RELs are intended to be compared to the modeled one-hour maximum

(or multi-hour as noted for specific reproductive/developmental toxicants) concentrations used in

the hazard index approach to risk assessment (described earlier). OEHHA recommends that these

acute RELs be used to evaluate exposures that occur no more frequently than every two weeks in

a given year. The two-week interval was chosen because in most acute toxicology experiments

two weeks is the duration of time an animal is observed for signs of adverse outcome following

exposure (U.S.EPA, 1996).

An assumption in making this recommendation is that the REL is protective of adverse health

effects that are not cumulative; thus, the effects of each peak exposure are independent of

previous or subsequent peak exposures that occur as often as every two weeks. This

recommendation is only valid for substances that do not bioaccumulate. When bioaccumulation is

known to occur and body burden is associated with an adverse effect, longer interexposure

periods should be specified.

The modeled one-hour peak concentrations are typically much greater than the maximum average

annualized concentrations used for determining chronic exposure and risk. Thus, it is assumed

that acute exposures are independent of the long-term average exposure based on the modeled

annualized maximum average concentration. However, under certain meteorological conditions

(poor mixing, persistent calm winds), it is conceivable that there are many hours in a day or within

a few days where exposures are close to the peak one-hour in any given year. Concentrations

close to the maximum one-hour exposure may occur many times during the year including on

consecutive days. In addition, it is conceivable that exposure concentrations close to the

maximum may occur in consecutive hours. Currently, OEHHA does not ascertain how often

exposures close to the one-hour maximum occur in a given day, week, month or year. This

contributes to the uncertainty in evaluating the adverse health effects of peak one-hour exposures.

 

subgroups, exposed to that scenario on an intermittent basis.” Three methods for deriving AREs

are described in the draft report: a NOAEL/UF approach, a benchmark approach, and a

categorical regression approach (see Appendix D of this report). An example of the derivation of

the Acute Reference Exposure (ARE) for one chemical is given for each approach. The

NOAEL/UF and benchmark approaches are similar to those described in this document.

However, we define acute exposure as a 1 hour exposure.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

16

In evaluating chemicals with reproductive/developmental toxicity, we found that the standard

experimental paradigm of repeated exposure over several days did not lend itself easily to

extrapolation to a one-hour Reference Exposure Level (REL). Since reproductive/developmental

endpoints are frequently manifested in a small window of time during gestation, the standard

protocol is to expose pregnant animals for several hours per day over several days during

gestation in order to increase the power of the study to detect an effect. The Scientific Review

Panel discussed this point during their February 10, 1999 meeting. Issues that affect the

extrapolation to one hour include not only when the sensitive gestational period is, but also

toxicokinetic issues. For example, the animals are exposed for 6 hours per day but unexposed the

remaining 18 hours in that day. A rapidly metabolized toxicant capable of inducing a reproductive

or developmental toxic response may not build up in the animal’s system to the point where it

would induce a response. A slowly metabolized chemical would build up in the animal despite the

intermittent exposure. Whether or not a single one-hour exposure could produce a reproductive

or developmental adverse outcome depends on the toxicokinetics governing the concentration of

the chemical in maternal and fetal tissues, timing of exposure, mechanism of action, and other

factors. These issues are not easily taken into account in extrapolating to a one-hour Reference

Exposure Level. As such, after public review and review by the Scientific Review Panel, OEHHA

chose to use a single day’s exposure from the key study (usually 4 to 7 hours) as the basis of the

REL calculation, without time extrapolation to an equivalent one-hour concentration. Thus, for

those RELs addressing a reproductive/developmental endpoint in this document, the REL is for

whatever exposure duration was chosen for a single day in the experimental protocol. For

example, for arsenic, the experimental paradigm involved exposing pregnant animals for 4 hours

per day over several days of gestation. Thus the REL for arsenic is for a 4 hour exposure rather

than a one-hour exposure. This will require those assessing risks to calculate a 4-hour maximum

for arsenic rather than a one-hour maximum to use in the hazard index approach.

1.7 Cumulative Effects of Multiple Chemical Exposures

Concomitant exposures to more than one chemical may cause effects that are equal to, less than,

or greater than predicted from the effects observed with exposures to the individual chemicals

(Ikeda, 1988; Jonker et al., 1990). Of the thousands of potential combinations of chemicals in

common use, only a small fraction has been tested for the potential that combined exposures

could have synergistic or antagonistic properties. Effects of multiple chemical exposures on

human health remain an area for future study. As noted earlier, in risk assessment exposures to

multiple chemicals that cause similar health effects are treated as additive in the hazard index

approach.

1.8 Pre-Existing Exposure Guidelines

Acute exposure levels have been developed by several different organizations. However, there

are no inhalation exposure values that were derived using a consistent basis to protect the public

from planned industrial emissions. Values designed for protection of the general public exist, but

they are intended to address accidental releases and use methodologies that we have not been able

to reproduce. Occupational exposure guidelines are available for hundreds of substances, but
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

17

have an inconsistent basis, often have not incorporated recently available data, and are not

designed to protect sensitive subpopulations. The existing exposure guidelines reviewed for

OEHHA’s acute severity levels are described below.

1.8.1 Description of Existing Guidelines

1.8.1.1 The California Ambient Air Quality Standards (CAAQS), promulgated by the Air

Resources Board based on recommendations from OEHHA, are specified concentrations and

durations of air pollutants which reflect the relationship between the intensity and composition of

air pollution to undesirable effects. When a CAAQS existed for a criteria air pollutant, it was

adopted as the acute REL. If necessary, a one-hour value was derived using time extrapolation

(described below).

1.8.1.2 An Emergency Exposure Guidance Level (EEGL) is defined by the National Academy

of Sciences (NRC, 1986) as the ceiling concentration of a substance in air that may be judged by

the Department of Defense to be acceptable for the performance of specific tasks during rare

emergency conditions lasting for periods of 1-24 hours. “Emergency” connotes an unexpected

situation with potential for loss of life. EEGLs are designed to provide guidelines for military

personnel operating under emergency conditions that are peculiar to military operations and for

which regulatory agencies have not set standards. The methods used to derive the EEGLs are not

always explicitly stated and EEGLS were not derived with the intent to protect the general public.

However, the levels derived for sulfuric acid and for xylenes were deemed acceptable for use as

levels protective against serious adverse effects.

1.8.1.3 Emergency Response Planning Guidelines (ERPGs) are defined by the American

Industrial Hygiene Association (1991) as concentration ranges where adverse health effects could

be observed. Although ERPGs were evaluated, they were not routinely adopted as acute severity

levels because the methods for their derivation were not consistent, the AIHA did not always

consider all relevant data, and they have a specific emphasis on responding to accidental releases.

Three ERPGs are available for each substance; the AIHA definitions are provided below:

1.8.1.3.1 The ERPG-1 is the maximum airborne concentration below which nearly all individuals

could be exposed for 1 hour without experiencing other than mild transient adverse health effects

or perceiving a clearly defined, objectionable odor.

1.8.1.3.2 The ERPG-2 is the maximum airborne concentration below which nearly all individuals

could be exposed for 1 hour without experiencing or developing irreversible or other severe

health effects which could impair an individual’s ability to take protective action.

1.8.1.3.3 The ERPG-3 is the maximum airborne concentration below which nearly all individuals

could be exposed for 1 hour without experiencing or developing life-threatening health effects.

1.8.1.4 Immediately Dangerous to Life and Health (IDLH) values are defined by NIOSH

(1994, 1995) as 30-minute concentrations from which a worker could escape without injury or

irreversible health effects in the event of respiratory protection equipment failure and above which
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

18

only “highly reliable” respirators are required. These levels were designed for healthy workers in

an exposure situation that is likely to cause death or immediate or delayed permanent adverse

health effects or prevent escape from such an environment.

1.8.1.5 The Short-term Public Emergency Guidance Level (SPEGL) is defined by the

National Academy of Sciences (NRC, 1986) as a suitable concentration for unpredicted, single,

short-term, emergency exposure of the general public. In contrast to the EEGL, the SPEGL

takes into account the wide range of susceptibility of the general public, but it is not designed for

repeated or multiple exposures.

1.8.1.6 The Threshold Limit Value-Time Weighted Average (TLV-TWA) and Short-Term

Exposure Limit (STEL) are developed by the American Conference of Governmental Industrial

Hygienists (ACGIH, 1991); similar, NIOSH recommended exposure limits also exist (NIOSH,

1994). The TLV-TWA is defined as the time-weighted average concentration for a normal 8-

hour workday and a 40-hour workweek to which nearly all workers may be repeatedly exposed,

day after day, without adverse effect. The STEL is defined as a 15-minute TWA exposure which

should not be exceeded at any time during the workday.

Occupational exposure limits have been used to derive chemical exposure guidelines for the

general public (U.S.EPA, 1994a; National Air Toxics Information Clearinghouse, 1991; Robinson

and Paxman, 1992). More than 600 ACGIH TLVs and NIOSH RELs are available. These values

have been attractive because of the large number of accessible values and the concept that they

are intended to protect a human population from inhalation exposures. However, these values

lack a consistent basis for derivation, are not designed for or recommended for protection of the

general public, and in many cases may not prevent adverse health effects among workers (Roach

and Rappaport, 1990).

1.8.1.7 U.S.EPA’s Acute Emergency Guidance Levels (AEGLs) are currently being

developed. Several draft AEGL values were recently released for public comment (62 CFR, No.

210). However, these values focus on emergency planning and response, not on routine

emissions and exposure, which are the focus of this document.

1.8.1.8 U.S.EPA’s Air Pollution Warning Levels (40 CFR, Subchapter C, Part 51,

Appendix L) indicate poor air quality that may endanger the public’s health and suggest that

additional control actions are necessary to reduce the level of the pollutant. Air Pollution

Warning Levels are available for the following criteria air pollutants: sulfur dioxide, particulates

10 μm or less in diameter, carbon monoxide, ozone, and nitrogen dioxide.

1.8.1.9 U.S.EPA’s Levels of Concern (U.S.EPA, 1987) are defined as the concentrations of

substances in air above which there may be severe irreversible health effects or death as a result of

a single exposure for a relatively short period of time. For most compounds, the level of concern

is derived from the existing guidelines listed above (IDLH, TLV, EEGL or ERPG).
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

19

1.8.2 Priority for Adopting Existing Guidelines

Almost all acute RELs were developed de novo for these guidelines. However, existing

guidelines for acute exposure were first reviewed. If they were found to be appropriate, they

were adopted as the relevant acute toxicity exposure level using the following order of preference

(also see Table 4). For the six criteria air pollutants carbon monoxide, nitrogen dioxide, sulfates,

ozone, hydrogen sulfide, and sulfur dioxide, the CAAQS for short-term (1-hour) exposure is

considered equivalent to a mild adverse effect level and is used as the REL, or one-hour values

were derived by extrapolation from the 24-hour standard.

When calculating response severity for levels above the REL, an extensive review was conducted

of the existing guidelines described above. Existing guidelines were chosen as a basis for severity

levels above the REL when they accurately and completely reflected the scientific literature,

considered sensitive populations and included appropriate margins of safety for public health

protection. On the basis of these criteria, existing guidelines were chosen in the following order.

For the small number of substances for which a SPEGL was available for acute noncancer

endpoints, this was the existing value of choice for preventing severe or disabling effects. If no

SPEGL existed but an EEGL was available, this was the next existing level of choice. ERPG-2s

were chosen for the severe or disabling effect level only if no EEGL existed. ERPG-3s were used

as estimates of levels protective against potential lethal effects, if appropriate. In the past, IDLHs

were poorly documented and were not deemed to be health-protective (Alexeeff et al., 1989).

Since they have been recently revised (NIOSH, 1995), they were considered for adoption for the

“life-threatening effect level” based on the adequacy of their documentation and their health

protectiveness.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

20

Table 4 . Order of preference for adopting existing guidelines for acute severity exposure levels

Acute severity level Order of preference1

Level Protective Against

Mild Adverse Effects 2

Criteria air pollutant ⇒ CAAQS appropriate ⇒ adopt value

⇒ not appropriate ⇒ derive value

Non criteria air pollutant ⇒ derive value

Level Protective Against

Severe Adverse Effects

U.S.EPA Air Pollution Warning Level

SPEGL

EEGL

ERPG-2

TLV-TWA

U.S.EPA Level of Concern

Appropriate guidelines do not exist ⇒ derive value

Level Protective Against

Life-threatening Effects

ERPG-3

IDLH

Appropriate guidelines do not exist ⇒ derive value if possible

1

 See Section 1.8.1 for definition of acronyms.

2

This level would be protective of essentially all adverse effects.

2. Hazard Identification

2.1 Nature of Adverse Effects

The toxic effects of chemicals are of varying types and degrees of severity. The most important

effects following an acute (one hour) exposure to a substance released into the atmosphere are

usually respiratory effects. Toxic effects from airborne substances may be due to exposure via the

skin, eyes, and upper and lower respiratory tract. Systemic effects, such as hemolysis or central

nervous system injury, may result from absorption of material though the lungs, and, to a lesser

extent, through the skin. For a toxic endpoint to be considered due to acute exposure, the effects

do not have to be observed immediately. Rather, the effects may be observed hours to days

following the acute exposure. For example, acute exposure to phosgene may result in pulmonary
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

21

edema several hours later. In the case of benzene, death may result from leukopenia days

following high-level acute exposure.

Certain chemicals, after a single exposure, have the potential to produce delayed adverse effects.

Often acute toxicity tests do not have a sufficient follow up period to allow thorough assessment

of the potential for delayed health effects from single exposures. With respect to two kinds of

delayed effects, cancer and reproductive or developmental harm, there is more information

available. Carcinogens are considered in the Air Toxics Hot Spots Program Risk Assessment

Guidelines Part II: Technical Support Document for Describing Available Cancer Potency

Factors. Reproductive and developmental toxicants are considered in this document because

substantial research effort has been devoted toward specifically identifying such delayed effects.

Some substances exert their toxic effects through their metabolites. For example, methylene

chloride’s acute toxicity is mediated through its metabolite, carbon monoxide. Whenever

possible, information on toxic metabolites is provided in the toxicity summaries. When detailed

information is available on the relationship of dose of the parent chemical to level of metabolite

and the metabolite level to degree of toxic response, this is taken into account in developing the

acute severity levels. However, RELs and other acute severity levels are always expressed in

terms of the concentration of the parent compound, not the metabolite.

2.2 Definition of Adverse Effect

OEHHA has chosen to adopt U.S.EPA’s general definition of adverse effects as “any effects

resulting in functional impairment and/or pathological lesions that may affect the performance of

the whole organism, or that reduce an organism’s ability to respond to an additional challenge”

(U.S.EPA, 1994a). All effects reported for a substance were not necessarily considered adverse.

For example, the perception of an odor, even if objectionable, was not considered an adverse

health effect unless accompanied by other symptoms or signs, such as nausea and vomiting.

OEHHA has chosen to follow the guidance provided by NAS (NRC, 1993) in developing the

acute severity levels. Thus, for each compound evaluated for its acute toxicity, multiple effect

level thresholds were identified. U.S.EPA’s effect severity levels (Table 5) provided some

guidance in categorizing adverse effects.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

22

Table 5. U.S.EPA Effect Severity Levels (U.S.EPA, 1994) and Corresponding OEHHA Levels

U.S.EPA

Severity Level

Effect Category Effect OEHHA Effect

Severity Level

0 NOEL No observed effects. < Mild

1 NOAEL Enzyme induction or other biochemical change,

consistent with possible mechanism of action, with no

pathologic changes and no change in organ weights.

< Mild

2 NOAEL Enzyme induction and subcellular proliferation or

other changes in organelles, consistent with possible

mechanism of action, but no other apparent effects.

< Mild

3 NOAEL Hyperplasia, hypertrophy, or atrophy, but without

changes in organ weight.

≤ Mild

4 NOAEL/

LOAEL

Hyperplasia, hypertrophy, or atrophy, with changes in

organ weight.

Mild

5 LOAEL Reversible cellular changes including cloudy swelling,

hydropic change, or fatty changes.

Mild / Severe

6 (LO)AEL Degenerative or necrotic tissue changes with no

apparent decrement in organ function.

Severe

7 (LO)AEL/

FEL

Reversible slight changes in organ function. Severe

8 FEL Pathological changes with definite organ dysfunction

that are unlikely to be fully reversible.

Severe

9 FEL Pronounced pathological change with severe organ

dysfunction and long-term sequelae.

Severe

10 FEL Life-shortening or death. Life-threatening

NOEL - no observed effect level; NOAEL - no observed adverse effect level; LOAEL - lowest

observed adverse effect level; AEL - adverse effect level; FEL - frank effect level.

In addition to the histochemical and pathological effects in Table 5, OEHHA’s system for

categorizing clinical symptoms and signs into severity levels is presented in Table 6.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

23

Table 6. OEHHA Categorization of Adverse Health Effects into Severity Levels1

Acute Exposure

Level

Symptoms Signs/Laboratory Findings

Mild Adverse Mild subjective complaints with few

to no objective findings:

Mild mucous membrane (eye, nose,

 throat) irritation

Mild skin irritation

Mild headache, dizziness, nausea

Statistically significant findings of

pre-clinical significance:

Mild conjunctivitis

Mild lung function changes2

Abnormal immunotoxicity

 test results

Mild decreases in

 hemoglobin concentration

Severe Adverse Potentially disabling effects that affect

one’s judgment and ability to take

protective actions; prolonged

exposure may result in irreversible

effects:

Severe mucous membrane

 irritation

Blurry vision

Shortness of breath, wheezing

Severe nausea

Severe headache

Incoordination

Drowsiness

Panic, confusion

Clinically significant findings:

Findings consistent with

 central or peripheral nervous

 system toxicity

Loss of consciousness

Hemolysis

Asthma exacerbation

“Mild” pulmonary edema

Clinically significant lung

 function changes2

Cardiac ischemia

Some cardiac arrhythmias

 e.g., atrial fibrillation

Renal insufficiency

Hepatitis

Reproductive/developmental

 endpoints

 e.g., infertility, spontaneous

 abortion, congenital

 anomalies

Life-threatening Potentially lethal effects:

Severe pulmonary edema

Respiratory arrest

Ventricular arrhythmias

Cardiac arrest

1

This table is intended to provide examples of health effects commonly considered for each level. It is

not meant to be a comprehensive list of all possible health effects. Please refer to the text of this

document and to the individual toxicology summaries for chemical-specific information.

2

 Refer to Table 7 for detailed categorization of lung function tests.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

24

2.3 Identification of Adverse Effect

Several factors need to be considered when identifying an appropriate adverse health endpoint for

each compound. These include weight of evidence, the strength, consistency, and specificity of

the associated adverse health effect, the temporal association, and the coherence (scientific

plausibility) of the health effect.

2.3.1 Weight of Evidence

Although a formal scheme has not been adopted, a descriptive analysis of the strengths and

weaknesses of the studies used to derive acute RELs and other toxicity exposure levels is

presented. Issues such as observation of a dose-response relationship, reproducibility of findings,

mechanism of action, and consistency with other studies were given weight in the OEHHA

evaluation of acute RELs.

2.3.2 Strength of Associated Adverse Health Effect

The strength of an association between chemical exposure and adverse effect is assessed.

Strength of association can be measured in terms of high observed effect incidence or high relative

risk, statistical significance of differences between control and exposed groups, and a positive

dose-response relationship. For example, if an adverse effect noted in a low dose exposure group

is not noted in a high dose exposure group, evidence for a causal association between the

chemical exposure and the effect is greatly reduced.

