TLV® Chemical Substances Committee

The Process forThe Process for Decision MakingDecision Making

Presented at the AIHceJune 3, 2002, San Diego, CA

Bill Wells PhD, CIH, CSP, ModeratorDennis Casserly, PhD, CIH & Marilyn Hallock, CIH Monitors

Forum OverviewForum Overview

• Scott Merkle: ACGIH® Structure

• Lisa Brosseau: TLV®-CS Committee

• Patrick Breysse: Conflict of Interest

• Philip Bigelow: Notations & Designations

• Dan Caldwell: Current Issues of Interest

ACGIHACGIH®® Structure Structure

Scott Merkle, CIH

National Institute of Environmental Health Sciences

Past-Chair, ACGIH®

Forum on ACGIHForum on ACGIH®® Exposure Assessment Exposure Assessment

GuidelinesGuidelines• Inaugural Forum at 2002 AIHce.

• Annual forum on ACGIH® activities to develop occupational exposure assessment guidelines and criteria.

• Focus of this forum – Current processes for developing TLVs® for chemical substances.

TLVsTLVs®® and BEIsand BEIs®®

• Threshold Limit Values for Chemical Substances

• Threshold Limit Values for Physical Agents

• Biological Exposure Indices for Chemical Substances

What Is ACGIHWhat Is ACGIH®®??

• Membership Society (founded in 1938)

• Not-for-profit, Non-governmental Association (501(c)(6) organization)

• Multi-Disciplinary Membership

• Traditionally Neutral on Public Positions

MembershipMembershipMarch 31, 2002March 31, 2002

53%

4% 3%

40%

Regular Associate Student Retired

Government& Academia

Private Industry& Others

Membership by Membership by Profession, Profession, 20012001

Industrial Hygienist 42%

Administrator/Manager 11%

OH&S Professional 6%

Environmental Professional 4%

Safety Professional 3%

Other (Engineer, Scientist, Toxicologist, Professor, etc.)

~33%

Revenue Sources

14%

6%

67%

13%

Technical Publications

Other Membership DuesEducation

2001 ACGIH® Statement of Activities

Revenue From Technical Publications ($2.2M)

34%

10%9%

14%

8%

19%

6%

2001 ACGIH® Statement of Activities

TLV®/BEI® Book & CD-Rom

TLV®/BEI® Documentation

Ind. Vent. Manual & CD-Rom

OEV Guide

Bioaerosols

Co-Op SalesOther House Pubs.

Technical Technical CommitteesCommittees

Committees provide the creativity,

initiative, and technical expertise that

has made ACGIH® what it is today and

what it will be tomorrow.

.

ACGIHACGIH®® Committees Committees

• Committees consist of members, who volunteer time toward developing scientific guidelines and publications– Primary goal is to serve the scientific

needs of occupational hygienists

– Committee expenses (travel) are supported by ACGIH®

– Time is donated by the members

CommitteesCommittees

Ex. Director& Staff

BEI

TLV-CS

TLV-PA

ExposureAssessment

Criteria

Air SamplingInstruments

Bioaerosols

Industria lVentilation

Assessment& Control

Methodology

Agr S&H

Construction

InfectiousAgents

SmallBusiness

OccupationalSector

Applications

Computer

International

PCCAIHA/ACGIH

Professional& IntersocietyCoordination

Awards

Finance

Nominating

Administration&

Governance

Air SamplingProcedures

AIHA/ACGIHOutreach

PublicPositions

Taskforces

Board of Directors

ACGIH Members

May 2002Merkle

CoreCore Mission Mission

Ex. Director& Staff

BEI

TLV-CS

TLV-PA

ExposureAssessm ent

Criteria

A ir Sam plingInstrum ents

Bioaerosols

IndustrialVentilation

Assessm ent& Control

M ethodology

Agr S&H

Construction

InfectiousAgents

SmallBusiness

OccupationalSector

Applications

Computer

International

PCCAIHA/ACGIH

Professional& IntersocietyCoordination

Awards

Finance

Nominating

Administration&

Governance

Air SamplingProcedures

AIHA/ACGIHOutreach

PublicPositions

Taskforces

Board of Directors

ACGIH Members

May 2002Merkle

Topics of Debate Topics of Debate Over the YearsOver the Years

The development and sharing of chemical toxicity data (pre- and post- OSHA & TSCA).