2.3.3 Consistency of Associated Adverse Health Effect

Consistency of an association between chemical exposure and adverse effect is also evaluated.

Relevant observations include similarity of effects noted in different studies and among different

populations and/or species. For example, if an effect was noted in only one of many studies of a

particular strain of laboratory rodent, evidence for a causal association between the chemical

exposure and the effect is weakened.

2.3.4 Specificity of Associated Adverse Health Effect

If an adverse health effect is specific to exposure to a substance, the case for causality is

strengthened. Arsine-induced hemolysis is an example of such a specific exposure-effect

relationship. Such highly specific associations are unusual, however, as chemical exposures

generally cause multiple effects and chemical-induced health effects are generally comparable to

similar health effects observed in the absence of exposure. For example, eye, nose, and throat

irritation, and headache may be observed following exposure to a wide variety of chemicals but

may also be caused by other common stimuli (e.g., viral infection).
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

25

2.3.5 Temporal Association

To strengthen the causal relationship, the adverse health effect should occur at a time following

exposure that is consistent with the nature of the effect. For example, respiratory irritation

immediately following exposure to an irritant vapor such as chlorine gas is temporally consistent,

whereas effects noted years later may not be. On the other hand, tumors noted immediately

following exposure might be temporally inconsistent with a causal relationship, while tumors

arising after a latency period of months or years would be temporally consistent.

2.3.6 Coherence of Adverse Health Effect

Coherence or scientific plausibility of the association is also examined. This is assessed in terms

of evidence that the effects are consistent with the pharmacokinetics and mechanism of action of

the chemical. For example, reports of asthma and dermatitis caused by nickel are consistent with

abnormal immunotoxicity tests following exposure to nickel compounds.

2.4 Criteria for Studies Utilized to Identify Adverse Health Effects

Although a wide variety of information may be reviewed, only key studies are used to develop

acute severity levels. The following criteria are used to determine the relevance and quality of

data used for level development.

Published, peer-reviewed data are preferred; exceptions include well-conducted industrysponsored studies that have been reviewed by other organizations but have not themselves been

published in the literature, and doctoral dissertations. For example, an industry study (IRDC,

1985a) reviewed in a published article (Donald et al., 1991) was chosen as the basis for the severe

adverse effect level for toluene. A doctoral dissertation (Anglen, 1981) reviewed in a published

article (Das and Blanc, 1992) was used as the basis for the chlorine REL (Appendix C). Abstracts

and review papers are not used for level development (the latter are considered secondary

sources). Studies involving a single chemical are given preference over those with multiple

simultaneous exposures, especially if these are not quantified.

Only studies that consider non-carcinogenic endpoints are considered for this document. For a

consideration of carcinogenic endpoints, please refer to the OEHHA document titled Technical

Support Document for Describing Available Cancer Potency Factors. Studies using multiple

exposure doses and clearly indicating dose-response information are preferred (e.g., the Kulle et

al. (1987) study used as the basis for the formaldehyde REL). However, in some cases, an

inadequate toxicology database may necessitate the use of older studies in which such information

is unclear. Usually such studies are chosen if they are the only existing acute inhalation studies

and are consistent with the general toxicology database (e.g., the Dudley and Miller (1937) study

used for the hydrogen selenide REL).
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

26

2.4.1 Selection of Key Studies

An important step in the development of an acute REL is the identification of research studies that

contribute most significantly to the weight of evidence as to the degree of hazard presented to

humans by a particular substance (U.S.EPA, 1987; 1994a). These studies may involve a human

population studied in an epidemiological, clinical, or experimental exposure setting, or they may

involve experimental studies with animals. The key studies are given greatest weight in estimating

a threshold for adverse effects and in identifying the nature of the critical adverse effect.

2.4.1.1 Human Data

Human data are logically most relevant to assessing human health effects associated with chemical

exposures. Much of the available human exposure data is via inhalation. Principles for evaluating

human exposure studies for use in determining health-based exposure levels have been discussed

(NRC, 1986). Whenever possible, RELs were developed based on human data; of the 51 acute

RELs in this document, 36 are based on human health effects.

Three types of human studies have been used in assessing health effects of chemicals: (1)

epidemiological studies, (2) controlled exposure experiments, and (3) case reports. Each of these

three study types can provide important information needed to protect public health. When using

these studies for risk assessment, several factors are important in evaluating their quality and in

determining the level of certainty associated with their use.

2.4.1.1.1 Epidemiological Data

Epidemiological studies generally produce data on effects of chemical exposure to a large number

of persons. Areas of concern when interpreting epidemiological studies include exposure

measurement, health effects measurement, and accounting for covariables and confounding

variables (Lebowitz, 1983). The population studied may consist of the general public or

employees exposed at the workplace to varying concentrations of airborne chemicals.

Exposure measures frequently represent the greatest weakness of available epidemiological

studies. Continuous, long-term exposure monitoring of individual subjects is rarely available.

Frequently it is necessary to use limited, short-term, exposure monitoring data, which in many

cases are not specific to the individuals under study, in order to derive an estimate of what the

individual exposures may have been. Occupational exposures may vary over time as industrial

hygiene practices change and individuals change jobs. The degree to which air concentrations can

be adequately estimated is critical in determining the usefulness of an epidemiological study.

Health effect measures in epidemiological studies also frequently differ from those reported in

experimental animal studies and must be carefully examined. Human health effect measurement

generally consists of recording observable effects and conducting non-invasive tests. Health

effects data are compared with those compiled from a non-exposed group and may be presented

as incidence, standardized mortality ratios, or relative risk ratios. Health effects with a long

latency may be missed if the study duration is inadequate.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

27

Covariables and confounding variables should be controlled or removed from the study. Coexposure to other chemicals is an important concern as a potentially confounding effect.

Occupational studies raise an additional concern in that generally healthy workers may be less

sensitive to the adverse effects of chemical exposures than others in the general population,

including children, the elderly, and persons with preexisting medical conditions. Bias may also be

present where a workplace is disproportionate by gender (NRC, 1986). While occupational

studies provide important information, they are rarely used as key studies for acute toxicity

exposure level development, as the duration of exposure is generally over a much longer period of

time than is relevant for the acute reference exposure levels.

Negative epidemiological studies present an additional difficulty in interpretation. Estimating the

power of the study to detect adverse effects can be useful in providing an indication of the

maximum incidence consistent with the failure to show that the exposed group was statistically

different from the control group. Also, statistical confidence limits can be put around a negative

finding, i.e. around the relative risk (RR) of 1.

2.4.1.1.2 Controlled Human Exposure Studies

Controlled exposure studies have the advantages of having quantified exposure concentrations

and of being conducted with human subjects, thus combining two important features of human

epidemiological and animal toxicity studies (Hackney and Linn, 1983). The limitations of such

studies are that they may (1) involve small sample sizes, (2) be of very short exposure duration,

and (3) assess effects through subjective measurements that might miss significant health effects.

In spite of these potential shortcomings, controlled studies in human subjects, especially in

sensitive subpopulations such as asthmatics, are given preference over animal studies in the acute

REL development process. Human studies were used only if they were consistent with the

standard ethical practices of investigation at the time they were conducted. The preferred study is

a modern, ethical study approved by an Institutional Review Board for Human Studies.

2.4.1.1.3 Case Reports

Individual case reports of adverse effects associated with exposures to a chemical can be useful,

especially as qualitative confirmation that effects observed and quantified in animals also occur in

exposed humans. Multiple case histories with the same endpoint are especially relevant.

However, these reports are generally not appropriate for quantitation because of the very small

sample size and the unquantified exposures (Goldstein, 1983).

2.4.1.2 Animal Data

Many acute toxicity animal studies have been conducted, although studies that address the range

of toxic effects (from mild to life-threatening) may not be available for many substances.

Identification of the most appropriate animal species requires consideration of all available data

relevant to prediction of human effects from animal observations. Studies of the most sensitive

species have frequently been selected as key studies. Such an approach has the advantage of
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

28

offering maximal protection, especially since humans may be more sensitive than laboratory

animals in response to chemical exposure (Lehman and Fitzhugh, 1954). However, the animal

species most sensitive to a substance is not necessarily that most similar to humans in developing

adverse effects from a particular exposure. In general, of the animals used in laboratory studies,

non-human primates are considered to be the most similar in response to exposures to toxic

substances.

Selection of the animal model and key study can be influenced by what is known about human

health effects, and relevant areas of similarity and dissimilarity between humans and the animal

species may be established (Calabrese, 1982). Comparison of human and animal

pharmacokinetics and metabolism may be useful in selecting the relevant animal model for

predicting human health effects. For example, hamsters and rabbits have much greater metabolic

rates than monkeys (Plopper et al., 1983). This may increase or decrease their susceptibility

relative to humans. However, in most instances it is not possible to determine which species

responds most like humans.

An experimental study should have a clear rationale and protocol, use Good Laboratory Practice

Standards, and use appropriate analysis methods (CFR 1983 a, b). Experimental study designs

and criteria recommended by the NTP have been reviewed (Chhabra et al., 1990). Appropriate

statistical analysis of the results is important (Muller et al., 1984). However, the goal of

protecting public health must be weighed with experimental design so that important endpoints

are not missed and that responses of relevant species are not ignored. Furthermore, it is

important that there not be disincentives to conducting good studies in order to avoid the

establishment of reference exposure levels.

3. Dose Response Assessment

3.1 Severity of Adverse Effects

Following acute exposure, health effects of varying severity may be observed and are determined

by the extent of exposure, or the dose. Although the relationship between exposure and health

outcome is a continuous one, effects may be categorized into discrete severity levels. Specific

toxic effects that may be observed at each level are identified for each chemical. The most easily

specified health effect for which exposure indices can be developed is death. Less severe effects,

though less well defined, may also result in significant adverse health consequences.

We have defined two additional graded categories of toxic effects. Except for death, these graded

effect levels are not sharply demarcated but each merges into adjacent categories. Figure 3

depicts how the dose-response relationship is a continuous phenomenon. The dose is a factor of

concentration and duration of exposure. In general, as dose increases, so does the severity of the

response. Increased severity of physiologic response (from one acute severity level to the next)

may involve the same receptor(s). For example, for hydrochloric acid, the REL (level protective

against mild adverse effects) is protective of eye and nose irritation. At higher exposure

concentrations, the severe adverse effect level is protective against severe eye, nose and throat

irritation. And at higher concentrations still, the life-threatening level protects against lower
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

29

respiratory effects, including pulmonary edema, which may lead to death (Acute Toxicity

Summary for Hydrochloric Acid, Appendix C).

Alternatively, for other compounds, increasing severity of response may involve different

receptors or organ systems. For example, the REL for methanol is based on subtle neurological

impairment, a mild adverse effect, while the level protective against severe adverse effect is

protective against developmental or reproductive toxicity (Acute Toxicity Summary for

Methanol, Appendix C).

It is important to note that exposure at or above the REL will not necessarily result in adverse

health consequences. Conversely, there may be individuals exhibiting idiosyncratic responses who

may experience unpredictable health effects at shorter exposure durations or at concentrations

below these levels. For a list of several common reactions (symptoms) and observable findings

(signs) that may be observed following exposure to hazardous substances and their categorization

into the aforementioned levels, see Table 6. It is not practical to include a comprehensive listing

of all reactions and endpoints reported or considered for the 51 chemicals evaluated so far;

therefore, only commonly considered endpoints are listed. Please refer to individual chemical

summaries (Appendix C) for a discussion of the reactions and toxicological endpoints reported for

individual chemicals.

3.2 Levels of Adverse Effect

In developing acute exposure levels and RELs, we have applied the methods described in the

NAS publication, Guidelines for Developing Community Emergency Exposure Levels (NRC,

1993). The three acute severity levels for one-hour exposure durations are defined below (also

see Figure 3). However, the risk management concerns of emergency planning and response are

not incorporated into these definitions. Instead, the levels are defined strictly based on

toxicological and medical criteria. Appendix A lists 51 chemicals for which acute RELs have

been developed by OEHHA. The toxicologic endpoints considered in deriving the RELs are also

listed. The acute toxicity summaries are included with these guidelines as Appendix C.

3.2.1 Level Protective Against Mild Adverse Effects

The level protective against mild adverse effects refers to the concentration of an airborne

substance (a gas, vapor, aerosol or aerosolized particle) below which exposure for one hour is

predicted to result in no adverse health effects in nearly all of the population. Exposure to

concentrations above this level may result in mild adverse health effects, such as enzyme induction

or biochemical changes consistent with the mechanism of action, and reversible subcellular or

cellular changes (U.S.EPA effect severity level 0-5, Table 5), mild irritation of the eyes, nose or

throat or other minor physiologic changes of short duration, such as subtle neurologic changes

detectable only by neuropsychological testing, not by clinical examination (e.g., REL for

methanol).

This level is intended to be protective of adverse health effects which are long-lasting (i.e., those

that persist beyond the duration of exposure) and those which affect judgment or impair the ability
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

30

to respond. For example, following exposure above the mild adverse effect level (but below the

severe adverse effect level), an irritant gas might produce eye and nose irritation and an organic

vapor may cause headaches; however, these effects are expected to resolve soon after exposure

ceases.

3.2.1.1 Lower Airway Responsiveness

Lower airway effects are often the most sensitive physiologic response following inhalation

exposure to certain chemicals. Because these endpoints are frequently used for REL

development, we have defined specific criteria for tests of lower airway function to be considered

in categorizing effect severity. In some individuals, the lower airways respond acutely to various

stimuli by decreased airway diameter (Woolcock, 1994). Although various methods are used to

measure pulmonary function, airway responsiveness is commonly and easily assessed and is a

sensitive indicator of airway narrowing in response to external agents (Gold, 1994; Woolcock,

1994). While varying spirometric criteria have been used for the determination of airway

hyperresponsiveness (Bernstein et al., 1992; Cherniak et al., 1995; Eschenbacher et al., 1992;

Jubber et al., 1993; Wiebicke et al., 1990), the standards used in this document are consistent

with previously specified guidelines and research protocols (Aris et al., 1995; Eiser et al., 1983;

Sterk et al., 1993).

To be considered a mild effect, pulmonary function changes detected by spirometry must be the

most sensitive adverse health effect observed for a particular chemical. Following inhalation

exposure to the chemical, the following spirometric changes (compared to pre-exposure findings)

are criteria for inclusion as a mild effect: (1) statistically significant but clinically insignificant

changes in forced expiratory volume in 1 second (FEV1) (i.e., <20% decrement in FEV1

compared to pre-exposure baseline); or (2) statistically or clinically significant changes in specific

airway resistance (SRaw) or airway conductance (SGaw) following inhalation challenge with the

chemical of interest (clinical significance is a 100% increase in SRaw or a 50% decrease in SGaw)

without a 20% drop in FEV1 or symptoms consistent with bronchoconstriction, such as chest

tightness, wheezing and shortness of breath (Table 7).
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

31

Table 7. System for categorization of pulmonary function into effect severity levels.

Endpoint1 Mild Severe Life-threatening

Spirometry Test

Result (compared

to baseline)

Statistically significant

but < 20% decrement in

FEV1

2

> 20% decrement in FEV1 Not applicable

Methacholine

Challenge Test

Result

> 100% increase in

specific airway

resistance (SRaw) or

> 50% decrease in airway

conductance (SGaw)

no symptoms of

bronchoconstriction

< 20% decrement in

FEV1

100% increase in specific

airway resistance (SRaw)

or

50% decrease in airway

conductance (SGaw)

accompanied by (1)

symptoms of

bronchoconstriction or

(2) > 20% decrement in

FEV1

Not applicable

Clinical Findings None anticipated Chest tightness, shortness

of breath, wheezing

Wheeze detected by

examination

Hypoxia or decreased

oxygen saturation

Status asthmaticus

Respiratory arrest

1

 A finding under one endpoint category is sufficient to categorize a response into a

particular severity level.

2 Forced expiratory volume in one second.

3.2.2 Level Protective Against Severe Adverse Effects

The hallmark of a severe adverse effect level outcome is a change in organ function and/or tissue

damage that may be detectable by clinical examination (U.S.EPA effect severity levels 5-9, Table

5). For example, loss of balance, asthma exacerbation, hemolysis, cardiac ischemia and adverse

outcomes of a pregnancy are all clinically significant findings. With some exceptions (such as

adverse outcome of a pregnancy), effects may be reversible, although prolonged exposure may

result in irreversible effects.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

32

Exposure to an airborne substance above the level protective against severe adverse effects for

one hour may lead individuals to seek assistance. Exposures above this level may be immediately

disabling by adversely affecting one’s judgment and the ability to take appropriate healthprotective actions during or directly following the exposure. In addition to protection against

immediate health effects, this level is meant to be protective of certain long-term effects

potentially resulting from exposure to hazardous substances, such as reproductive endpoints.

This document does not address carcinogenic effects. Exposure above this level may, but does

not necessarily, result in prolonged or irreversible effects following cessation of exposure.

Although exposure at or above the level protective against severe adverse effects is undesirable

and may require protective action, it does not a priori indicate that injury or illness would occur.

This level is designed to protect the natural diversity of individuals within the population. With

increasing exposure concentration or duration above the severe effect level, there is greater

likelihood of serious or irreversible health effects occurring in a greater proportion of the

population. Examples of adverse health effects above this level include severe eye irritation,

marked upper or lower respiratory tract irritation (including dyspnea or bronchospasm),

disorientation, blurred vision, vomiting, hemoglobinuria, arrhythmias and adverse outcomes of an

existing or subsequent pregnancy.

Since the lower airway is often the most sensitive endpoint for severe adverse effects following

inhalation exposure, criteria for pulmonary function testing considered under this level have been

specified by OEHHA (Table 7). Pulmonary function test results considered under this level are a

20% or greater decrement in FEV1 compared to baseline, with or without symptoms of

bronchoconstriction such as wheezing, chest tightness and shortness of breath. Alternatively, a

100% increase in SRaw or a 50% decrease in SGaw compared to baseline, accompanied by

symptoms of bronchoconstriction, is also consistent with a severe adverse effect. Another

pulmonary function test result that is consistent with a severe adverse effect level endpoint is

forced expiratory volume in 1 second to forced vital capacity ratio less than 70% (FEV1/FVC <

70%), which suggests obstructive airway disease. Other measures of the integrity of the lung,

such as the diffusing capacity (DL), a measure of the efficiency of gas exchange across the airblood barrier, may be taken into consideration, but would not be the sole determinant of the acute

severity exposure level.

Examples of aid that may be required above this level include: physical assistance needed because

severe eye irritation hampers escape; medical intervention to prevent the progression of adverse

health effects such as those due to hemolysis; and sheltering in place because activities outdoors

may result in greater exposure and adverse health effects, such as vomiting, than a protected

indoor setting.

As with all health effects, certain individuals may be more susceptible to adverse health

consequences following exposure above the level protective against severe adverse effects. These

sensitive individuals may suffer health effects that may require assistance at a lower level of

exposure than the general population. For example, individuals with asthma, who are likely

following exposure to sulfur dioxide to exhibit bronchoconstriction at a lower concentration than
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

33

the general population, may require greater protection from this substance than nonasthmatic

persons. Acute severity exposure levels are designed to be protective for the range of susceptible

persons in the general population.

3.2.3 Level Protective Against Life-threatening Effects

Any exposure above this level for more than one hour is potentially lethal, especially to sensitive

individuals; and, as exposure duration increases, death becomes a high probability for all exposed

persons (U.S.EPA severity effect level 10, Table 5). If death does not occur, the probability of

severe, irreversible injury increases with increasing exposure duration or concentration. Examples

of adverse health effects considered under this level include severe acute pulmonary edema and

respiratory or cardiac arrest. Only exposures that are potentially life-threatening shortly after

exposure (within minutes to days) are considered. Exposures with the potential to cause medical

conditions that result in death months to years following exposure are not considered. For

example, carcinogenic effects are not considered in this document. Health consequences that are

immediately severe and may lead to death months later, such as pulmonary edema, are taken into

account in developing the level protective against severe adverse health effects.

3.3 Estimation of Threshold or Low Response Concentrations

Noncancer health effects assessment has been based on the concept that a threshold concentration

or dose exists below which no adverse effects would occur. While such thresholds are observed

among individuals, the existence and magnitude of a population threshold below which no

members of the population would experience adverse effects cannot be demonstrated. The entire

population of concern is not examined, rather a sample of the population from which inferences

are drawn is studied. Therefore, it is not possible to distinguish whether a concentration is truly

below a population threshold level for an adverse effect or is rather a level associated with a

relatively low incidence of adverse effects which cannot be distinguished from background rates in

the population.

Two major strategies were used for dose-response assessment methods to determine thresholds of

responses. These are the Benchmark Concentration (BC) approach and the No Observed

Adverse Effect Level (NOAEL) approach. A description of an alternative approach that has been

proposed but not yet adopted by U.S.EPA, Categorical Regression Analysis, is provided in

Appendix D. As explained earlier, existing exposure guidelines were first reviewed, and if

appropriate, adopted as RELs and other acute severity levels. When appropriate standards did

not exist (the majority of cases), the methodologies described here were used.

Of the methods presented, the preferred one is the Benchmark Concentration approach. A

comprehensive evaluation of the literature specific to a toxicant and of the quantal dose-response

data is required to estimate levels using the BC method. Supporting toxicological data will not,

however, always be sufficient to permit this level of quantification. Furthermore, the methods are

not generally applicable for chemicals with large data gaps. We were able to use the BC approach

to develop 2 RELs and several levels protective against severe or life-threatening effects.

Limitations in available data preclude development of more RELs using the BC approach.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

34

3.3.1 Benchmark Concentration

The importance of a dose-response relationship in the evaluation of effects of chemical exposure

is well established. The NOAEL approach (explained below) does not explicitly incorporate this

information. This led to explorations of the concept that a concentration estimated to be

associated with a predefined low risk could provide an alternative to the NOAEL (Crump, 1984;

Dourson et al., 1985; Dourson, 1986; Gaylor, 1988; Gaylor, 1989; Hartung, 1987; Mantel and

Bryan, 1961; Mantel et al., 1975;). Crump (1984) proposed the term “benchmark dose” and

extensively evaluated this concept. In this document, the term benchmark concentration (BC) is

used since inhalation toxicology data are described in terms of air concentrations.

The BC method is a mathematical and statistical approach to calculate chemical exposure levels

(Alexeeff et al., 1992, 1993; Crump, 1984; Lewis and Alexeeff, 1989). In this document, the BC

is defined as the 95% lower confidence limit of the concentration expected to produce responses

in five of every 100 subjects exposed at this dose. A log-normal concentration versus response

relationship is used to identify the concentration expected to produce a 5% increase in toxic

response (TC05) via a maximum likelihood estimate. This is graphically depicted in Figure 4.

3.3.1.1 Selection of Appropriate Benchmark Concentration Criteria

Suggested response levels for the BC have ranged from one in one million (Mantel and Bryan,

1961) to 10% (Dourson et al., 1985). The 1 to 5% response range approximates the lower limit

of adverse effect detection likely to occur in typical human epidemiological and laboratory animal

studies (Gaylor, 1992). In 1995, using developmental toxicity data, the U.S.EPA Benchmark

Dose Workshop concluded that a 1% response rate was likely to be too low, while either 5% or

10% response rates were adequate for the purposes of estimating a benchmark concentration

(Barnes et al., 1995). One reason for this conclusion was the large difference (29-fold) between

observed NOAELs and the 1% benchmark using developmental toxicity data. Subsequently, the

U.S.EPA (IRIS, 1997) has used a 10% response rate for benchmark concentrations when deriving

chronic inhalation reference concentrations (RfCs). However, in the case of a steep doseresponse relationship, the selection of benchmark incidence is less influential on the final value.

For acute exposure studies, 1 and 5% incidence benchmark concentrations differed, on average,

by less than 2-fold from the respective NOAEL (Fowles and Alexeeff, 1996). Therefore,

OEHHA chose a 5% response rate for the BC.
1 10 100 1000

Chemical Concentration in Air

99

90

75

50

25

10

5

Maximum likelihood estimate

95% lower confidence limit

Figure 4. Log-probit modeling of dose-response data. A benchmark 

concentration (BC) was estimated for a 5% increase in 

response (MLE05). 

MLE 05

% Response

BC05
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

36

It is important to select an appropriate mathematical model for the type of data used for

benchmark concentration calculations. The log-normal model is among the most widespread

models used for toxicity testing and has traditionally been used extensively for determination of

acute lethality and other dichotomous responses (Finney, 1971; Rees and Hattis, 1994).

Furthermore, the log-normal distribution aspect of the model is biologically plausible and accounts

for some degree of inter-individual variability (Rees and Hattis, 1994). Hattis (1996) showed that

the log-normal relationship effectively modeled data from 126 human studies. The Weibull model

is used by U.S.EPA when determining benchmark concentrations for the chronic inhalation RfCs

(US EPA, 1997). However, a comparison of the Weibull and Probit models by OEHHA for acute

inhalation toxicity data indicated that the Probit model provided a better statistical fit to relatively

steep dose-response slopes. Furthermore, the uncertainty in the estimates using Probit, as

measured by the distance between maximum likelihood estimates and the respective 95%

confidence interval, was reduced (Fowles and Alexeeff, 1996). For these reasons, the Probit

model was chosen over the Weibull model for use in deriving acute BCs for this document. The

log-normal model is described as follows:

P(d) = a0 + [(1 - a0)Φ(a1 + (a2 * log10d))]

where P(d) is the probability of a response occurring at dose d, Φ is the cumulative distribution

function of the standard normal distribution, and a0, a1, and a2 are background, intercept, and

slope terms, respectively. The model makes no assumption of a background response in the test

population in absence of control data. If controls were observed to exhibit a response, then that

response was factored into the calculation.

The 95 percent lower confidence limit on concentration (LCL) takes into account the variability

of the test population and is dependent on the number of subjects in the study. The 95% LCL

was recommended by the Benchmark Dose Workshop for use in benchmark calculations (Barnes

et al., 1995). The advantages of the BC are that it reflects the shape of the dose-response curve

and takes into account the number of subjects involved in the study. In addition, it is not

necessary to obtain a no-observed adverse-effect level in order to determine an exposure level and

the BC does not require an additional uncertainty factor if the NOAEL is estimated from a

lowest-observed adverse effect level (see section 3.3.2 below).

In spite of its advantages, the experimentally derived BC value contains areas of uncertainty. For

example, the studies used to estimate the BC may have been performed with animals rather than

humans. Also, the experimental duration of exposure may differ from that which is of interest for

the establishment of exposure levels. Additionally, the dose of toxicant delivered to the target

tissue may differ between species and among humans and may depend on the type of activity in

which the individual is engaged. In general, higher levels of activity result in increased respiratory

rates and in increased doses of inhaled chemicals delivered to the lungs, and possibly systemically.

Another area of uncertainty is that there can be a large degree of variability in the number of

people who respond at any exposure dose. For example, there may be over a 10-fold variability in

the irritation threshold (the concentration of a substance at which irritation of the eyes, nose

and/or throat is first detectable) for chlorine (Anglen, 1980). The BC will likely need to be

modified by UFs to account for these concerns.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

37

The use of UFs to estimate chemical exposure levels from BCs is based on similar

recommendations for calculating U.S.EPA’s “reference dose” or RfD (Barnes et al., 1995).

Uncertainty factors are applied to the BC for the following areas of uncertainty (Table 8):

(1) animal to human extrapolation: 3-fold.

(2) human intraspecies variability: 10-fold when estimating an exposure level based on an

animal study, or 3-fold when based on a human study performed in healthy adults. This

UF is reduced to 1 if using data that includes an assessment of sensitive human subpopulations. This UF can also be 10 if data indicate a wide variability in response in the

human population.

Table 8. Uncertainty Factors Used with Benchmark Concentrations

Type of Study Intraspecies Variability Interspecies Uncertainty Total

Uncertainty

Animal 10 3 30

Human (average) 3 (10) 1 3 (10)

Human (sensitive) 1 1 1

The BC is considered by some investigators to account for interspecies as well as experimental

variability (Barnes et al., 1995). To acknowledge the greater degree of certainty in a BC for

acute inhalation toxicity compared to the NOAEL approach, an UF of 3, instead of the

conventional 10, is applied when estimating the acute chemical exposure level from animal data

(Table 8).

Acute Toxicity Exposure Level = BC/(UFs)

where 1 < UF < 10

The rationale for the above UFs is illustrated in Figures 5 and 6. When using animal data, a BC

has greater precision than a NOAEL at estimating a true threshold of response in the animal

population. This is because the estimate of the number of animals affected at a given

concentration can be estimated with accuracy. The result of using more precise methodology is a

reduction in the total uncertainty involved in extrapolating to a threshold of response for sensitive

individuals. The precise magnitude of this reduction is, by definition, unknown. It is clear that

the increased precision in estimating an animal threshold does not reduce human variability in

response. Therefore, OEHHA proposes that the typical 10-fold UF for interspecies
LOAEL UF

 10-Fold

Chemical Concentration (Log scale)

Percent Responding

Animals

Humans

Figure 5. Estimation of a human threshold from animal data. Hypothetical distributions 

of human and laboratory animal responses to increasing concentrations of a chemical are 

shown. 

BC

3-Fold

LOAEL

Estimated

 NOAEL

REL

NOAEL

Intraspecies 

 UF

10-Fold

Interspecies

 UF

10-Fold

LOAEL (Lowest observed adverse effect level): An example of an experimental LOAEL is 

shown, in this case the experimental LOAEL represents approximately 25% incidence in the 

experimental animal population. If no NOAEL is determined in the experiment, a NOAEL is 

estimated using an uncertainty factor of up to 10.

NOAEL (No observed adverse effect level): An example of an animal experimental NOAEL is 

shown. The NOAEL can be estimated from the LOAEL using an uncertainty factor of up to 10. 

BC (Benchmark concentration): An example of an experimental benchmark concentration is 

shown. In this case, the BC represents less than 10% incidence in the animal population, and, 

when combined with an uncertainty factor of 3, provides an estimate for a NOAEL in average 

humans. A further uncertainty factor of up to 10 is needed to protect sensitive individuals.

Estimated NOAEL (humans): A NOAEL for average humans is estimated from the animal data 

using an uncertainty factor of up to 10. 

0
LOAEL UF

up to 10-Fold

Intraspecies 

UF 10-Fold

Chemical Concentration (Log scale)

Distribution of Responses

REL

Figure 6. Estimation of an REL that is at or below the threshold for sensitive individuals 

from healthy human experimental data. A hypothetical distribution of human responses 

to an increasing concentration of a chemical is shown. 

LOAEL

BC

3-Fold

 NOAEL

LOAEL (Lowest observed adverse effect level): An example of an experimental LOAEL is 

shown. In this case the experimental LOAEL represents a 25% incidence in the general 

population. If no NOAEL is determined in the experiment, a NOAEL is estimated using an 

uncertainty factor of up to 10.

NOAEL (No observed adverse effect level): An example of an experimental NOAEL is shown. 

The NOAEL can be estimated from the LOAEL using an uncertainty factor of up to 10. In the 

case shown, the NOAEL represents less than 10% incidence in the general population and, 

when combined with an uncertainty factor of up to 10, results in a reference exposure level that 

is protective of the vast majority of individuals.

BC (Benchmark concentration): An example of an experimental benchmark concentration is 

shown. In the case shown, the BC represents less than 10% incidence in the general population, 

and, when combined with an uncertainty factor of up to 3, results in a reference exposure level 

that is protective of the vast majority of individuals.

0
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

40

differences be reduced to 3-fold (the rounded geometric mean of possible UFs between 1 and 10).

While the geometric mean is 3.16, U.S.EPA uses a single intermediate UF of 3.00 rather than

3.16, while two intermediate UFs accumulate to 10 (U.S.EPA, 1994a). Thus, to maintain

consistency with U.S.EPA practice, UFs of 3 would generally be used for intraindividual

variability to reflect decreased residual uncertainty when using a BC. However, there may be

some circumstances where it is appropriate to use an uncertainty factor of 10 in this approach, for

example, where evidence indicates a wide variability in response to a toxicant in the human

population. When a REL is derived by applying the BC to an animal study, the UF for human

variability remains 10-fold. However, in the case of a BC calculation from a study involving

healthy human subjects, an UF of 3 is proposed since the total uncertainty in estimating a

threshold for sensitive humans is reduced by using human, rather than animal, studies. Finally, if a

BC can be determined in a study of a sensitive population, no UFs need be applied (U.S.EPA,

1994a; NRC, 1993).

As with the NOAEL method, if the duration of the experiment differs from that for which one is

developing the REL, time extrapolation is performed to determine an appropriate exposure

concentration. The principles used in time extrapolation in the example below will be described in

detail in section 3.4.1.

Example:

Formaldehyde is used as an example to illustrate the use of the benchmark concentration

to calculate an acute reference exposure level. The most sensitive noncancer endpoint for

formaldehyde toxicity is eye irritation. Kulle and colleagues (1987) observed mild to

moderate eye irritation in human subjects exposed to formaldehyde for 3 hours. Using a

log-probit analysis (Crump, 1983), OEHHA calculated a 3-hour BC05 of 0.44 ppm

formaldehyde (see Figure 7). The 3-hour BC05 was adjusted to a 1-hour exposure level

using the formula C

n

 * T =K, where n=2. (See Section 3.4.1 on Time Extrapolation for

the rationale for the use of this equation.) These calculations are summarized below:

180-minute acute exposure level = 0.44 ppm

C = 60-minute acute exposure level

C

2

 * (60 min)= (0.44 ppm)

2

 * (180 min)

C = 0.76 ppm

Figure 7 contains a graphic representation of the derivation of a BC for formaldehyde.

3.3.2 Use of No-Observed-Adverse-Effect-Levels (NOAEL)

A No-Observed-Adverse-Effect-Level (NOAEL) may be defined as an exposure level with no

biologically or statistically significant increase in the frequency or severity of adverse effects

among an exposed population relative to a control group. The NOAEL must be tempered by
2.4 2.6 2.8 3.0 3.2 3.4

2

3

4

5

6

Formaldehyde Concentration (Log ppb)

Irritation Response (Probit scale)

5% response BC(05) = 435 ppb

MLE

95% LCL

Figure 7. This figure depicts the derivation of the benchmark 

concentration [BC(05)] for formaldehyde. These data, taken from Kulle and 

colleagues (1987), are the result of 3-hour exposures to formaldehyde 

resulting in mild to moderate irritation. The BC(05) is the 95% lower 

confidence limit (LCL) of the dose producing a 5% response rate.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

42

appropriate statistical interpretation. A NOAEL is sometimes incorrectly viewed as an estimate

of a threshold level for adverse effects. However, a NOAEL could be associated with a

substantial (1-20%) but undetected incidence of adverse effects among the exposed population, or

alternatively it could be many-fold lower than a true population threshold (Gaylor, 1992;

Leisenring and Ryan, 1992). This is so because only a subset of individuals from the population

has been observed, and because the experiment may not have been designed to observe all adverse

effects associated with the substance. Therefore one may not safely conclude that the study

concentration or dose is not associated with any adverse effects. Experimental exposure levels

are usually selected following a range-finding experiment. U.S.EPA (1994a) determined that a

NOAEL not associated with any biological effect (a “no observed effect level” or NOEL)

identified from a study with only one dose level is unsuitable for derivation of an RfC for chronic

exposure; likewise, a NOEL is inadequate for determining acute severity levels. Because there is

a limited availability of multi-dose studies for the variety of chemicals considered, OEHHA

considers a NOAEL without an associated LOAEL identified in the same study (termed a freestanding NOAEL) to be acceptable for use in deriving an acute REL if there are no other suitable

studies and as long as the overall health hazard information for that substance is consistent with

the NOAEL study.

3.3.2.1 Derivation of Acute Reference Exposure Levels Using NOAELs

The NOAEL approach is based on the application of uncertainty factors (UFs) to the maximum

dose level causing no observable adverse effects for that endpoint (California Department of

Health Services, 1991):

NOAEL / UF = acute reference exposure level.

The NOAEL is an estimate of a threshold level for the absence of toxic effects in a study

population and is determined directly from the observations reported in a specific scientific study.

Prior to the determination of a NOAEL, the literature is examined to identify the relevant toxicity

endpoints, such as lethality or respiratory tract irritation. Toxic endpoints are evaluated and a

dose-response relationship is determined. Acute severity effect levels are then established: (1) the

most sensitive adverse effect is used to define the NOAEL for the REL (usually a mild adverse

effect); (2) severe adverse effects, such as chemical injury which would be irreversible without

medical intervention and reproductive endpoints, are used to identify NOAELs for the level

protective against severe adverse effects; and (3) lethality or potentially fatal effects are used to

identify NOAELs for the level protective against life-threatening effects.

3.3.3 Use of Lowest-Observed-Adverse-Effect-Levels (LOAEL)

A Lowest-Observed-Adverse-Effect-Level (LOAEL) may be defined as the lowest exposure level

with a biologically and/or statistically significant increase in the frequency or severity of adverse

effects among an exposed population relative to a control group. The highest exposure

concentration which results in biologic effects that are not considered adverse may be termed the

lowest observed effect level (LOEL); this is identical to the NOAEL (U.S.EPA, 1994a). If a

NOAEL is not identifiable from the literature, it is estimated from the lowest exposure
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

43

concentration reported to produce the adverse effect; this is the lowest observed adverse effect

level (LOAEL). An uncertainty factor is applied to the LOAEL to estimate the NOAEL:

LOAEL/UF = NOAEL

A one-to-ten-fold uncertainty factor has been proposed to account for the higher health risk

potentially associated with a LOAEL compared with a NOAEL (U.S.EPA, 1994a). In general, a

factor of 10 has been used in most previous assessments by U.S.EPA and OEHHA. An

uncertainty factor is applied to calculate a threshold level (NOAEL) from the LOAEL.

The relationship between LOAELs and NOAELs has been examined for chronic exposures. The

effectiveness of a ten-fold LOAEL-to-NOAEL uncertainty factor was confirmed for several

inhalation exposure data sets (Gift et al., 1993). Kadry and associates (1995) showed that among

a small data set (4 chemicals) LOAEL to NOAEL ratios were less than 5. However, where only a

LOAEL has been observed, the magnitude of the difference between the observed concentration

and the maximum concentration where adverse effects would not be detected is uncertain.

OEHHA staff consider a10-fold UF for extrapolation from a LOAEL to a NOAEL to be

protective when applied to all types of studies.