– TLVs® based on “analogy”

How to assess risks for carcinogenic effects.

The (Mis)use of TLVs® for non-occupational exposures.

1940s -Present

1960s -Present

1980s - Present

Topics of Debate Topics of Debate Over the YearsOver the Years

International “harmonization” of values, or of the underlying definitions and principles.

Marshalling the resources needed to support the development of voluntary guidelines.

Concerns that influences from corporate

and governmental interests can contaminate the process.

– Castleman & Ziem (1988); Legal challenges (2000-2001).

1980s - Present

1990s –Present

1990s -Present

Legal ChallengesLegal Challengesof 2001of 2001

In December 2000, ACGIH® was named as a defendant in 3 separate lawsuits --

• The “Staples” Case -- Carlin David Staples, et. al. vs. DOW Chemical Company, et. al.

• The “RCFC” Case -- Refractory Ceramic Fibers Coalition, et. al. vs. ACGIH.

• The “Trona” Case -- Anchor Glass Container Corp., et. al. vs. ACGIH, U.S. DOL, and U.S. DHHS.

LessonsLessons• TLVs® provide vitally important benchmarks for

occupational exposure assessment.

• The status of TLVs® as guidelines,not standards, is not understood by many outside our profession.

• The “3 C’s” of the TLV® development process.– Communication,– Confidentiality, – Conflict of Interest.

Role of the TLVRole of the TLV®® in the in the Overall Context of Risk Overall Context of Risk

ManagementManagement

Research Risk Assessment

Risk Management

Development of regulatory options

Evaluation of social, economic & politicalconsequences

Regulatory decisionsand rulemaking

Toxicity assessment

Risk characterization

Exposure assessment

Risk Risk CharacterizationCharacterization

The process of organizing, evaluating, and communicating information about the nature, strength of evidence, and likelihood of adverse health effects from particular exposures.

Final Report: The Presidential/Congressional Commission on Risk Assessment and

Risk Management, 1997

ACGIHACGIH®® Statement Statement of Positionof Position

ACGIH is not a standards setting body.

TLVs® and BEIs® —

• Are an expression of scientific opinion.

• Are not consensus standards.

• Are based solely on health factors; it may not be economically or technically feasible to meet established TLVs® or BEIs®.

ACGIHACGIH®® Statement Statement of Positionof Position

TLVs® and BEIs® —

• Should NOT be adopted as standards without an analysis of other factors necessary to make appropriate risk management decisions.

• Can provide valuable input into the risk characterization process. The full written Documentation for the numerical TLV® or BEI® should be reviewed.

Chemical Substances Chemical Substances TLVTLV®® Committee Committee

Lisa Brosseau, ScD, CIH

Associate Professor

University of Minnesota

Chair, TLV®-CS Committee

ACGIHACGIH®® CommitteesCommittees

• Committees consist of members, who volunteer time toward developing scientific guidelines and publications– Primary goal is to serve the scientific

needs of occupational hygienists

– Committee expenses (travel) are supported by ACGIH®

– Time is donated by the members

A Short Historical A Short Historical PerspectivePerspective

• 1941 TLV® Committee Created– Committee of Technical Standards creates

Subcommittee on Threshold Limits (becomes independent committee in 1944)

• 1946 List Published– First published list of “Maximum Allowable

Concentrations” (MACs) for 150 chemical substances (renamed Threshold Limit Values in 1948)

HistoryHistory

• 1955 Written Documentation– TLV® Committee begins to write

Documentation for each TLV® (207 completed by 1958)

– Published 1st edition in 1962 (257 substances)

HistoryHistory• Important Additions and Changes

– 1961 - Skin Notation– 1962 - Carcinogens Appendix– 1963 - Excursion factors– 1964 - Notice of Intended Changes

• 1968 - TLVs® for Physical Agents Committee

– 1972 - Cancer classifications defined– 1980 - Operational guidelines & procedures– 1981 - List of Substances & Issues Under Study

HistoryHistory• More Changes

– 1983 - Established Biological Exposure Indices (BEI®) Committee

– 1993 - Deleted STELS for many substances– 1995 - CD-ROM– 1998 - Reformatted TLV® Book to include

information on “TLV® Basis - Critical Effects”

Committee Committee StructureStructure

• Chair– Recommendations from Committee & Staff; Board appoints

• Vice-Chair, Subcommittee Chairs, Members– Recommended by Chair, appointed by Board

• Three Subcommittees, each with Chair– Dusts & Inorganics (D&I)– Hydrogen, Oxygen & Carbon Compounds (HOC)– Miscellaneous Compounds (MISCO)

• Staff Support (Liaison, Clerical, Literature Searching)

Chemical Substance Chemical Substance SubcommitteesSubcommittees

• Approximately 10 members on each• Membership from academia, government,

unions, industry• Membership represents four key

disciplines:– Industrial Hygiene– Toxicology– Occupational Medicine– Occupational Epidemiology

Other Other SubcommitteesSubcommittees

• Chemical Selection– Recommendations to HOC, D&I, MISCO

• Membership– Recruitment, screening, recommendations

• Notations– Definitions, new proposals

• Communications– Explaining our decisions

Committee Committee StructureStructure

Board of Directors

Administrative Subcommittees

(Membership, Chemical Selection)

Steering Committee

Miscellaneous Compounds Subcommittee

(MISCO)

Hydrogen, Oxygen, Carbon

Subcommittee (HOC)

Dust & Inorganics

Subcommittee (D&I)

Chair of TLV® Committee

Staff

TLVTLV®® Development Development ProcessProcess

Under StudyList

DraftDoc.

Committee & BoardApproval

NIC

Committee Review

& RevisionExternal

Input

AdoptedValue

Committee Review

& Revision

Committee & BoardApproval

TLVsTLVs®® Defined Defined• TLV® — more than just “THE NUMBER”

• Documentation describes:– Critical health effects– Quality of the data relied upon and areas of

uncertainty– Possible sensitive subgroups– Type of TLV® (TWA, STEL, C) and reason for

selection– Notations

Core TLVCore TLV®® Principles Principles• Focus on airborne exposures in

occupational settings• Utilize the “threshold” concept• Primary users are industrial hygienists• Goal is toward protection of “nearly all”

workers

Technical, economic, and analytic feasibility are NOT considered

The Essential Ingredients The Essential Ingredients for Developing TLVsfor Developing TLVs®®

Published / Peer Reviewed Science

+Dedicated Volunteerism

+Professional Integrity

& Judgment

WarningsWarnings• NOT to be used as an index of relative

toxicity• NOT for estimating toxic potential of

continuous, uninterrupted exposures or other extended work periods

• NOT as proof/disproof of existing disease• NOT to evaluate or control air pollution• NOT legal standards

SummarySummary

• Prefer human over animal data

• Use uncertainty factors, if necessary (but no “rules”)

• Look for threshold of effects

• Consider irritation an important health endpoint

• Not concerned with levels of risk

• Look for the “worst case” health endpoint

• Always select an exposure level

• Explain the reasons for our recommendations

Policies and ProcessesPolicies and Processes for for

Limiting Conflict of InterestLimiting Conflict of Interest

Patrick N. Breysse, PhD, CIHJohns Hopkins University

Bloomberg School of Public HealthVice-Chair, ACGIH®

BackgroundBackground• Historical Perspective

– assumed membership limited to government and academics controlled conflicts of interest

– industry involvement as consultants, and as providers of data both formally and informally.

• Industry representatives could be non-voting members of ACGIH® as of 1992

• Voting rights granted in 2000

Background Background (cont.)(cont.)

• The OSHA proposal to re-adopt the TLVs® as PELs resulted in increased scrutiny of the TLV® process and the role of “guidelines”

• In the late 1980s and early 1990s ACGIH® was criticized as being “industry influenced” and for not limiting conflicts of interest

Background Background (cont.)(cont.)

• As a result of these events and other factors the ACGIH® began, in the mid-1990s, to:– Review of the TLV® process – Reevaluate of the role of industry

membership– Reevaluate conflict of interest policies and

procedures

MembershipMembership

• Regular member– professional whose primary employment is

with a government agency or an educational institution

• Associate member• Student member• Retired member• Organizational member

Associate MemberAssociate Member• Not eligible for Regular membership

• Eligible to serve as voting members of appointive committees

• May hold elective office as a Director-at-Large on the Board of Directors, and may vote on committee matters and ACGIH® elections.