The RAAC recommended that OEHHA delineate situations where uncertainty factors less than 10

could be used in the REL development process. Although the use of an uncertainty factor less

than 10 (an intermediate uncertainty factor) may be appropriate under certain circumstances,

application of UFs less than 10 to acute exposures by other organizations (e.g., AIHA’s ERPGs,

see Section 1.8.1) appears to be subjective and guidance in specific criteria as to when it is

appropriate is lacking. As discussed elsewhere, use of the benchmark concentration approach can

address this issue directly. However, in most circumstances there is insufficient data for a

benchmark concentration approach. Consequently, OEHHA developed specific criteria for the

use of an intermediate uncertainty factor. Based on an analysis of LOAELs and NOAELs

reported in various toxicological studies, we found that in certain circumstances (extrapolating

from a LOAEL to a NOAEL for both mild (sensory) irritation and lethal effects), UFs less than 10

are justified (Alexeeff et al., 1997). OEHHA uses UFs less than 10 in the following cases: (1) for

extrapolating from a LOAEL to a NOAEL for mild adverse effects; and (2) for potentially lethal

effects (life-threatening level). In the case of the mild adverse effect, an analysis by Alexeeff et

al., (1997) (Appendix F) of LOAEL to NOAEL ratios for over 100 datasets indicated that the

95th percentile of that ratio is 6.2. The distribution is skewed to the right. For some chemicals, a

UF of 10 may not be adequate. OEHHA has chosen a UF of 6 to extrapolate from the LOAEL to

the NOAEL based on the analysis. OEHHA has followed precedence set by U.S.EPA (1994a) in

the use of an intermediate uncertainty factor of 3 when using lethality data to determine a level

protective against life-threatening effects. It is suggested that further analysis of the LOAEL to

NOAEL relationship be undertaken to better evaluate the use and magnitude of this adjustment

factor. Results of such a detailed analysis could be used to improve the exposure level setting

procedure in the future.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

44

Example:Thirty six healthy human volunteers reported eye irritation after being exposed

to 0.06 ppm acrolein for 5 minutes (Darley et al., 1960). Subjects wore carbon-filter respirators

during exposure, so that only the eyes were exposed to the test mixture. An uncertainty factor of

6 was applied for estimation of a NOAEL from the 5-minute LOAEL of 0.06 ppm. An additional

uncertainty factor of 10 was applied to account for sensitive individuals, resulting in a total

uncertainty factor of 60. For a complete derivation of this REL for Acrolein see Appendix C.

If there exist multiple, non-identical NOAELs and LOAELs for the same compounds, the study of

the best quality reporting the highest value for a NOAEL (preferred) or the lowest value for the

LOAEL is used for the development of acute severity levels. Preferably, a study should report a

NOAEL as well as a LOAEL. However, this is not always done. As stated above, a freestanding NOAEL (i.e., a NOAEL reported at the highest exposure concentration studied, with no

reported LOAEL) is used as the basis for an acute toxicity exposure level only when there are no

other appropriate studies on which to base the level and the dose-response data are consistent

with other dose response information reported in the scientific literature.

3.3.4 Accounting for Uncertainties in the Database

Acute RELs and other toxicity exposure levels must address uncertainties in the available data.

These areas of uncertainty are accounted for with the use of extrapolation factors or uncertainty

factors. Uncertainty factors are used extensively with human or animal toxicity data to estimate

“safe” or “acceptable” exposure levels for humans (Dourson and Stara, 1983). Uncertainty factors

are used by OEHHA in deriving acute RELs to account for the following, discussed below :

1)potentially greater susceptibility to the toxic effects of exposure to substances in humans

compared with laboratory animals (Dourson and Stara, 1983; Vettorazzi, 1976);

2)the uncertainty involved in extrapolating from LOAELs to NOAELs (Gift et al., 1993;

Dourson and Stara, 1983); 

3)the large range of individual variability in the human population, e.g., low risk vs. high risk

individuals (Vettorazzi, 1976; Hattis, 1996).

4)other deficiencies in the study design (Bigwood, 1973; Dourson and Stara, 1983; Lehman and

Fitzhugh, 1954; NRC, 1993);

The use of uncertainty factors for determining “safe” or “acceptable” levels has been discussed

extensively in the toxicologic literature (Alexeeff et al., 1994; Bigwood, 1973; CDHS, 1991;

Dourson and Stara, 1983; NAS, 1977; U.S.EPA, 1989; Vettorazzi, 1976). While most of the

applications have focused on long-term exposure, many of the factors are applicable to acute

inhalation exposure and are based on acute experiments. Uncertainty factors used for each

chemical are presented in Table 9.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

45

Table 9. Uncertainty factors used in derivation of acute RELs

Chemical Interspecies Sensitive

Individuals

LOAEL to

NOAEL2

Methodology

Used3

Total UF

Acrolein N/A 10 6 NOAEL 60

Acrylic acid 10 10 N/A NOAEL 100

Ammonia N/A 3 N/A BC 3

Arsenic 10 10 10 NOAEL 1000

Arsine 10 10 N/A NOAEL 100

Benzene 10 10 N/A NOAEL 100

Benzyl chloride 10 10 6 NOAEL 600

Carbon disulfide 10 10 N/A NOAEL 100

Carbon monoxide1 N/A 1 1 NOAEL 1

Carbon

tetrachloride

10 10 10 NOAEL 1000

Chlorine N/A 10 N/A NOAEL 10

Chloroform 10 10 N/A NOAEL 100

Chloropicrin 10 10 N/A NOAEL 100

Copper N/A 10 N/A NOAEL 10

Dioxane N/A 10 6 NOAEL 60

Epichlorohydrin N/A 10 6 NOAEL 60

Ethylene glycol

monobutyl ether

N/A 10 N/A NOAEL 10

Ethylene glycol

monoethyl ether

10 10 N/A NOAEL 100

Ethylene glycol

monoethyl ether

acetate

10 10 10 NOAEL 1000

Ethylene glycol

monomethyl ether

10 10 10 NOAEL 1000

Formaldehyde N/A 10 N/A BC 10

Hydrochloric acid N/A 1 N/A NOAEL 1

Hydrogen cyanide 10 10 N/A NOAEL 100

Hydrogen fluoride N/A 10 N/A NOAEL 10

Hydrogen selenide 10 10 6 NOAEL 600

Hydrogen sulfide N/A 1 1 NOAEL 1

Isopropyl alcohol N/A 10 N/A NOAEL 10

Mercury 10 10 10 NOAEL 1000

Methanol N/A 10 N/A NOAEL 10

Methyl bromide 10 10 N/A NOAEL 100
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

46

Chemical Interspecies Sensitive

Individuals

LOAEL to

NOAEL2

Methodology

Used3

Total UF

Methyl

chloroform

N/A 10 N/A NOAEL 10

Methyl ethyl

ketone

N/A 10 6 NOAEL 60

Methylene

chloride

N/A 10 N/A NOAEL 10

Nickel N/A 1 6 NOAEL 6

Nitric acid N/A 1 N/A NOAEL 1

Nitrogen dioxide1 N/A 1 N/A NOAEL 1

Ozone1 N/A 1 1.3 LOAEL 1.3

Perchloroethylene N/A 10 6 NOAEL 60

Phenol N/A 10 N/A NOAEL 10

Phosgene 10 10 N/A NOAEL 100

Propylene oxide 10 10 6 NOAEL 600

Sodium hydroxide N/A 10 6 NOAEL 60

Styrene N/A 10 N/A NOAEL 10

Sulfates1 N/A 1 N/A NOAEL 1

Sulfur dioxide1 N/A 1 1 NOAEL 1

Sulfuric

acid/oleum

N/A 1 N/A NOAEL 1

Toluene N/A 10 N/A NOAEL 10

Triethylamine N/A 10 N/A NOAEL 10

Vanadium N/A 10 N/A NOAEL 10

Vinyl chloride N/A 10 N/A NOAEL 10

Xylenes N/A 10 N/A NOAEL 10

1

The California Ambient Air Quality Standard was used as the basis for the acute REL;

uncertainty factors may differ from those described in this document since different

methodology was used for the derivation.

2 N/A = Not applicable; when used in “Interspecies” column, indicates that human study was

used as basis for REL; when used in “LOAEL to NOAEL” column, indicates that NOAEL

was reported in study.

3 NOAEL = No observed adverse effect level methodology; BC = Benchmark concentration

methodology.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

47

3.3.4.1 Differences Between Human and Animal Susceptibility

Although it is preferable to use human studies, risk assessment of chemicals must often rely on

observation of experimental animals. Of the many thousands of chemicals in existence, most have

not been studied in human populations, and where human studies exist, there is often poor

knowledge of exposure. Furthermore, confounding factors may render cause and effect

conclusions difficult. A great wealth of scientific information shows that species differ markedly

in anatomic, physiologic, and metabolic characteristics, and can vary greatly in terms of

susceptibility to adverse effects from exposure to chemicals. However, the differences between

animal and human responses to toxic substances have not been delineated for all compounds of

interest.

To account for this area of uncertainty, a default factor of 10 is generally incorporated for

extrapolation from animals to humans based on an assumption that an average human is likely to

be at most 10-fold more susceptible to the effects of the substance than experimental animals.

This is truly an “uncertainty” factor since we are unsure how humans would respond in contrast to

the animals tested (Figure 5). However, the uncertainty factor is based on the potential for

greater sensitivity of humans and the larger surface area of humans, suggesting a 2- to 100-fold

uncertainty factor (Krasovskii, 1976; Lewis and Alexeeff, 1989; Rall, 1969; Watanabe et al.,

1992; Weil, 1972; Willhite et al., 1986).

The use of uncertainty factor methodology is in contrast to practice in cancer risk assessment,

where an allometric surface area correction and a 95% upper confidence limit of the slope of the

dose response is used. The UF approach is identical to that used by U.S.EPA (1994a) and

recommended by NAS for drinking water standards. Limited support for the concept of a 10-fold

uncertainty factor was provided by Dourson and Stara (1983). Khodair and associates (1995)

showed that among a small data set (6 chemicals) animal NOAEL to human NOAEL ratios were

less than 4. Clearly, additional work in this area is warranted. Recently, Schmidt et al. (1997)

evaluated interspecies variation between human and five other animal species. Sixty compounds

had human data that could be matched to one or more animal species. The animal to human

Maximum Tolerated Dose (MTD) ratio of 10 represented approximately the 85th percentile. In

other words, an UF of 10 to account for interspecies variability would be protective for 85% of

chemicals. Thus, use of this factor alone would not likely be protective of most individuals.

However, this adjustment is not made without consideration of an intraspecies variability factor as

well. An analysis by Stickney et al. (1997) indicated that the use of the 10-fold interspecies and

10-fold intraspecies uncertainty factors together would be protective of the 99th percentile of the

population. The use of interspecies uncertainty factors and the degree of protection afforded by

those uncertainty factors for different endpoints (e.g., lethality, irritation) warrants further

research.

In Figure 1, we indicate that a dosimetric adjustment, such as the Human Equivalent

Concentration (HEC) adjustment used by U.S.EPA might be appropriate in some circumstances.

We did not conduct any HEC adjustments in developing the RELs for chemicals presented in

Appendix C. However, we may in the future use dosimetric adjustment to partially account for

differences in animals and humans with respect to dose at a specified concentration.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

48

3.3.4.2 Increased Susceptibility of Sensitive Individuals

Acute RELs are intended to protect identifiable sensitive individuals from harm due to chemical

exposure. However, RELs may not necessarily protect individuals who may develop an

idiosyncratic response which cannot be predicted from scientific investigation of the chemical.

Susceptibility to harm from chemical exposure may vary among individuals due to genetic

variability within the population, resulting in lower levels of protective biological mechanisms or

increased metabolic activation (Hattis, 1996; U.S.EPA, 1994a; Eichelbaum et al., 1992;

Grandjean, 1992). Additionally, susceptibility to chemical-related health effects may vary over

time for the same individual due to changing factors such as age, health status, and activity level.

Thus, sensitive individuals may include children, pregnant women and their fetuses, elderly

persons, those with existing diseases such as lung, heart or liver disease, and persons engaging in

physical activity (U.S.EPA, 1994a). Other factors, such as acute illness, may cause short-term

variations in individual susceptibility. Seasonal changes in absorption and toxicity have also been

noted in laboratory animals (Barton and Huster, 1987).

Healthy workers, the subject of most epidemiological studies, are often found to have lower rates

of morbidity and mortality than the general population (Monson, 1986; Wen et al., 1983). In

studies of experimental animals, highly homogeneous, healthy strains are generally used. Such

strains may have much less variability in response than a more heterogeneous human population.

Chizhikov (1973) found that animals in poor health were more likely to experience adverse effects

from chronic oral exposure to chemicals than were healthy animals.

A 10-fold uncertainty factor is used to account for variability within the human population. But,

in this case, the factor is not actually accounting for something unknown; instead it is accounting

for the variability in the general population which we know exists but do not have enough data to

quantify (Figure 6). This factor accounts for the greater susceptibility to chemical toxicity of

various sensitive subpopulations, including infants and children.

A high degree of interindividual variability (2-to-30-fold) in response to chemical exposure has

been reported (Krasovskii, 1976; Weil, 1972). Hattis (1996) has shown that human variability in

response to some medications may range over more than 3 orders of magnitude (>1,000-fold).

Similar interindividual variability has been shown in airway responsiveness and lung volume

among normal and asthmatic subjects (Bylin et al., 1995; O’Connor et al., 1987). In a study of

asthmatic subjects, Horstman et al. (1986) found that there was a 7-fold distribution in the range

of sulfur dioxide concentrations required to produce bronchoconstriction. Thus, it is reasonable

to conclude that asthmatics may be at least seven times as sensitive to the effects of sulfur dioxide

as normal individuals. The interindividual variability has been recently modeled, indicating a

distribution that ranges from 1 to >20 with a value of 10 for the 85th percentile (Gillis et al.,

1997). Thus, based on this analysis, the use of a 10-fold uncertainty factor would not be

protective of approximately 15% of the population. Further research into the considerations,

circumstances, subpopulations, and endpoints of greater susceptibility is needed.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

49

For acute RELs derived from NOAELs or LOAELs in healthy adults, OEHHA has applied a 10-

fold uncertainty factor to address the greater susceptibility of sensitive individuals. In accordance

with U.S.EPA guidelines (U.S.EPA, 1994a), when an exposure level is estimated from a study

that includes the assessment of a sensitive human sub-population, an intraspecies factor of 1 is

used. Since the true degree of variability of response in the human population is unknown, the

effectiveness of this method in providing protection to nearly all individuals is uncertain. A

summary of uncertainty factors used for acute REL development is given in Tables 9 and 10.

Table 10. Uncertainty factors used in the derivation of acute RELs

Methodology, study type Nature of uncertainty Uncertainty Factor

Benchmark concentration,

animal study

Interspecies 3

Intraspecies 10

Benchmark concentration,

human study

Interspecies 1

Intraspecies--study includes

sensitive subjects

1

Intraspecies--study does not

include sensitive subjects

3 or 10

NOAEL, animal study Interspecies 3 or 10

Intraspecies 10

NOAEL, human study Interspecies 1

Intraspecies--study includes

sensitive subjects

1

Intraspecies--study does not

include sensitive subjects

10

NOAEL, any study LOAEL--mild effects 6

LOAEL--other than mild

effects

10

As noted by Dourson and Stara (1983), the steepness of the dose-response relationship affects the

adequacy of the uncertainty factor for sensitive individuals. They summarized the range of dose
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

50

response slopes reported by Weil (1972), indicating that, based on studies of acute lethality, a 10-

fold factor was health-protective in most cases. However, in our experience, dose response

curves for acute lethality exposures are generally steeper than those for non-lethal exposures

(Table 11).

Table 11. Comparison of slopes of mild and lethal effectsa.

Chemical Mild EffectsbLethalityc

Acrolein

(irritation)

3.3 14.4

Ammonia

(irritation)

6.9 14.3

Vinyl chloride

(CNS effects)

7.5 31.9

a

Log-normal dose-response slope values are the mean of up to 5 studies.

b Human data for mild effects include: Hine et al., 1961; MacEwen et al., 1970; IBT, 1973;

Verberk et al., 1977; Lester et al., 1963.

c

Animal LC50 studies include: U.S.EPA 1992a; U.S.EPA 1992b; Philippin et al., 1970;

Champeix and Catilina 1967; Silver and McGrath 1948; Appelman et al., 1982;

Kapeghian et al., 1982; Prodan et al., 1975.

Because the true variability is unknown, there may be a portion of the population for whom the

acute RELs will not be protective. It is OEHHA’s intent that, to the maximal extent possible, the

levels will protect the general population including those in the high end of susceptibility. As

information defining susceptible individuals becomes available, it is our intent to adjust the

methodology as necessary to protect such individuals.

3.4 Effects of Exposure Duration

Studies of adverse health effects associated with exposures in humans or experimental animals are

generally conducted for time periods different from that which is of interest in the acute exposure

scenario. Typical exposure scenarios involve several hours for human exposures and several daily

exposures for two weeks in animals. OEHHA acute RELs, on the other hand, are

designed to be protective for one-hour exposures (with the exception of some

reproductive/developmental toxicants where the REL is for several hour exposures).
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

51

Acute inhalation toxicology studies (exposure duration of 8 hours or less) are preferred over other

exposure routes. In their absence, studies using exposures of longer durations may be employed

if appropriate (e.g., symptoms noted after short period of time; reproductive/developmental

endpoints). If inhalation toxicity data are unavailable, studies on other exposure routes may be

used. Studies that include an adequate follow-up period (hours to days, depending on the

chemical and endpoint) to account for delayed health effects are preferred to those that terminate

observation immediately following exposure. In order to adjust experimental exposure durations

to one-hour, OEHHA uses a method termed “time extrapolation.”

3.4.1 Time Extrapolation

“Haber’s Law” states that the product of the concentration (C) and time of exposure (T) required

to produce a specific physiologic effect is equal to a constant level or severity of response (K), or

C * T = K (Rinehart and Hatch, 1964). When the duration of experimental exposure differs from

the desired exposure duration for which an acute exposure level is being calculated (in this case 1

hour), a modification of Haber’s Law is used to adjust the experimental exposure duration to the

desired duration of the acute exposure level:

C

n * T = K,

where n is a chemical-specific parameter greater than zero (ten Berge, 1986). When n is equal to

1 (n=1), the toxicity of a chemical is equally dependent on changes in concentration and duration

of exposure; when n is less than 1 (n<1), the duration of exposure is a greater determinant of

toxicity than the concentration; finally, when n is greater than 1 (n>1), the toxicity of a chemical is

determined to a greater extent by exposure concentration than by duration. Ideally, the

magnitude of n should be determined for all chemicals by evaluating the concentration versus

response relationships for several different exposure durations. However, this information is

available for only a limited number of substances. Empirically derived values of the exponent n

range from 0.8-3.5 (ten Berge, 1986). The time-concentration-response relationship depends on

the time-frame considered and the endpoint measured. There are usually multiple “n” values for a

single chemical that are applicable to different response endpoints. For example, the “n” for

irritation of ammonia is 4.6, while the “n” for lethality of ammonia is 2.

A risk assessment document published by the NAS (NRC, 1987) includes a general statement that

Haber’s Law does not apply for “some irritants”. However, no specific references are cited by

NAS in support of this statement. It is likely that the basis of this statement is the observation

that for some substances, irritation appears to be solely concentration dependent. However, the

modified Haber’s Law presented here is able to accommodate any such empirical observations.