• May not vote on amendments to the Bylaws, serve as an officer on the Board of Directors, or as Chair of an appointive Committee or as a member of the Nominating Committee.

Conflict of Interest Conflict of Interest Policy and Procedures Policy and Procedures

DevelopmentDevelopment

• Reviewed COI policies of numerous groups• Use the National Academy of Sciences model

as the starting point• Held extensive discussions with TLV®

committee and Board of Directors• Adopted COI Policy on September 17, 2000

BIAS BIAS (NAS definition)(NAS definition)

“Views stated or positions taken that are largely intellectually motivated or arise from close identification or association of an individual with a particular point of view or the positions or perspectives of a particular group.”

BIASBIAS

• NAS position– Must create a committee with a balance of

potentially biasing backgrounds or professional or organizational perspectives

• TLV® Committee approach– Attempt to create a balance of opinions

and views by maintaining a diversity of professional affiliations, disciplines and activities among its membership

Conflict of Interest Conflict of Interest (NAS definition)(NAS definition)

“Any financial or other interest which conflicts with the service of an individual because it: (1) could impair the individual’s objectivity, or (2) could create an unfair competitive advantage for any person or organization.”

Conflict of InterestConflict of Interest

• Basis for Conflicts of Interest:– Employment– Financial benefit– Personal– Professional

• Avoid perceived as well as real conflict of interest

Conflict of InterestConflict of Interest

• Committee members serve as individuals– they do not represent organizations and/or

interest groups

• Members are selected based on expertise, soundness of judgement, and ability to contribute

Conflict of InterestConflict of Interest

• NAS position:– Significant conflict of interest will disqualify

an individual

• TLV® Committee approach:– Try to minimize or eliminate its effects

while allowing member to participate as fully as possible in Committee activities

Full d isclosure ofpossib le conflicts of

in terest

D iscussion with in fu llcom m ittee andsubcom m ittees

M anagem ent ofperceived and

real CO Is

C om m itteeand

subcom m itteechairs

Bo

ard

of

Dir

ect

ors

Ove

rsig

ht

COI Process at ACGIHCOI Process at ACGIH®®

Conflict of InterestConflict of Interest• Annual discussion of conflict of interest in full

committee– Definitions– Case studies

• Annual declaration by each member– Professional employment background– Current professional activities– Consulting– Research funding– Financial holdings

Conflict of InterestConflict of Interest

• Subcommittee– Subcommittee Chair will discuss and

remind as new substances are taken up– Subcommittee Chair will work with

individual members to minimize conflicts:• Authorship?• Co-author or external review?• Voting?

Conflict of InterestConflict of Interest

• It is each Member’s responsibility to ensure they have considered and addressed any conflicts

• Failure to report conflict of interest can result in immediate termination of membership on the Committee

High Degree of High Degree of ConflictConflict

• Requires “direct” and substantial personal, professional and/or financial involvement with the substance

• In most cases the member should:– not author the Documentation– not participate in discussions about the

recommended TLV®

– should abstain from voting on the TLV®

• The member may discuss matters of science and express opinions about individual studies

High Degree of High Degree of Conflict Conflict (cont.)(cont.)

• In some cases it may be possible for the member to participate in authorship of the Documentation as a co-author (following full discussion with and approval from the subcommittee and committee chairs)– they should not participate in drafting or

discussing the TLV® Recommendation or value, however

High Degree of High Degree of Conflict ExamplesConflict Examples

• A member working with a regulatory agency who plays a role in developing regulations for the substance

• A member affiliated with an academic institution and their research forms the central basis for the TLV®

• A member who works for a company that is a major producer and who plays a direct role in the development of internal exposure levels

Medium Degree of Medium Degree of ConflictConflict

• Based on “indirect” and modest personal, professional and/or financial involvement with the substance

• The matter should be carefully discussed with the subcommittee chair and members and appropriate steps taken to mitigate the conflict– Typically this will mean assigning a co-author or a

reviewer for the Documentation– In some cases, abstention from voting on the TLV®

is also appropriate.

Medium Degree of Medium Degree of Conflict ExamplesConflict Examples

• Member who works for a regulatory agency that regulates the chemical substance, does not have a direct role in developing regulations but may be concerned with enforcing regulations

• Member who works for an academic institution and their research may be concerned with the chemical substance but is not central to the determination of a TLV®

Medium Degree of Medium Degree of Conflict Examples Conflict Examples (cont).(cont).

• Member employed by a company that is a major producer of the chemical substance but who plays a minor role in the internal development of exposure levels

Low Degree of Low Degree of ConflictConflict

• The member is affiliated with an organization that has a financial or other interest in the substance but has a very minor or nonexistent role with respect to the substance – In most cases, simply informing the

subcommittee and committee members about low level conflicts is all that is needed

Continuing EvolutionContinuing Evolution

• The implementation of the COI Policy requires constant re-evaluation of conflicts, their impacts and management strategies

• We are learning as we go

• Developing implementation guidelines that are appropriate for each committee

TLVTLV®® Notations Notations and Designationsand Designations

Philip Bigelow, PhD, CIHAssociate Professor

Florida A&M University Institute of Public Health

TLV®-CS Committee

TLVs® – More than a number !

– Core principles focus on protection of workers– Use threshold concepts to protect against:

• Chronic effects• Acute effects• Freedom from irritation, stress, other effects

– Numerical values are important• TLV®-TWA

• TLV®-STEL

• TLV®-Ceiling

– Notations are also part of the TLV®

Why Notations and Why Notations and Designations?Designations?

– To aid in worker protection by:• Identifying agents for which the cutaneous

route is important • Identifying agents that have potential to

produce sensitization• Identifying agents that have been studied to

assess their carcinogenicity potential• Identifying agents that have a Biological

Exposure Index• Note: other notations may be added to reflect

contemporary occupational health practice

Guidance for Guidance for Interpreting NotationsInterpreting Notations

• INTRODUCTION TO THE CHEMICAL SUBSTANCES– Guidelines and philosophy for using TLVs®

– SKIN notation– SENsitizer notation– Biological Exposure Indices (BEI®) notation

• See also INTRODUCTION TO THE BIOLOGICAL EXPOSURE INDICES

• Appendix A: Carcinogenicity• NOTE: Absence of a notation may reflect absence

of scientific evidence not “no effect”

Guidance for Interpreting Guidance for Interpreting the SKIN Notationthe SKIN Notation

• Significant contributions to overall exposure by cutaneous route, mucous membranes or eyes by vapor or direct skin contact

• Evidence that dermal absorption may be important in expressed toxicity

• Biological monitoring should be considered• Notation not related to skin irritation, dermatitis

or skin sensitization

SKIN Notation ExampleSKIN Notation Example

• Methyl n-butyl ketone TLV®-TWA 5 ppm; TLV®-STEL 10 ppm; SKIN (neuropathy)– No dermal LD50 reported

– Human study showed absorption rate up to 8.0 microgram/min/cm2

– Significant contribution to dose and TLV® based on systemic toxicity

Guidance forGuidance for Interpreting the SEN Notation Interpreting the SEN Notation

• Refers to the potential for the agent to produce significant sensitization, as confirmed by human or animal data

• May or may not be critical effect• TLV® values not intended to protect those

workers already sensitized (goal is to prevent sensitization)

• May reflect risk of dermal and/or inhalation sensitization (must consult Documentation)

SEN Notation ExampleSEN Notation Example

• Formaldehyde TLV®-Ceiling 0.3 ppm; SEN; A2 (irritation, cancer)– Extensive human experience

• Sensory irritation at low levels• Debilitating dermatitis, rhinitis,

conjunctivitis, and asthma at low levels• Case and epidemiology studies provide

evidence of skin and respiratory sensitization

Other Evidence Used Other Evidence Used to Assess to Assess

Sensitization RiskSensitization Risk• Human

– Human Repeat Insult Patch Test– In vitro immunological tests

• Animal– Guinea pig maximization test– Murine local lymph node assay– Mouse ear swelling test– No current suitable test for respiratory allergens

Guidance for Interpreting Guidance for Interpreting the BEIthe BEI®® Notation Notation

• Refers to existence of a Biological Exposure Index (BEI®) for the agent

• Biomonitoring serves as a complement to exposure assessment by air sampling

• Most BEIs® based on direct correlation to TLV® (conc. of determinant at TLV® exposure)