For example, in those cases for which data exist to allow the determination of a concentrationtime relationship for irritants (e.g. chlorine, ammonia), an analysis by OEHHA revealed that both

concentration and time of exposure contributed to the overall severity of effect, as described by

C

n * T = K. As concentration becomes the more important factor, the value of “n” will increase.

Values of “n” greater than 3 suggest a strong predominance of concentration over time.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

52

A modified Haber’s Law was applied to all of the chemical data sets analyzed in this document.

This is consistent with a role for both concentration and time in the determination of the

magnitude of irritation and other acute effects.

Examples of time extrapolation using different empirically derived values of “n” are given as

follows.

Example:

(a)For illustrative purposes, an example of time extrapolation for carbon tetrachloride is used.

The empirically derived value for “n” in this case is 2.8 (ten Berge, 1986). A NOAEL for

lethality in rats of 7,300 ppm for 1.5 hours was reported by Adams et al. (1952). A 1-hour

level protective against life-threatening effects is estimated as follows:

C

2.8 (1 hr) = 7,3002.8 (1.5 hr),

where C represents the desired 1-hour concentration in ppm. Solving this equation for C

yields a value of 8,440 ppm.

(b)The example of ammonia is given to further illustrate time extrapolation. The empirically

derived value for the exponent “n” for ammonia is 4.6 (refer to Acute Toxicology Summary

for Ammonia, Appendix C for further information on its derivation). A hypothetical 6-hour

exposure study in a sensitive human population reported that the no adverse effect level for

severe mucous membrane irritation was 48 mg/m3 ammonia. The equivalent 1-hour

concentration for this effect is calculated as follows:

C

4.6 (1 hr) = 484.6 (6 hr),

where C represents the 1-hour concentration for the effect described above. Solving for C

yields a 1-hour concentration of 71 mg/m3.

The value for the exponent “n” used by OEHHA in the acute toxicity summaries was chosen as

follows. First, when an empirically derived value for the exponent was available from the open

literature, this was adopted for time extrapolation, using the modification of Haber’s Law as

described above. The values from the American Institute of Chemical Engineers (AICE, 1989)

are included in Table 12, but were not used in the Technical Support Document since AICE

(1989) does not give references for the sources of data. When a derived value was not available

and there were insufficient data from which to determine a value de novo, a default value for “n”

was used. As seen in Table 12, the published or OEHHA derived values for “n” range from 0.8 to

4.6. The mean value in this range rounds to 2, while the interquartile range (25%-75%), where

most of the “n” values are found, is from 1 to 2.2.

As noted in Section 1.6.1, the time extrapolation to one hour in the case of repeated dose studies

for reproductive/developmental endpoints was not considered appropriate by the Scientific

Review Panel. OEHHA chose a single day’s exposure for each chemical (ranged from 1 to 8
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

53

hours) as the exposure duration for which the REL is to be applied. Thus, no time extrapolation is

used for reproductive-developmental toxicants.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

54

Table 12. Value of the exponent n for various gases and vapors

Chemical n Species/Effect References, Comments

Acrolein 1.2 rat/lethality (local

irritant)*

US EPA (1992a,b), derived by OEHHA

Acrylonitrile 1.1 rat/lethality (systemic) Dudley & Neal (1942); Appel et al. (1981), derived

by ten Berge et al. (1986)

Allyl chloride 0.5 rat/lethality (local irritant) Adams et al. (1940), derived by OEHHA

Ammonia 4.6 human/irritation Rosenbaum et al. (1993)

2.0

2

rat/lethality (local irritant) Appelman et al. (1982)

Arsine 2.2 rat/lethality (systemic) IRDC (1985b), derived by OEHHA for 0.5 to 1 hr

(n dependent on exposure duration)

1.0 rat/lethality (systemic) IRDC (1985), derived by OEHHA for 4 hr to 1 hr

(n dependent on exposure duration)

2 mice/lethality (systemic) Levvy (1947)

Benzene 2 not given AICE (1989)

Bromine 2.2 mice/lethality (local

irritant)

Bitron & Aharonson (1978), derived by ten Berge et

al. (1986)

Carbon monoxide 1 not given AICE (1989)

Carbon

tetrachloride

2.8 rat/lethality (systemic) Adams et al. (1952), derived by ten Berge et al.

(1986)

Chlorine 2.8 rat/lethality (local irritant) Zwart & Woutersen (1988), derived by OEHHA for

0.5 hr to 1 hr (n dependent on exposure duration)

1.0 rat/lethality (local irritant) Zwart & Woutersen (1988), derived by OEHHA for

4 hr to 1 hr (n dependent on exposure duration)

1.3 mouse/lethality (local

irritant)

Zwart & Woutersen (1988), derived by OEHHA

3.5 mouse/lethality (local

irritant)

Bitron & Aharonson (1978), derived by ten Berge et

al. (1986)

Chlorine

pentafluoride

2 rat, mouse, dog,

monkey/lethality (local

irritant)

Darmer et al. (1972), derived by ten Berge et al.

(1986)

Crotonaldehyde 1.2 rat/lethality (local irritant) Rinehart (1967), derived by ten Berge et al. (1986)

Dibutylhexamethyle

ne-diamine

1 rat/lethality (local irritant) Kennedy & Chen (1984), derived by ten Berge et al.

(1986)

1,2-dichloroethylene 2 (not applicable)/lethality

(systemic)

US EPA (1996), based on the mid-point range of n

values from lethality data of ten Berge et al. (1986)

Dimethyldichlorosilane2 (not applicable)/lethality

(local irritant)

US EPA (1996), based on the mid-point range of n

values from lethality data of ten Berge et al. (1986)

Ethylene dibromide 1.2 rat/lethality (systemic) Rowe et al. (1952), derived by ten Berge et al.

(1986)
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

55

Table 12. Value of the exponent n for various gases and vapors (cont.)

Chemical n Species/Effect References, Comments

Ethylene imine 1.1 rat, guinea pig/lethality

(local irritant)

Carpenter et al. (1948), derived by ten Berge et

al. (1986)

Fluorine 1.9 rat/lethality (local irritant) US EPA (1996), derived from LC50 data of

Keplinger & Suissa (1968)

1.8 mouse/lethality (local

irritant)

US EPA (1996), derived from LC50 data of

Keplinger & Suissa (1968)

1.6 guinea pig/lethality (local

irritant)

US EPA (1996), derived from LC50 data of

Keplinger & Suissa (1968)

Formaldehyde 2 not given AICE (1989)

Hydrazine 2 (not applicable)/lethality

(systemic)

US EPA (1996), based on the mid-point range of

n values from lethality data of ten Berge et al.

(1986)

Hydrogen chloride 1 rat, mouse/lethality (local

irritant)

Darmer et al. (1972), derived by ten Berge et al.

(1986)

1.5 rat/lethality (local irritant) Hartzell et al. (1985), derived by OEHHA

Hydrogen cyanide 2.7 numerous species/lethality

(systemic)

Barcroft (1931), derived by ten Berge et al.

(1986)

Hydrogen fluoride 2 rabbits, guinea

pigs/lethality (local

irritant)

Machle (1934), derived by ten Berge et al. (1986)

Hydrogen fluoride

(low humidity)

1 rat/lethality (local irritant) Haskell Lab. (1988), derived by OEHHA

Hydrogen sulfide 2.2 cat, rabbit/lethality

(systemic/local irritant)

Lehmann (1892), derived by ten Berge et al.

(1986)

8.2 lethality (systemic/local

irritant)

Arts et al. (1989)

Methyl bromide 4.0 severe morbidity

(systemic/local irritant)

Pharmaco LSR, Inc. (1994) derived by OEHHA,

DPR 1996

1 not given AICE (1989)

Methylenechlorobromide1.6 rat/lethality (systemic) Torkelson et al. (1960), derived by ten Berge et

al. (1986)

Methylhydrazine 1.0 squirrel monkey/lethality

(systemic and local

irritant)

Haun et al. (1970), derived by OEHHA

1.0 dog/lethality (systemic and

local irritant)

Haun et al. (1970), derived by OEHHA

Methyl isocyanate 1.1 human/eye irritation Mellon Inst. (1963), derived by OEHHA

0.5 rat/lethality (local irritant) Kimmerle & Eben (1964), derived by OEHHA

0.7 rat/lethality (local irritant) Dow Chem. (1990), derived by OEHHA

Methyl mercaptan 2 (Not applicable)/lethality

(systemic and local

irritant)

US EPA (1996), based on the mid-point range of

n values from lethality data of ten Berge et al.

(1986)

Methyl t-butyl ether 2.0 lethality (systemic) Snam Progretti (1980), derived by ten Berge et al.

(1986)
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

56

Table 12. Value of the exponent n for various gases and vapors (cont.)

Chemical n Species/Effect References, Comments

Nitrogen dioxide 3.5 guinea pig, mouse, dog,

rat, rabbit/lethality (local

irritant)

Hine et al. (1970), derived by ten Berge et al.

(1986)

Nitric acid 3.5 not applicable (local

irritant)

US EPA (1996), based on NO2 from Hine et al.

(1970)

Perfluoroisobutylen

e

1.2 rat/lethality (local irritant) Smith et al. (1982), derived by ten Berge et al.

(1986)

Phosgene 1 lethality (local irritant) Rinehart & Hatch (1964)

Propylene oxide 2.2 rat/lethality (local irritant) Rowe et al. (1956), derived by OEHHA

1.5 guinea pig/lethality (local

irritant)

Rowe et al. (1956), derived by OEHHA

Sulfur dioxide 1 not given AICE (1989)

Tetrachloroethylene 2.0 rat/lethality (systemic) Rowe et al. (1952), derived by ten Berge et al.

(1986)

Toluene 2.5 not given AICE (1989)

Trichloroethylene 0.8 rat/lethality (systemic) Adams et al. (1951), derived by ten Berge et al.

(1986)

* Parentheses denotes whether the chemical acts locally or systemically to produce the effect.

When extrapolating from an exposure duration that is greater than 1-hour to a 1-hour level, the

value of n=2 was used by OEHHA. The value of n=2 was chosen because it represents a whole

number near the midpoint of the range of values, as described above. When extrapolating from an

experimental exposure duration of less than 1 hour to a 1-hour level, the value of n=1 was used.

Using a value of n=1 is more health-protective than a value of n=2. A value of n=1 results in a

relatively rapid decrease in the derived REL when extrapolations are made from shorter to longer

exposures. For example, when extrapolating from a 10 minute exposure to a 60 minute exposure

for chloropicrin, using n=1 results in an extrapolated NOAEL of 132 ppb; when using n=2, the

extrapolated NOAEL is 320 ppb. The default values for “n” bracket the interquartile range of

possible values, and they are applied using health protective assumptions (Table 13).

Table 13. Exponents used by OEHHA for extrapolation to 1-hour acute RELs1.

Exponent (n)

From less than 1 hour 1

From greater than 1 hour 2

1 Exponent, n, used in the formula Cn

 T = K
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

57

4.0 Supporting Data

The summaries describing the development of the REL for each chemical are found in Appendix

C. In addition, a list of abbreviations is provided in Appendix E. All acute toxicity exposure level

estimates (including those for RELs) will include a discussion of the information upon which the

calculations are based. This discussion includes the following key elements.

1. Physical and chemical properties: Descriptions include information on volatility, reactivity,

stability, toxic secondary compounds, flammability, density, water solubility, color, taste,

odor, and some additional properties.

2. Occurrence and use: The typical uses of the chemical are described as well as where it is

likely to be found.

3. Routes of exposure: The routes of exposure that may lead to toxic effects are mentioned for

each substance. Since the intent of this document is to provide information on airborne

toxicants, the data presented focuses on inhalation exposure studies and may be supplemented

by relevant non-inhalation toxicology studies. If inhalation data are unavailable or are of poor

quality for a particular chemical, other routes of exposure may be considered for the

development of acute severity levels. For extrapolation from oral to inhalation exposures,

methodology presented by U.S.EPA (1994a) should be used (see the Acute Toxicity

Summary for carbon tetrachloride, Appendix C, as an example).

4. Summary of toxic effects: Toxic effects are described for relevant endpoints. Where possible,

all of the following attributes are mentioned: endpoint, test species, concentration or dose,

duration and frequency of exposure, type of effect level (such as NOAEL), reversibility of

findings, uncertainty factors applied, and acute severity levels calculated. Endpoints of

toxicity testing include, but are not restricted to, lethality, upper and lower respiratory effects,

including mucous membrane irritation, and systemic effects. Results from studies on a

chemical’s mutagenicity, reproductive and developmental toxicity and immunotoxicity are also

mentioned, where appropriate.

5. Pharmacokinetics and metabolism: A brief discussion of pharmacokinetics is included if

information is available. This may include significant routes of absorption, distribution,

metabolism, and excretion. The inhalation route of exposure is examined preferentially.

Metabolites of the parent compound are identified.

6. Other planning levels: Inhalation exposure levels from other sources, such as TLVs, EEGLs,

SPEGLs, and IDLHs are examined. It is important to compare acute severity levels

developed by OEHHA with existing values as a quality assurance measure and also to

determine whether the use of other existing guidelines might lead air pollution control officers

and planners into predicting that exposures are safe at potentially toxic concentrations. The

most scientifically valid and health-protective level is generally recommended by OEHHA;

however, a discussion of the strengths and weaknesses of each existing level is not included in

the toxicity summaries.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

58

7. Quality assurance measures: Weak or conflicting data are reviewed. Studies are evaluated for

any recognized violations of sound laboratory or statistical practices. Any study with

significant flaws is not used to justify RELs or acute exposure levels.

8. Sources of data: In the absence of well-documented experimental dose-response studies in

humans, reliance on toxicological data from animal studies and human data from workplace

and other accidental exposures is appropriate. In addition, in vitro toxicity studies are

consulted.

9. References: If a complete literature database search is available for a chemical but only a few

were used for the acute toxicology summaries, only the latter are cited in the document;

however, the complete reference list will be made available on request. OEHHA has

completed literature searches for all of the chemicals for which acute RELs were developed in

this document.

5.0 Areas for Further Research

• There are a number of chemicals lacking adequate data on acute toxicity. While we were able

to develop RELs for the 51 compounds in this document, we could not develop levels

protective against severe adverse effects or life-threatening effects in a number of instances

due to the limitations of the database. The following chemicals fall into that category:

acrolein; acrylic acid; inorganic arsenic compounds; benzyl chloride; chloroform; chloropicrin;

copper compounds; dioxane; epichlorohydrin; ethylene glycol monobutyl ether; ethylene

glycol monoethyl ether acetate; hydrogen sulfide; isopropyl alcohol; inorganic mercury

compounds; methanol; methyl chloroform; methylene chloride; inorganic nickel compounds;

nitric acid, ozone; perchloroethylene; phenol phosgene; propylene oxide; selenium

compounds; sodium hydroxide; sulfates, sulfur dioxide; sulfuric acid; toluene; triethylamine;

vanadium pentoxide; xylenes. Research is needed to adequately characterize the full-spectrum

of effects following acute exposure of these substances.

• There are about 450 chemicals on the Air Toxics Hot Spots list of substances to be quantified

(Appendix B). This is the list of substances which facilities must report in their emissions

inventories. We have to date only evaluated information on 52 of these compounds and

developed acute RELs for 51 of these compounds. While not all of the 450 chemicals have

reported emissions in California, more work needs to be done in analyzing available literature

for the remaining compounds.

• The application of uncertainty factors to account for extrapolation from a LOAEL to a

NOAEL warrants further analysis. When evaluating dose-response relationships, the slope of

the dose-response curve determines the distance between the LOAEL and the NOAEL from a

particular study. Some endpoints tend to have steep dose-response slopes and may not

warrant a 10-fold uncertainty factor to extrapolate from a LOAEL to a NOAEL; other

endpoints have a shallow dose-response slope and may warrant a 10-fold (or higher)

uncertainty factor for extrapolating from the LOAEL to the NOAEL. In this document, we
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

59

have used an intermediate uncertainty factor of 6 to extrapolate from the LOAEL to a

NOAEL for mild irritation and a factor of 3 for that extrapolation for lethality. This is based

on an analysis of the distribution of the LOAEL to NOAEL ratios for 112 datasets. If further

analysis suggests revisions of the UF, it will be revised in future acute REL updates. With

further analysis, we may also be able to adjust the uncertainty factor for this extrapolation for

other toxicological endpoints.

• A related issue is the application of subchronic or repeated exposure studies to evaluating

acute toxicity. We have not used subchronic exposures routinely to evaluate acute toxicity

RELs. In addition, there are issues such as cumulative tissue injury that may be seen with

repeated exposures that impact the quantitative analysis of acute toxicity. Further research

into these areas is warranted.

• An interspecies factor of 10 is commonly used to extrapolate from animal studies to the

human response. In some cases, there may be reason that a smaller uncertainty factor could

be used. For example, in lethality studies, the exposure to irritant chemicals producing lung

edema may have very similar dose-response slopes because the basic loss of cellular integrity

at high doses is not a phenomenon that would be very different from one species to another.

The available analyses supporting use of the 10-fold interspecies uncertainty factor were

conducted on studies of toxicity by the oral route of administration. Further analysis of

available data on chemicals for which there is both human and animal data for the same

endpoints, and by the inhalation route of exposure is warranted. In addition, the existing

analyses are limited in terms of toxicological endpoints examined. Interspecies variability may

differ significantly for different toxicological endpoints. This is another area where research is

needed.

• The uncertainty factor typically used to account for intraspecies (interindividual) variability in

the human population is 10. Interindividual variability has been recently modeled indicating a

distribution that ranges from 1 to 720 for a specified set of chemicals (Gillis et al., 1997). The

value of 10 represented the 85th percentile in this analysis. Further research into the factors

contributing to interindividual variability, better characterization of sensitive subpopulations,

and endpoints characterized by large interindividual variability is warranted. Furthermore, the

degree of protection of infants and children, a sensitive subpopulation by virtue of both

increased exposure and potential increased susceptibility, afforded by a 10-fold interindividual

uncertainty factor needs more research.

• We have used time extrapolation with a modified Haber’s Law to extrapolate from the

experimental duration in the acute study to an equivalent concentration for a one-hour

exposure. There are empirical data for the value of n in Haber’s equation for some chemicals.

More data would be valuable for additional chemicals. Further analysis of the validity of the

Haber’s Law application for different toxicological endpoints such as irritation would also be

useful.

• We currently use an additive approach to assessing the impacts of multiple chemicals on a

target organ. Some interactions may be synergistic and others antagonistic. There is a need
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

60

for key studies on the additivity or synergism of chemicals that act on the same target organ.

Further literature evaluation would also be helpful to elucidate whether the additive approach

is the most valid approach.

References

Adams EM, Spencer HC, Irish DD. The acute vapor toxicity of allyl chloride. J Ind Hyg Tox

1940;22(2):79-86.

Adams EM, Spencer HC, Rowe VK, et al. Vapor toxicity of trichloroethylene determined by

experiments on laboratory animals. Arch Ind Hyg Occup Med 1951;4:469-481.

Adams EM, Spencer HC, Rowe VK, McCollister DD, Irish DD. Vapor toxicity of carbon

tetrachloride determined by experiments on laboratory animals. Arch Ind Hyg Occup Med

1952;6:50-66.

Alexeeff GV, Lipsett MJ, Kizer KW. Problems associated with the use of Immediately Dangerous

to Life and Health (IDLH) values for estimating the hazard of accidental chemical releases. Am

Ind Hyg Assoc J 1989;50:598-605.

Alexeeff GV, Lewis DC, Lipsett MJ. Use of toxicity information in risk assessment for accidental

release of toxic gases. J Hazard Mater 1992;29:387-403.

Alexeeff GV, Lewis DC, Ragle NL. Estimation of potential health effects from acute exposure to

hydrogen fluoride using a “benchmark dose” approach. Risk Anal 1993;13:63-69.

Alexeeff GV, Shusterman DJ, Howd RA, Jackson RJ. Dose-response assessment of airborne

methyl isocyanate (MITC) following a metam sodium spill. Risk Anal 1994;14:191-198.

Alexeeff GV, Fowles JR, Hill M, Dodge D. Stochastic evaluation of acute inhalation thresholds

from reported LOAELs. [abstract #851]. Toxicologist 1997;36(1 pt 2):167.

(ACGIH) American Conference of Governmental Industrial Hygienists, Inc. Documentation of

the Threshold Limit Values and Biological Exposure Indices, 6th ed. Cincinnati (OH): ACGIH;

1991.

(AIHA) American Industrial Hygiene Association. Emergency response planning guidelines,

Akron (OH): American Industrial Hygiene Association; 1988, 1990, 1991.

(AICE) American Institute of Chemical Engineers. Guidelines for chemical process quantitative

risk analysis. New York (NY): Center for Chemical Process Safety of the American Institute of

Chemical Engineers; 1989. p. 148-159.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

61

Anglen DM. Sensory response of human subjects to chlorine in air [dissertation]. Ann Arbor

(MI): University of Michigan; 1981.

Appel KE, Peter H, Bolt M, Bolt HM. Interaction of acrylonitrile with hepatic microsomes of rats

and men. Toxicol Lett 1981;7(4-5):335-339

Appleman LM, ten Berge WF, Reuzel PGJ. Acute inhalation toxicity study of ammonia in rats

with variable exposure periods. Am Ind Hyg Assoc J 1982;43:662-665.

Aris RM, Tager I, Christian D, Kelly T , Balmes JR. Methacholine responsiveness is not

associated with O3-induced decreases in FEV1. Chest 1995;107:621-628.

Arts JH, Zwart A, Schoen ED, Klokman-Houweling JM. Determination of concentration-timemortality relationships versus LC50s according to OECD guideline 403. Exp Pathol 1989;37(1-

4):62-66.

Barcroft J. The toxicity of atmospheres containing hydrocyanic acid gas. J Hyg 1931;31(1):1-34.

Barnes DG, Daston GP, Evans JS, Jarabek AM, Kavlock RJ, Kimmel CA, Park C, Spitzer HL.

Benchmark Dose Workshop: criteria for use of a benchmark dose to estimate a reference dose.

Regul Toxicol Pharmacol 1995;21:296-306.

Barnes DG, Dourson M. Reference Dose (RfD): Description and use in health risk assessments.

Regul Toxicol Pharmacol 1988;8:471-486.

Barton JC, Huster WJ. Seasonal changes in lead absorption in laboratory rats. Environ Health

Perspect 1987;73:209-14

Bernstein DI, Ploysongsang Y, Mittman RJ, Piymahunt A, Bernstein IL. The relationship between

airway responsiveness measured before and after the allergen-induced late asthmatic response.

Chest 1992;101:437-441.

Bigwood EJ The acceptable daily intake of food additives. CRC Crit Rev Toxicol 1973;2:41-93.

Bitron MD, Aharonson EF. Delayed mortality of mice following inhalation of acute doses of

CH2O, SO2Cl2, and Br2. Am Ind Hyg Assoc J 1978;39(2):129-138.

Bylin G, Lagerstrand L, Hedenstierna G, Wagner PD. Variability in airway conductance and lung

volume in subjects with asthma. Clin Physiol 1995;15:207-218.

Calabrese EJ. Principles of animal extrapolation. New York: John Wiley; 1982.

(CAPCOA) California Air Pollution Control Officers Association. Air Toxics Hot Spots Program

revised 1992 risk assessment guidelines. Cameron Park (CA): CAPCOA Toxics Committee;

1993.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

62

California Department of Health Services. Health risk assessment of aerial application of

malathion-bait. Health Hazard Assessment Division. Sacramento (CA); 1991. p. 8-1 to 8-45.

Carpenter CP, Smyth HF Jr, Shaffer CB. The acute toxicity of ethylene imine to small animals. J

Ind Hyg Toxicol. 1948;30:2-6.

Chhabra RS, Huff JE, Schwetz BS, Selkirk J. An overview of prechronic and chronic

toxicity/carcinogenicity experimental study designs and criteria used by the National Toxicology

Program. Environ Health Perspect 1990;86:313-21

Champeix J, Catilina P. Les Intoxicants par l’acrolein. Paris, France: Masson and Co.; 1967.

Cherniak RM. Physiologic diagnosis and function in asthma. Clin Chest Med 1995;16:567-581.

Chizhikov VA. [Effect of harmful substances on animals with weakened health under chronic

feeding conditions] [Russian] Gig Sanit 1973;38(7):7-12.

Crump KS and Co., Inc. Probit (Log-Normal). (Software for IBM-PC.) Ruston (LA); 1983.

Crump KS. A new method for determining allowable daily intakes. Fundam Appl Toxicol

1984;4:860-866.

Darley EF, Middleton JT, Garber MJ. Plant damage and eye irritation from ozone-hydrocarbon

reactions. J Agric Food Chem 1960;8:483-485.

Darmer KI Jr, Haun CC, MacEwen JD. The acute inhalation toxicology of chlorine pentafluoride.

Am Ind Hyg Assoc J. 1972;33(10):661-668.

Das R, Blanc PD. Chlorine gas exposure and the lung: a review. Toxicol Ind Health

1993;9(3):439-455.

Donald JM, Hooper K, Hopenhayn-Rich C. Reproductive and developmental toxicity of toluene:

A review. Environ Health Perspect 1991;94:237-244.

Dourson ML, Stara JF. Regulatory history and experimental support of uncertainty (safety)

factors. Regul Toxicol Pharmacol 1983;3:224-238.

Dourson ML. New approaches in the derivation of acceptable daily intake (ADI). Comm Toxicol

1986;1:35-48.

Dourson ML, Hertzberg RC, Hartung R, Blackburn K. Novel methods for the estimation of

acceptable daily intake. Toxicol Indust Health 1985;1:23-33.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

63

Dow Chemical. Unpublished experiments on methyl isocyanate. Midland (MI): Dow Chemical

Company; 1990.

Dudley HC, Miller JW. 1937. Toxicology of selenium. IV. Effects of exposure to hydrogen

selenide. US Public Health Rep. 1937;52:1217-1231.

Dudley HC, Neal PA. Toxicology of acrylonitrile (vinyl cyanide). I. A study of the acute toxicity.

J Ind Hyg Toxicol 1942;24(2):27-36.

Eichelbaum M, Kroemer HK, Mikus G. Genetically determined differences in drug metabolism

as a risk factor in drug toxicity. Toxicol Lett 1992;64-65 Spec No:115-22

Eiser NM, Kerrebijn KF, Quanjer PH [editors, European Society for Clinical Respiratory

Physiology Working Group “Bronchial hyperreactivity”]. Guidelines for standardization of

bronchial challenges with (nonspecific) bronchoconstricting agents. Bull Europ Physiopath Resp

1983;19:495-514.

Eschenbacher WL, Moore TB, Lorenzen TJ, Weg JG, Gross KB. Pulmonary responses of

asthmatic and normal subjects to different temperature and humidity conditions in an

environmental chamber. Lung 1992;170:51-62.

Finney DJ. Probit Analysis. Cambridge England: Cambridge University Press; 1971.

Fowler BA, Weisburg JB. Arsine poisoning. N Engl J Med 1974;291:1171-1174.

Fowles JR, Alexeeff GV. Evaluation of benchmark dose criteria for acute inhalation reference

exposure levels [abstract #741]. Toxicologist 1996; 30:145.

Gates M, Williams J, Zapp JA. Arsenicals, in: Summary Technical Report of Division 9, NRDC.

Vol. 1, Chemical warfare agents, and related chemical problems, Part 1. Washington (DC):

National Defense Research Committee, Office of Scientific Research and Development; 1946.

p. 83-114.

Gaylor DW. Applicability of cancer risk assessment techniques to other toxic effects. Toxicol

Indust Health 1988;4:453-459.

Gaylor DW. Quantitative risk analysis for quantal reproductive and developmental effects.

Environ Health Perspect 1989;79:243-246.

Gaylor DW. Incidence of developmental defects at the no observed adverse effect level

(NOAEL). Regul Toxicol Pharmacol 1992;15(2 Pt 1):151-60

Gift JS, Webb CK, Jarabek AM. Suitability of LOAEL-to-NOAEL 10-fold uncertainty factor for

health assessments of inhaled toxicants [abstract]. Toxicologist 1993;13:140.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

64

Gillis CA, Keenan RE, Carlson-Lynch HL, Price PS. Characterization of the interindividual

(UFH) factor: alternative models and approaches. [abstract #1053]. Toxicologist 1997;36:207.

Gold WG, Pulmonary function testing. In: Murray JF, Nadel JA, editors. Respiratory medicine.

2nd ed. Philadelphia: W.B. Saunders; 1994. p. 815-817.

Goldstein BD. Toxic substances in the atmospheric environment. A critical review. J Air Pollut

Control Assoc 1983;33(5):454-467.

Grandjean P. Individual susceptibility to toxicity. Toxicol Lett 1992;64-65 Spec No:43-51.

Guth DJ, Jarabek AM, Wymer L, Hertzberg RC. Evaluation of risk assessment methods for shortterm inhalation exposure. Air & Waste Management Association Meeting; 1991; Vancouver,

British Columbia, paper no. 91.173.2.

Hackney JD, Linn WS. Controlled clinical studies of air pollutant exposure: evaluating scientific

information in relation to air quality standards. Environ Health Perspect 1983;52:187-191.

Hartung R. Dose-response relationships. In: Tardiff RG, Rodricks JV, eds. Toxic substances and

human risk. New York: Plenum Press; 1987. pp. 29-46.

Hartzell CR, Johnson GV. In vivo MAC values and in vitro experimentation. Anesth Analg

1985;64(4):386-387.

Haskell Laboratories. Test results of acute inhalation studies with anhydrous hydrogen fluoride.

1988. EPA/OTS ID: #FYI-OTS-0388-0607.

Hattis D. Variability in susceptibility--how big, how often, for what responses to what agents?

Environ Toxicol Pharmacol 1996; 2:135-145.

Haun CC, MacEwen JD, Vernot EH, Eagan GF. Acute inhalation toxicity of

monomethylhydrazine vapor. Am Ind Hyg Assoc J 1970;31(6):667-677

Hine CH, Meyers F, Ivanhoe F, Walker S, and Takahashi GH. Simple tests of respiratory function

and study of sensory response in human subjects exposed to respiratory tract irritants. In:

Proceedings of the afternoon sessions, the fifth air pollution medical research conference:

symposium on human exposures to air pollutants. Berkeley (CA): California State Department of

Health; 1961. p. 20-38.

Hine CH, Meyers FH, Wright RW. Pulmonary changes in animals exposed to nitrogen dioxide,

effects of acute exposures. Toxicol Appl Pharmacol 1970;16(1):201-213.

Homan ER. Quantitative relationships between toxic doses of anti-tumor chemotherapeutic agents

in animals and man. Cancer Chemother Rep 1972;3:13-19.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

65

Horstman D, Roger LJ, Kehrl H, Hazucha M. Airway sensitivity of asthmatics to sulfur dioxide.

Toxicol Ind Health 1986;2:289-298.

Ikeda M. Multiple exposure to chemicals. Regul Toxicol Pharmacol 1988;8:414-421.

(IBT) Industrial BIO-TEST Laboratories, Inc. Report to International Institute of Ammonia

Refrigeration: Irritation threshold evaluation study with ammonia. IBT No 1973;663-03161

(March 23, 1973).

(IRDC) International Research and Development Corporation. Two-generation inhalation

reproduction/fertility study on a petroleum derived hydrocarbon with toluene. API Medical

Research Publication no. 32-32854. Washington (DC): American Petroleum Institute; 1985a.

(IRDC) International Research & Development Corporation. Three acute inhalation toxicity

studies of arsine on rats (final report). Report No. 533-001, 533-002, and 533-003. Mattawan

(MI): IRDC; 1985b.

Jonker D, Woutersen RA, van Bladeren PJ, Til HP, Feron VJ. 4-week oral toxicity study of a

combination of eight chemical in rats: comparison with the toxicity of the individual compounds.

Food Chem Toxicol 1990;28:632-631.

Jubber AS, Foster RW, Hassan NA, Carpenter JR, Small RC. Airway response to inhaled

methacholine in normal human subjects. Pulm Pharmacol 1993;6:177-184.

Kadry AM, Khodair AJ, Skowronski GA, Abdel-Rahman MS. Evaluation of the current method

for extrapolating subchronic and chronic test results for estimation of lifetime exposure levels

[abstract]. Toxicologist 1995;15:33.

Kapeghian JC, Mincer HH, Jones AB, Verlangieri AJ, Waters IW. Acute inhalation toxicity of

ammonia in mice. Bull Environ Contam Toxicol 1982;29(3):371-378.

Kennedy GL Jr, Chen HC. Inhalation toxicity of dibutylhexamethylenediamine in rats. Food Chem

Toxicol. 1984;22(6):425-429.

Keplinger ML, Suissa LW. Toxicity of fluorine short-term inhalation. Am Ind Hyg Assoc J.

1968;29(1):10-18.

Khodair AJ, Kadry AM, Skowronski GA, Abdel-Rahman MS. Comparison of animal and human

data to estimate the no adverse effect level (NOAEL) in humans [abstract]. Toxicologist

1995;15:33.

Krasovskii GN. Extrapolation of experimental data from animals to man. Environ Health Perspect

1976; 13:51-58.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

66

Kulle JT, Sauder LR, Hebel JR, Green D, Chatham MD. Formaldehyde dose-response in healthy

nonsmokers. J Air Pollution Control Assoc 1987;37:919-924.

Lebowitz MD. Utilization of data from human population studies for setting air quality standards:

evaluation of important issues. Environ Health Perspect 1983;52:193-205.

Lehmann KB. Experimentele Studien uber den Einfluss technisch und hygienisch wichtiger Gase

und Dampfe auf den Organismus [German]. Arch Hyg 1892;14:135-189.

Lehman AJ, Fitzhugh OG. 100-Fold margin of safety. Assoc Food Drug Off USQ Bull

1954;18:33-35.

Leisenring W, Ryan L. Statistical properties of the NOAEL. Regul Toxicol Pharmacol 1992;15(2

Pt 1):161-171

Lester D, Greenberg LA, Adams WR. Effects of single and repeated exposures of humans and

rats to vinyl chloride. Am Ind Hyg Assoc J 1963;3:265-275.

Levvy GA. A study of arsine poisoning. Quart J Exp Physiol 1947;34:47-67.

Lewis DC, Alexeeff GV, Gravitz N. “Risk assessment of acute health effects of air pollutants.”

Presented at the POLMET conference. 1988.

Lewis DC, Alexeeff GV. Quantitative risk assessment of noncancer health effects for acute

exposure to air pollutants. Proceedings of the 82nd Annual Meeting of the Air and Waste

Management Association; Anaheim (CA); 1989. p. 89-91.

MacEwen J, Theodore J, Vernot EH. Human exposure to EEL concentration of

monomethylhydrazine. AMRL-TR- 1970;70-102,23. Wright-Patterson Air Force Base (OH):

SysteMed Corp.; 1970.

Machle W, Thamann F, Kitzmiller K, Cholak J. The effects of the inhalation of hydrogen fluoride.

I. The response following exposure to high concentrations. J Ind Hyg 1934;16(2):129-145.

Mantel N, Bryan WR. Safety testing of carcinogenic agents. J Nat Cancer Inst 1961;27:455-470.

Mantel N, Bohidar NR, Brown CC, Ciminera JL, Tukey JW. 1975. An improved Mantel-Bryan

procedure for ‘safety’ testing of carcinogens. Cancer Res 1975;35:865-872.

Mellon Institute. Special report 26-23. (methyl isocyanate) Pittsburgh, PA; 1963.

Monson RR. Observations on the healthy worker effect. J Occup Med 1986;28(6):425-33.

Muller KE, Barton CN, Benignus VA. Recommendations for appropriate statistical practice in

toxicologic experiments. Neurotoxicology 1984;5(2):113-25
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

67

National Academy of Sciences, Safe Drinking Water Committee. Chemical contaminants: safety

and risk assessment. In: Drinking water and health. Washington (DC): National Academy of

Sciences; 1977. p. 19-62

(NATICH) National Air Toxics Information Clearinghouse. NATICH database report on state,

local and EPA air toxics activities. Research Triangle Park (NC): EPA; 1991.

(NIOSH) National Institute for Occupational Safety and Health. Documentation for immediately

dangerous to life or health concentrations (IDLHs). Cincinnati, OH: Division of Standards

Development and Technology Transfer, NIOSH; 1994. NTIS Pub. no. PB-94-195047.

(NIOSH) National Institute for Occupational Safety and Health. Documentation for immediately

dangerous to life or health concentrations (IDLHs). NIOSH chemical listing and documentation

of revised IDLH values; 1995. Available at: URL: http://www.cdc.gov/niosh/intridl4.html

(NIOSH) National Institute for Occupational Safety and Health. Pocket guide to chemical

hazards. Washington (DC): U.S. Department of Health and Human Services; 1994.

(NRC) National Research Council, Committee on Toxicology. Criteria and methods for preparing

emergency exposure guidance level (EEGL), short term public emergency guidance level

(SPEGL) and continuous exposure guidance level (CEGL) documents. Washington (DC):

National Academy Press; 1986.

(NRC) National Research Council. Committee on Toxicology, Guidelines for developing

community emergency exposure levels for hazardous substances. Washington (DC): National

Academy Press; 1993.

(NRC) National Research Council. Committee on Risk Assessment of Hazardous Air Pollutants.

Science and judgment in risk assessment. Washington (DC): National Academy Press; 1994.

O’Connor G, Sparrow D, Taylor D, Segal M, Weiss S. Analysis of dose-response curves to

methacholine. Am Rev Respir Dis 1987;136:1412-1417.

Peterson DP, Bhattacharyya MH. Hematological response to arsine exposure: quantitation of

exposure response in mice. Fundam Appl Toxicol 1985;5:499-505.

Pharmaco:LSR, Inc. An up-and-down acute inhalation toxicity study of methyl bromide in the

dog (four exposure phase). E. Millstone (NJ): Pharmaco:LSR, Inc.; 1994.

Philippin C, Gilgen A, Grandjean E. Etude toxicologique et physiologique de l’acroleine chez la

souris. Int Arch Arbeitsmed 1970;26:281-305.

Plopper CG, Mariassay AT, Wilson DW, Alley JL, Nishio SJ, Nettesheim P. Comparison of nonciliated tracheal epithelial cells in six mammalian species. Exp Lung Res 1983;5:281-294.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

68

Prodan L, Suciu I, Pislaru V, Ilea E, Pascu L. Experimental acute toxicity of vinyl chloride

(monochloroethene). Ann N Y Acad Sci 1975;246:154-158.

Rall DP. Difficulties in extrapolating the results of toxicity studies in laboratory animals to man.

Environ Res 1969;2:360-367.

Rees DC, Hattis D. Developing quantitative strategies for animal to human extrapolation. In:

Hayes AW, editor. Principles and methods of toxicology. 3rd ed. New York: Raven Press; 1994.

p. 275-315.

Rinehart WE. The effect on rats of single exposures to crotonaldehyde vapor. Am Ind Hyg Assoc

J. 1967;28(6):561-6.

Rinehart WE, Hatch T. Concentration-Time (CT) as an expression of dose in sublethal exposures

to phosgene. Am Ind Hyg Assoc J 1964;25:545-553

(RAAC) Risk Assessment Advisory Committee. A review of the California Environmental

Protection Agency’s risk assessment practices, policies and guidelines. Sacramento, CA; 1996.

Roach SA, Rappaport SM. But they are not thresholds: a critical analysis of the documentation of

Threshold Limit Values. Am J Ind Med 1990;17(6):727-753

Robinson JC, Paxman DG. The role of threshold limit values in U.S. air pollution policy. Am J

Ind Med 1992;21:383-396.

Rosenbaum JR, Alexeeff GV, Lewis DC. Use of benchmark dose methodology to combine data

sets in the development of an acute REL for ammonia [abstract]. Toxicologist 1993;13:282.

Rowe VK, Spencer HC, McCollister DD, Adams EM. Toxicity of ethylene dibromide determined

on experimental animals. Arch Ind Hyg Occup Med 1952;158-173.

Rowe VK, McCollister DD, Spencer HC, Adams EM, Irish DD. Vapor toxicity of

tetrachloroethylene for laboratory animals and human subjects. Arch Indust Hyg Occup Med

1952;5(6):566-579.

Rowe VK, Hollingsworth RL, Oyen F, et al. Toxicology of propylene oxide determined on

experimental animals. Arch Ind Health 1956;13:228-236.

Schmidt CW, Gillis CA, Keenan RE, Price PS. Characterizing inter-chemical variation in the

interspecies uncertainty factor (UFA) [abstract #1057]. Toxicologist 1997;36:208.

Silver SD, McGrath FP. A comparison of acute toxicities of ethylene imine and ammonia in mice.

J Ind Hyg Toxicol 1948;30(1):7-9.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

69

Smith LW, Gardner RJ, Kennedy GL Jr. Short-term inhalation toxicity of perfluoroisobutylene.

Drug Chem Toxicol 1982;5(3):295-303

Snam Progretti. Research reports on MTBE: Toxicological data. 1980.

Sterk PJ, Fabbri LM, Quanjer PhH, Cockroft DW, O’Byrne PM, Anderson SD, Juniper EF, Malo

J-L. [Report of Working Party, Standardization of Lung Function Tests, European Community

for Steel and Coal] Airway responsiveness: standardized challenge testing with pharmacological,

physical and sensitizing stimuli in adults. Eur Resp J 1993;6(Suppl 16):53-83.

Stickney JA, Keenan RE, Swartout JC, Gillis CA, Carlson-lynch HL, Dourson, ML, Harvey T,

Price PS. A probabilistic framework for the reference dose. [abstract # 1054]. Toxicologist. 1997.

36:208.

ten Berge WF, Zwart A, Appelman LM. Concentration-time mortality response relationship of

irritant and systemically acting vapours and gases. J Hazard Mater 1986;13:301-309.

Torkelson TR, Oyen F, Rowe VK. The toxicity of bromochloromethane as determined on

laboratory animals. Am Ind Hyg Assoc J 1960;21:275-286.

(U.S.EPA) United States Environmental Protection Agency. Federal Emergency Management

Agency and U.S. Department of Transportation. Technical guidance for hazards analysis:

Emergency planning for extremely hazardous substances. Washington (DC); 1987. p. 1-1 to 1-10,

B-1 to D-27.

(U.S.EPA) United States Environmental Protection Agency. Benchmark dose methods for

development of inhalation reference doses. EPA/600/8-88/066F. Washington(DC): Office of

Health and Environmental Assessment; 1989. p. 4-1 to 4-12.

(U.S.EPA) United States Environmental Protection Agency. Guidelines for developmental

toxicity risk assessment. Notice 56 CFR Sect. 63798-63826 (1991).

(U.S.EPA) U.S. Environmental Protection Agency. Acute inhalation toxicity of acrolein in

hamsters (final report). EPA/OTS: 88-920002323. Washington (DC): Office of Toxic Substances;

1992a.

(U.S.EPA) U.S. Environmental Protection Agency. Acute inhalation toxicity of acrolein vapor by

one and four hour exposures. (project report). EPA/OTS: 88-920001468S. Washington (DC):

Office of Toxic Substances; 1992b.

(U.S.EPA) United States Environmental Protection Agency. Methods for derivation of inhalation

reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F.

Washington (DC): Office of Research and Development; 1994a.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

70

(U.S.EPA) United States Environmental Protection Agency. Methods for exposure-response

analysis and health assessment for acute inhalation exposure to chemicals. Development of the

acute reference exposure (Draft). Research Triangle Park (NC): Environmental Criteria and

Assessment Office, Office of Health and Environmental Assessment; 1994b.

(U.S.EPA) United States Environmental Protection Agency. Health effects test guidelines. Acute

inhalation toxicity. EPA/OPPTS870.1300. Washington (DC): Office of Pesticides, Prevention and

Toxic Substances; 1996.

(U.S.EPA) United States Environmental Protection Agency. 62 CFR No. 210; Oct. 30, 1997.

(U.S.EPA) United States Environmental Protection Agency. Methods for exposure-response

analysis for acute inhalation exposure to chemicals. Development of the Acute Reference

Exposure. External Review Draft. EPA/600/R-98/051. Washington (DC). Office of Research and

Development; 1998.

Verberk MM. Effects of ammonia in volunteers. Int Arch Occup Health 1977;39:73-81.

Vettorazzi G. Safety factors and their application in the toxicological evaluation. In: The

evaluation of toxicological data for the protection of public health. Colloquium on the evaluation

of toxicological data for the protection of public health. Oxford: Pergamon Press; 1976. p. 207-

223.

Watanabe K, Bois FY, Zeise L. Interspecies extrapolation: a reexamination of acute toxicity data.

Risk Anal 1992;12:301-310.

Weil CS. Statistics versus safety factors and scientific judgment in the evaluation of safety for

man. Toxicol Appl Pharmacol 1972; 21:454-463.

Wen CP, Tsai SP, Gibson RL. Anatomy of the healthy worker effect: a critical review. J Occup

Med 1983;25(4):283-289.

Wiebicke W, Jorres R, Magnussen H. Comparison of the effects of inhaled corticosteroids on the

airway response to histamine, methacholine, hyperventilation, and sulfur dioxide in subjects with

asthma. J Allergy Clin Immunol 1990;86:915-923.

Willhite CC, Hill RM, Irving DW. Isotretinoin-induced craniofacial malformations in humans and

hamsters. J Craniofac Genet Dev Biol 1986;Suppl 2:193-209.

Woolcock AJ. Asthma. In: Murray JF, Nadel JA, editors. Respiratory medicine. 2nd ed.

Philadelphia: W.B. Saunders; 1994. p.1288-1330.

Zwart A, Woutersen RA. Acute inhalation toxicity of chlorine in rats and mice: timeconcentration-mortality relationships and effects on respiration. J Hazard Mater 1988;19(2):195-

208.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

71
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

A - 1

Appendix A

Acute Reference Exposure Levels Summary Table

and Table of Hazard Index Target Organs
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

A - 2

Table A-1. Acute Reference Exposure Levels (RELs), Averaging Times,

 and Toxicologic Endpoints

Chemical Name (CAS #) REL

(μg/m3)

Avg

time

(h)

Sp.1 Toxicologic Endpoints Severity2

Acrolein (107-02-8) 1.9 x 10-1 1 H Eye Irritation Mild

Acrylic Acid (79-10-7) 6 x 1031 R Respiratory Irritation Mild

Ammonia (7664-41-7) 3.2 x 1031 H Eye and Respiratory Irritation Mild

Arsenic and Inorganic Arsenic

Compounds

1.9 x 10-1 4 M Reproductive/Developmental Severe

Arsine (7784-42-1) 1.6 x 1021 M Hematologic System Severe

Benzene (71-43-2) 1.3 x 1036 R Reproductive/developmental Severe

Benzyl Chloride (100-44-7) 2.4 x 1021 M&

R

Eye and Respiratory Irritation Mild

Carbon Disulfide (75-15-0) 6.2 x 1036 R Reproductive/Developmental Severe

Carbon Monoxide3 (630-08-0) 2.3 x 1041 H Cardiovascular System Mild

Carbon Tetrachloride (56-23-5) 1.9 x 1037 R Reproductive/Developmental Severe

Chlorine (7782-50-5) 2.1 x 1021 H Respiratory Irritation Mild

Chloroform (67-66-3) 1.5 x 1027 R Reproductive/Developmental Severe

Chloropicrin (76-06-2) 2.9 x 1011 M Eye and Respiratory Irritation Mild

Copper and Compounds 1 x 1021 H Respiratory Irritation Mild

1,4-Dioxane (123-91-1) 3 x 1031 H Eye and Respiratory Irritation Mild

Epichlorohydrin (106-89-8) 1.3 x 1031 H Eye and Respiratory Irritation Mild

Ethylene Glycol Monobutyl

Ether (111-76-2)

1.4 x 1041 H Eye and Respiratory Irritation Mild

Ethylene Glycol Monoethyl

Ether (110-80-5)

3.7 x 1026 R Reproductive/Developmental Severe

Ethylene Glycol Monoethyl

Ether Acetate (111-15-9)

1.4 x 1026 Rb Reproductive/Developmental Severe

Ethylene Glycol Monomethyl

Ether (109-86-4)

9.3 x 1016 R Reproductive/Developmental Severe

Formaldehyde (50-00-0) 9.4 x 1011 H Eye Irritation Mild

Hydrogen chloride (7647-01-0) 2.1 x 1031 H Eye and Respiratory Irritation Mild

Hydrogen Cyanide (74-90-8) 3.4 x 1021 Mk CNS4 - serious Severe

Hydrogen Fluoride (7664-39-3) 2.4 x 1021 H Eye and Respiratory Irritation Mild

Hydrogen Selenide 5 x 1001 GP Eye and Respiratory Irritation Mild

Hydrogen Sulfide (7783-06-4)34.2 x 1011 H Respiratory Irritation Mild

Isopropyl Alcohol (67-63-0) 3.2 x 1031 H Eye and Respiratory Irritation Mild

Mercury (Inorganic)

(7439-97-6)

1.8 x 1001 R Reproductive/Developmental Severe

Methanol (67-56-1) 2.8 x 1041 H CNS4 - mild Mild

Methyl Bromide (74-83-9) 3.9 x 1031 H CNS- mild (anorexia, nausea,

headache;

Mild

Methyl Chloroform (71-55-6) 6.8 x 1041 H CNS - mild Mild

Methyl Ethyl Ketone (78-93-3) 1.3 x 1041 H Eye and Respiratory Irritation Mild

Methylene Chloride (75-9-2) 1.4 x 1041 H CNS - mild Mild
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

A - 3

Chemical Name (CAS #) REL

(μg/m3)

Avg

time

(h)

Sp.1 Toxicologic Endpoints Severity2

Nickel and Nickel Compounds 6 x 1001 H Respiratory Irritation; Immune

Response

Mild

Nitric Acid (7697-37-2) 8.6 x 1011 H Respiratory Irritation Mild

Nitrogen Dioxide3

(10102-44-0)

4.7 x 1021 H Respiratory Irritation Mild

Ozone3 (10028-15-6) 1.8 x 1021 H Eye and Respiratory Irritation Mild

Perchloroethylene (127-18-4) 2 x 1041 H CNS - mild; Eye and Respiratory

Irritation

Mild

Phenol (108-95-2) 5.8 x 1031 H Eye and Respiratory Irritation Mild

Phosgene (75-44-5) 4 x 1001 R Respiratory Irritation Mild

Propylene Oxide (75-56-9) 3.1 x 1031 M Eye and Respiratory Irritation Mild

Sodium Hydroxide (1310-93-2) 8 x 1001 H Skin, Eye, and Respiratory

Irritation

Mild

Styrene (100-42-5) 2.1 x 1041 H Eye and Respiratory Irritation Mild

Sulfates31.2 x 1021 H Respiratory Irritation Mild

Sulfur Dioxide3

 (7446-09-5)

6.6 x 1021 H Respiratory Irritation Mild

Sulfuric Acid and Oleum 1.2 x 1021 H Respiratory Irritation Mild

Toluene (108-88-3) 3.7 x 1041 H CNS - mild;

Eye and Respiratory Irritation

Mild

Triethylamine (121-44-8) 2.8 x 1031 H CNS - mild; Eye Irritation Mild

Vanadium Pentoxide

(1314-62-1)

3 x 1011 H Respiratory Irritation Mild

Vinyl Chloride (75-01-4) 1.8 x 1051 H CNS - mild; Eye and Respiratory

Irritation

Mild

Xylenes (m,o,p-isomers) 2.2 x 1041 H Eye and Respiratory Irritation Mild

1

 Species used in key study for REL development: D = dog; GP = guinea pig: H = human;

 M = mouse; Mk = monkey; R = rat; Rb = rabbit

2

 Refers to effect severity levels-- see Hazard Identification section of main text or Table 6

3

 California Ambient Air Quality Standard

4

 CNS = Central Nervous System.
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

A - 4

Table A-2. Hazard Index Target Organs

Chemical Name (CAS #) Target Organs

Acrolein (107-02-8) Respiratory System; Eye

Acrylic Acid (79-10-7) Respiratory System; Eye

Ammonia (7664-41-7) Respiratory System; Eye

Arsenic and Inorganic Arsenic

Compounds

Reproductive/Developmental

Arsine (7784-42-1) Hematologic System

Benzene (71-43-2) Reproductive/developmental; Immune System;

Hematologic System;

Benzyl Chloride (100-44-7) Respiratory System; Eye

Carbon Disulfide (75-15-0) Reproductive/Developmental; Nervous System

Carbon Monoxide (630-08-0) Cardiovascular System

Carbon Tetrachloride (56-23-5) Reproductive/Developmental; Nervous System;

Alimentary Tract

Chlorine (7782-50-5) Respiratory System; Eye

Chloroform (67-66-3) Nervous System;

Reproductive/Developmental

Chloropicrin (76-06-2) Respiratory System; Eye

Copper and Compounds Respiratory System

1,4-Dioxane (123-91-1) Respiratory System; Eye

Epichlorohydrin (106-89-8) Respiratory System; Eye

Ethylene Glycol Monobutyl

Ether (111-76-2)

Respiratory System; Eye

Ethylene Glycol Monoethyl

Ether (110-80-5)

Reproductive/Developmental

Ethylene Glycol Monoethyl

Ether Acetate (111-15-9)

Reproductive/Developmental; Nervous System

Ethylene Glycol Monomethyl

Ether (109-86-4)

Reproductive/Developmental

Formaldehyde (50-00-0) Eye; Respiratory System; Immune System

Hydrogen Chloride (7647-01-0) Respiratory System; Eye

Hydrogen Cyanide (74-90-8) Nervous System

Hydrogen Fluoride (7664-39-3) Respiratory System; Eye

Hydrogen Sulfide (7783-06-4) Headache and Nausea in Response to Odor

Isopropyl Alcohol (67-63-0) Respiratory System; Eye

Mercury (Inorganic)

(7439-97-6)

Reproductive/Developmental

Methanol (67-56-1) Nervous System
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

A - 5

Chemical Name (CAS #) Target Organs

Methyl Bromide (74-83-9) Nervous System; Respiratory Irritation;

Reproductive/developmental

Methyl Chloroform (71-55-6) Nervous System

Methyl Ethyl Ketone (78-93-3) Respiratory System; Eye

Methylene Chloride (75-9-2) Nervous System

Nickel and Nickel Compounds Respiratory System; Immune System

Nitric Acid (7697-37-2) Respiratory System

Nitrogen Dioxide

(10102-44-0)

Respiratory System

Ozone (10028-15-6) Eye; Respiratory System

Perchloroethylene (127-18-4) Nervous system; Eye; Respiratory System

Phenol (108-95-2) Respiratory System; Eye

Phosgene (75-44-5) Respiratory System

Propylene Oxide (75-56-9) Respiratory System; Eye;

Reproductive/developmental

Selenium: He2S Respiratory System; Eye

Sodium Hydroxide (1310-93-2) Eye; Skin; Respiratory System

Styrene (100-42-5) Respiratory System; Eye;

Sulfates Respiratory System

Sulfur Dioxide

 (7446-09-5)

Respiratory System

Sulfuric Acid and Oleum Respiratory System

Toluene (108-88-3) Nervous System; Eye; Respiratory System;

Reproductive/developmental??

Triethylamine (121-44-8) Nervous System; Eye

Vanadium Pentoxide

(1314-62-1)

Respiratory System; Eye

Vinyl Chloride (75-01-4) Nervous System; Eye; Respiratory System

Xylenes (m,o,p-isomers) Eye; Respiratory System
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 1

Appendix B

Substances Listed Under the Air Toxics Hot Spots Act

for Which Emissions Must be Quantified
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 2

Appendix B

Substances for which Emissions Must Be Quantified

 75070 Acetaldehyde

 60355 Acetamide

 67641 Acetone

 75058 Acetonitrile

 98862 Acetophenone

 53963 2-Acetylaminofluorene [PAH-Derivative, POM]

 107028 Acrolein

 79061 Acrylamide

 79107 Acrylic acid

 107131 Acrylonitrile

 107051 Allyl chloride

 7429905 Aluminum

 1344281 Aluminum oxide (fibrous forms)

 117793 2-Aminoanthraquinone [PAH-Derivative, POM]

 92671 4-Aminobiphenyl [POM]

 61825 Amitrole

 7664417 Ammonia

 6484522 Ammonium nitrate

 7783202 Ammonium sulfate

 62533 Aniline

 90040 o-Anisidine

 - Anthracene [PAH, POM], (see PAH)

 7440360 Antimony

 * Antimony compounds

 including but not limited to:

 1309644 Antimony trioxide

 7440382 Arsenic

 1016 Arsenic compounds (inorganic)

 including but not limited to:

 7784421 Arsine

 1017 Arsenic compounds (other than inorganic)

 7440393 Barium

 * Barium compounds

 - Benz[a]anthracene [PAH, POM], (see PAH)

 71432 Benzene

 92875 Benzidine (and its salts) [POM]

 1020 Benzidine-based dyes [POM]

 including but not limited to:

 1937377 Direct Black 38 [PAH-Derivative, POM]

 2602462 Direct Blue 6 [PAH-Derivative, POM]

 16071866 Direct Brown 95 (technical grade) [POM]

 - Benzo[a]pyrene [PAH, POM], (see PAH)

 - Benzo[b]fluoranthene [PAH, POM], (see PAH)

 271896 Benzofuran

 98077 Benzoic trichloride {Benzotrichloride}

 - Benzo[j]fluoranthene [PAH, POM], (see PAH)

 - Benzo[k]fluoranthene [PAH, POM], (see PAH)

 98884 Benzoyl chloride

 94360 Benzoyl peroxide

 100447 Benzyl chloride

 7440417 Beryllium

 * Beryllium compounds

 92524 Biphenyl [POM]

 111444 Bis(2-chloroethyl) ether {DCEE}

 542881 Bis(chloromethyl) ether

 103231 Bis(2-ethylhexyl) adipate

 7726956 Bromine

 * Bromine compounds (inorganic)

 including but not limited to:

 7758012 Potassium bromate

 75252 Bromoform

 106990 1,3-Butadiene

 141322 Butyl acrylate

 71363 n-Butyl alcohol

 78922 sec-Butyl alcohol

 75650 tert-Butyl alcohol

 85687 Butyl benzyl phthalate

 7440439 Cadmium

 * Cadmium compounds

 156627 Calcium cyanamide

 105602 Caprolactam
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 3

 2425061 Captafol

 133062 Captan

 63252 Carbaryl [PAH-Derivative, POM]

 1050 Carbon black extracts

 75150 Carbon disulfide

 56235 Carbon tetrachloride

 463581 Carbonyl sulfide

 1055 Carrageenan (degraded)

 120809 Catechol

 133904 Chloramben

 56757 Chloramphenicol

 57749 Chlordane

 108171262 Chlorinated paraffins (average chain length, C12;

 approximately 60% chlorine by weight)

 7782505 Chlorine

 10049044 Chlorine dioxide

 79118 Chloroacetic acid

 532274 2-Chloroacetophenone

 1058 Chlorobenzenes

 including but not limited to:

 108907 Chlorobenzene

 25321226 Dichlorobenzenes (mixed isomers)

 including:

 95501 1,2-Dichlorobenzene

 541731 1,3-Dichlorobenzene

 106467 p-Dichlorobenzene {1,4-Dichlorobenzene}

 120821 1,2,4-Trichlorobenzene

 510156 Chlorobenzilate [POM] {Ethyl-4,4'-

 dichlorobenzilate}

 13909096 1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-

 nitrosourea {Methyl CCNU}

 67663 Chloroform

 107302 Chloromethyl methyl ether (technical grade)

 1060 Chlorophenols

 including but not limited to:

 120832 2,4-Dichlorophenol

 87865 Pentachlorophenol

 95954 2,4,5-Trichlorophenol

 88062 2,4,6-Trichlorophenol

 95830 4-Chloro-o-phenylenediamine

 76062 Chloropicrin

 126998 Chloroprene

 95692 p-Chloro-o-toluidine

 7440473 Chromium

 * Chromium compounds (other than hexavalent)

 18540299 Chromium, hexavalent (and compounds)

 including but not limited to:

 10294403 Barium chromate

 13765190 Calcium chromate

 1333820 Chromium trioxide

 7758976 Lead chromate

 10588019 Sodium dichromate

 7789062 Strontium chromate

 - Chrysene [PAH, POM], (see PAH)

 7440484 Cobalt

 * Cobalt compounds

 1066 Coke oven emissions

 7440508 Copper

 * Copper compounds

 1070 Creosotes

 120718 p-Cresidine

 1319773 Cresols (mixtures of) {Cresylic acid}

 including:

 108394 m-Cresol

 95487 o-Cresol

 106445 p-Cresol

 98828 Cumene

 80159 Cumene hydroperoxide

 135206 Cupferron

 1073 Cyanide compounds

 including but not limited to:

 74908 Hydrocyanic acid

 110827 Cyclohexane

 66819 Cycloheximide

 1163195 Decabromodiphenyl oxide [POM]

 1075 Dialkylnitrosamines

 including but not limited to:

 924163 N-Nitrosodi-n-butylamine

 1116547 N-Nitrosodiethanolamine

 55185 N-Nitrosodiethylamine

 62759 N-Nitrosodimethylamine
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 4

 621647 N-Nitrosodi-n-propylamine

 10595956 N-Nitrosomethylethylamine

 615054 2,4-Diaminoanisole

 1078 Diaminotoluenes (mixed isomers)

 including but not limited to:

 95807 2,4-Diaminotoluene {2,4-Toluenediamine}

 334883 Diazomethane

 226368 Dibenz[a,h]acridine [POM]

 224420 Dibenz[a,j]acridine [POM]

 - Dibenz[a,h]anthracene [PAH, POM], (see PAH)

 194592 7H-Dibenzo[c,g]carbazole

 - Dibenzo[a,e]pyrene [PAH, POM], (see PAH)

 - Dibenzo[a,h]pyrene [PAH, POM], (see PAH)

 - Dibenzo[a,i]pyrene [PAH, POM], (see PAH)

 - Dibenzo[a,l]pyrene [PAH, POM], (see PAH)

 132649 Dibenzofuran [POM]

 - Dibenzofurans (chlorinated) (see Polychlorinated

 dibenzofurans) [POM]

 96128 1,2-Dibromo-3-chloropropane {DBCP}

 84742 Dibutyl phthalate

 - p-Dichlorobenzene {1,4-Dichlorobenzene} (see

 Chlorobenzenes)

 91941 3,3'-Dichlorobenzidine [POM]

 72559 Dichlorodiphenyldichloroethylene {DDE} [POM]

 75343 1,1-Dichloroethane {Ethylidene dichloride}

 94757 Dichlorophenoxyacetic acid, salts and esters

 {2,4-D}

 78875 1,2-Dichloropropane {Propylene dichloride}

 542756 1,3-Dichloropropene

 62737 Dichlorovos {DDVP}

 115322 Dicofol [POM]

 - - Diesel engine exhaust

 9901 Diesel engine exhaust, particulate matter

 9902 Diesel engine exhaust, total organic gas

 # Diesel fuel (marine)

 111422 Diethanolamine

 117817 Di(2-ethylhexyl) phthalate {DEHP}

 64675 Diethyl sulfate

 119904 3,3'-Dimethoxybenzidine [POM]

 60117 4-Dimethylaminoazobenzene [POM]

 121697 N,N-Dimethylaniline

 57976 7,12-Dimethylbenz[a]anthracene [PAH-Derivative,

 POM]

 119937 3,3'-Dimethylbenzidine {o-Tolidine} [POM]

 79447 Dimethyl carbamoyl chloride

 68122 Dimethyl formamide

 57147 1,1-Dimethylhydrazine

 131113 Dimethyl phthalate

 77781 Dimethyl sulfate

 534521 4,6-Dinitro-o-cresol (and salts)

 51285 2,4-Dinitrophenol

 42397648 1,6-Dinitropyrene [PAH-Derivative, POM]

 42397659 1,8-Dinitropyrene [PAH-Derivative, POM]

 25321146 Dinitrotoluenes (mixed isomers)

 including but not limited to:

 121142 ––2,4-Dinitrotoluene

 606202 ––2,6-Dinitrotoluene

 123911 1,4-Dioxane

 - Dioxins (Chlorinated dibenzodioxins) (see

 Polychlorinated dibenzo-p-dioxins) [POM]

 630933 Diphenylhydantoin [POM]

 122667 1,2-Diphenylhydrazine {Hydrazobenzene} [POM]

 1090 Environmental Tobacco Smoke

 106898 Epichlorohydrin

 106887 1,2-Epoxybutane

 1091 Epoxy resins

 140885 Ethyl acrylate

 100414 Ethyl benzene

 75003 Ethyl chloride {Chloroethane}

 - Ethyl-4,4'-dichlorobenzilate (see Chlorobenzilate)

 74851 Ethylene

 106934 Ethylene dibromide {1,2-Dibromoethane}

 107062 Ethylene dichloride {1,2-Dichloroethane}

 107211 Ethylene glycol

 151564 Ethyleneimine {Aziridine}

 75218 Ethylene oxide

 96457 Ethylene thiourea

 1101 Fluorides and compounds

 including but not limited to:

 7664393 Hydrogen fluoride

 1103 Fluorocarbons (brominated)
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 5

 1104 Fluorocarbons (chlorinated)

 including but not limited to:

 76131 Chlorinated fluorocarbon {CFC-113}

 50000 Formaldehyde

 - - Gasoline engine exhaust

 including but not limited to:

 - - Gasoline engine exhaust (condensates & extracts)

 9910 Gasoline engine exhaust, particulate matter

 9911 Gasoline engine exhaust, total organic gas

 1110 Gasoline vapors

 111308 Glutaraldehyde

 1115 Glycol ethers and their acetates

 including but not limited to:

 111466 Diethylene glycol

 111966 Diethylene glycol dimethyl ether

 112345 Diethylene glycol monobutyl ether

 111900 Diethylene glycol monoethyl ether

 111773 Diethylene glycol monomethyl ether

 25265718 Dipropylene glycol

 34590948 Dipropylene glycol monomethyl ether

 629141 Ethylene glycol diethyl ether

 110714 Ethylene glycol dimethyl ether

 111762 Ethylene glycol monobutyl ether

 110805 Ethylene glycol monoethyl ether

 111159 Ethylene glycol monoethyl ether acetate

 109864 Ethylene glycol monomethyl ether

 110496 Ethylene glycol monomethyl ether acetate

 2807309 Ethylene glycol monopropyl ether

 107982 Propylene glycol monomethyl ether

 108656 Propylene glycol monomethyl ether acetate

 112492 Triethylene glycol dimethyl ether

 126078 Griseofulvin

 76448 Heptachlor

 118741 Hexachlorobenzene

 87683 Hexachlorobutadiene

 1120 Hexachlorocyclohexanes

 including but not limited to:

 58899 Lindane

 77474 Hexachlorocyclopentadiene

 67721 Hexachloroethane

 680319 Hexamethylphosphoramide

 110543 Hexane

 302012 Hydrazine

 7647010 Hydrochloric acid

 - Hydrocyanic acid (see Cyanide compounds )

 7783064 Hydrogen sulfide

 123319 Hydroquinone

 - Indeno[1,2,3-cd]pyrene [PAH, POM], (see PAH)

 1125 Isocyanates

 including but not limited to:

 822060 Hexamethylene-1,6-diisocyanate

 101688 Methylene diphenyl diisocyanate {MDI} [POM]

 624839 Methyl isocyanate

 - Toluene-2,4-diisocyanate (see Toluene diisocyanates)

 - Toluene-2,6-diisocyanate (see Toluene diisocyanates)

 78591 Isophorone

 67630 Isopropyl alcohol

 80057 4,4'-Isopropylidenediphenol [POM]

 7439921 Lead

 1128 Lead compounds (inorganic)

 including but not limited to:

 301042 Lead acetate

 - Lead chromate (see Chromium, hexavalent)

 7446277 Lead phosphate

 1335326 Lead subacetate

 1129 Lead compounds (other than inorganic)

 108316 Maleic anhydride

 7439965 Manganese

 * Manganese compounds

 7439976 Mercury

 * Mercury compounds

 including but not limited to:

 7487947 Mercuric chloride

 593748 Methyl mercury {Dimethylmercury}

 67561 Methanol

 72435 Methoxychlor [POM]

 75558 2-Methylaziridine {1,2-Propyleneimine}

 74839 Methyl bromide {Bromomethane}

 74873 Methyl chloride {Chloromethane}

 71556 Methyl chloroform {1,1,1-Trichloroethane}

 56495 3-Methylcholanthrene [PAH-Derivative, POM]
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 6

 3697243 5-Methylchrysene [PAH-Derivative, POM]

 101144 4,4'-Methylene bis(2-chloroaniline) {MOCA} [POM]

 75092 Methylene chloride {Dichloromethane}

 101779 4,4'-Methylenedianiline (and its dichloride) [POM]

 78933 Methyl ethyl ketone {2-Butanone}

 60344 Methyl hydrazine

 74884 Methyl iodide {Iodomethane}

 108101 Methyl isobutyl ketone {Hexone}

 80626 Methyl methacrylate

 1634044 Methyl tert-butyl ether

 443481 Metronidazole

 90948 Michler's ketone [POM]

 1136 Mineral fibers (fine, manmade)

 (fine mineral fibers which are manmade and are

 airborne particles of a respirable size greater

 than 5 microns in length, less than or equal to

 3.5 microns in diameter, with a length to

 diameter ratio of 3:1)

 including but not limited to:

 1056 Ceramic fibers

 1111 Glasswool fibers

 1168 Rockwool fibers

 1181 Slagwool fibers

 1135 Mineral fibers (other than manmade)

 including but not limited to:

 1332214 Asbestos

 12510428 Erionite

 1190 Talc containing asbestiform fibers

 1313275 Molybdenum trioxide

 - Naphthalene [PAH, POM], (see PAH)

 7440020 Nickel

 * Nickel compounds

 including but not limited to:

 373024 Nickel acetate

 3333393 Nickel carbonate

 13463393 Nickel carbonyl

 12054487 Nickel hydroxide

 1271289 Nickelocene

 1313991 Nickel oxide

 12035722 Nickel subsulfide

 1146 Nickel refinery dust from the pyrometallurgical

 process

 61574 Niridazole

 7697372 Nitric acid

 139139 Nitrilotriacetic acid

 98953 Nitrobenzene

 92933 4-Nitrobiphenyl [POM]

 7496028 6-Nitrochrysene [PAH-Derivative, POM]

 607578 2-Nitrofluorene [PAH-Derivative, POM]

 302705 Nitrogen mustard N-oxide

 100027 4-Nitrophenol

 79469 2-Nitropropane

 5522430 1-Nitropyrene [PAH-Derivative, POM]

 156105 p-Nitrosodiphenylamine [POM]

 684935 N-Nitroso-N-methylurea

 59892 N-Nitrosomorpholine

 100754 N-Nitrosopiperidine

 930552 N-Nitrosopyrrolidine

 - - PAHs (Polycyclic aromatic hydrocarbons) [POM]

 including but not limited to:

 1151 PAHs, total, w/o individ. components reported

 1150 PAHs, total, with individ. components also

 reported

 120127 Anthracene

 56553 Benz[a]anthracene

 50328 Benzo[a]pyrene

 205992 Benzo[b]fluoranthene

 205823 Benzo[j]fluoranthene

 207089 Benzo[k]fluoranthene

 218019 Chrysene

 53703 Dibenz[a,h]anthracene

 192654 Dibenzo[a,e]pyrene

 189640 Dibenzo[a,h]pyrene

 189559 Dibenzo[a,i]pyrene

 191300 Dibenzo[a,l]pyrene

 193395 Indeno[1,2,3-cd]pyrene

 91203 Naphthalene

 # PAH-Derivatives (Polycyclic aromatic hydrocarbon

 derivatives) [POM]

 (including but not limited to those substances
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 7

 listed in Appendix A with the bracketed

 designation [PAH-Derivative, POM])

 56382 Parathion

 1336363 PCBs (Polychlorinated biphenyls) [POM]

 82688 Pentachloronitrobenzene {Quintobenzene}

 79210 Peracetic acid

 127184 Perchloroethylene {Tetrachloroethane}

 50066 Phenobarbital

 108952 Phenol

 106503 p-Phenylenediamine

 90437 2-Phenylphenol [POM]

 75445 Phosgene

 7723140 Phosphorus

 - - Phosphorus compounds:

 7803512 Phosphine

 7664382 Phosphoric acid

 10025873 Phosphorus oxychloride

 10026138 Phosphorus pentachloride

 1314563 Phosphorus pentoxide

 7719122 Phosphorus trichloride

 126738 Tributyl phosphate

 78400 Triethyl phosphine

 512561 Trimethyl phosphate

 78308 Triorthocresyl phosphate [POM]

 115866 Triphenyl phosphate [POM]

 101020 Triphenyl phosphite [POM]

 85449 Phthalic anhydride

 - - Polychlorinated dibenzo-p-dioxins {PCDDs or

 Dioxins} [POM]

 including but not limited to:

 1086 Dioxins, total, wo individ. isomers reported

 {PCDDs}

 1085 Dioxins, total, with individ. isomers also

 reported {PCDDs}

 1746016 2,3,7,8-Tetrachlorodibenzo-p-dioxin {TCDD} [POM]

 40321764 1,2,3,7,8-Pentachlorodibenzo-p-dioxin [POM]

 39227286 1,2,3,4,7,8-Hexachlorodibenzo-p-dioxin [POM]

 57653857 1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin [POM]

 19408743 1,2,3,7,8,9-Hexachlorodibenzo-p-dioxin [POM]

 35822469 1,2,3,4,6,7,8-Heptachlorodibenzo-p-dioxin [POM]

 - - Polychlorinated dibenzofurans {PCDFs or

 Dibenzofurans} [POM]

 including but not limited to:

 1080 Dibenzofurans (Polychlorinated dibenzofurans)

 {PCDFs} [POM]

 51207319 2,3,7,8-Tetrachlorodibenzofuran [POM]

 57117416 1,2,3,7,8-Pentachlorodibenzofuran [POM]

 57117314 2,3,4,7,8-Pentachlorodibenzofuran [POM]

 70648269 1,2,3,4,7,8-Hexachlorodibenzofuran [POM]

 57117449 1,2,3,6,7,8-Hexachlorodibenzofuran [POM]

 72918219 1,2,3,7,8,9-Hexachlorodibenzofuran [POM]

 60851345 2,3,4,6,7,8-Hexachlorodibenzofuran [POM]

 67562394 1,2,3,4,6,7,8-Heptachlorodibenzofuran [POM]

 55673897 1,2,3,4,7,8,9-Heptachlorodibenzofuran [POM]

 # POM (Polycyclic organic matter)

 (including but not limited to those substances

 listed in Appendix A with the bracketed

 designation of [POM], [PAH, POM], or

 [PAH-Derivative, POM])

 57830 Progesterone

 1120714 1,3-Propane sultone

 57578 beta-Propiolactone

 123386 Propionaldehyde

 114261 Propoxur {Baygon}

 115071 Propylene

 75569 Propylene oxide

 - 1,2-Propyleneimine (see 2-Methylaziridine)

 110861 Pyridine

 91225 Quinoline

 106514 Quinone

 1165 Radionuclides

 including but not limited to:

 24267569 Iodine-131

 1166 Radon and its decay products

 50555 Reserpine [POM]

 # Residual (heavy) fuel oils

 7782492 Selenium

 * Selenium compounds

 including but not limited to:

 7446346 Selenium sulfide

 1175 Silica, crystalline
Determination of Acute Reference Exposure Levels for Airborne Toxicants

March 1999

B - 8

 7440224 Silver

 * Silver compounds

 1310732 Sodium hydroxide

 100425 Styrene

 96093 Styrene oxide

 7664939 Sulfuric acid

 100210 Terephthalic acid

 79345 1,1,2,2-Tetrachloroethane

 7440280 Thallium

 * Thallium compounds

 62555 Thioacetamide

 62566 Thiourea

 7550450 Titanium tetrachloride

 108883 Toluene

 - 2,4-Toluenediamine (see 2,4-Diaminotoluene)

 1204 Toluene diisocyanates

 including but not limited to:

 584849 Toluene-2,4-diisocyanate

 91087 Toluene-2,6-diisocyanate

 95534 o-Toluidine

 8001352 Toxaphene {Polychlorinated camphenes}

 79005 1,1,2-Trichloroethane {Vinyl trichloride}

 - 1,1,1-Trichloroethane (see Methyl chloroform)

 79016 Trichloroethylene

 - 2,4,6-Trichlorophenol (see Chlorophenols)

 121448 Triethylamine

 1582098 Trifluralin

 95636 1,2,4-Trimethylbenzene

 540841 2,2,4-Trimethylpentane

 51796 Urethane {Ethyl carbamate}

 7440622 Vanadium (fume or dust)

 108054 Vinyl acetate

 593602 Vinyl bromide

 75014 Vinyl chloride

 75354 Vinylidene chloride

 1206 Wood preservatives (containing arsenic and

 1210 Xylenes (mixed xylenes)

 including:

 108383 m-Xylene

 95476 o-Xylene

 106423 p-Xylene

 7440666 Zinc

 * Zinc compounds

 including but not limited to:

 1314132 Zinc oxide