• BEIs® used as guidelines in evaluation of potential hazards

BEIBEI®® Notation Example Notation Example

• Methanol TLV® 200/250 ppm; SKIN; BEI® (neuropathy; vision; CNS)– BEI®

• Methanol in urine – 15 mg/L • End of workshift • Notations

–B – background–Ns – nonspecific

Guidance for Interpreting Guidance for Interpreting the Carcinogenicity Notationthe Carcinogenicity Notation

• Appendix A: Carcinogenicity• Goal to synthesize information to be useful to

practicing industrial hygienist• 5 category system that evolves to reflect advances in

science• Exposures to carcinogens should be kept to a

minimum – For A1 agents with a TLV® and for A2 and A3 agents exposure by all routes should be controlled

• For agents with no designation – no human or animal data available to assign

A1 Confirmed A1 Confirmed Human CarcinogenHuman Carcinogen

• The agent is carcinogenic to humans based on the weight of evidence from epidemiologic studies– Committee requires convincing epidemiologic

evidence to support– Vinyl chloride – VCM induced angiosarcoma– Benzene – leukemia– Asbestos – lung cancer

A2 Suspected A2 Suspected Human CarcinogenHuman Carcinogen

• Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as A1, OR

• the agent is carcinogenic in experimental animals at dose(s), by route(s) of exposure, at site(s), of histologic types, or by mechanism(s) considered relevant to worker exposure.

A2 Suspected Human A2 Suspected Human Carcinogen ExamplesCarcinogen Examples

• Ethylene oxide– Positive in chronic inhalation bioassays in 2

species; human epidemiology studies weak – Mutagenic in short term tests– Known alkylating properties

• Silica– Presence of fibrosis in workers required for

increase cancer risk in humans– Carcinogenocity observed in rat but findings

weak

A3 Confirmed Animal A3 Confirmed Animal CarcinogenCarcinogen with Unknown with Unknown Relevance to HumansRelevance to Humans

• The agent is carcinogenic in experimental animals at relatively high dose, by route(s) of administration, at site(s), of histological type(s) , or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.

A3 Confirmed Animal A3 Confirmed Animal CarcinogenCarcinogen with Unknown with Unknown Relevance to Humans ExamplesRelevance to Humans Examples

• N-Propanol (on NIC)– Tumors after intubation dosing and subcutaneous

injection– No human cancer studies

• Chloroform– Liver tumors with intubation doses >300 mg/kg– Male rat kidney cancer – alpha-2-urinary globulin

mechanism– Other animal bioassays equivocal findings– No human cancer studies

A4 Not Classifiable as A4 Not Classifiable as a Human Carcinogena Human Carcinogen

• Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

A4 A4 Not Classifiable as aNot Classifiable as aHuman Carcinogen ExampleHuman Carcinogen Example

• Butylated hydroxytoluene (BHT)– Antioxidant – no human cancer data– IARC – no evidence in mice; limited evidence

in rats– BHT fed animals lived significantly longer than

controls– No effect in dogs at 0.9 g/kg/day– Genotoxicity studies negative

A5 A5 Not Suspected as a Not Suspected as a Human CarcinogenHuman Carcinogen

• The agent is not suspected to be a human carcinogen on the basis of properly conducted epidemiologic studies in humans. These studies have sufficiently long follow-up, reliable exposure histories, sufficiently high dose, and adequate statistical power to conclude that exposure to the agent does not convey a significant cancer risk to humans, OR,

• the evidence suggesting a lack of carcinogenicity in experimental animals is supported by mechanistic data.

A5 A5 Not Suspected as a Not Suspected as a Human Carcinogen ExampleHuman Carcinogen Example

• Nickel (elemental/metallic)– Extensive human epidemiologic findings are negative– Genotoxicity studies negative– Chronic bioassays negative

• Trichloroethylene– Extensive animal bioassays negative but initial studies

did evoke concern; genotoxicity tests mixed– Human epidemiology studies negative

The The DocumentationDocumentation• TLV® — more than just “THE NUMBER”

• Documentation describes:– Critical health effects– Quality of the data relied upon and areas of

uncertainty– Possible sensitive subgroups– Type of TLV® (TWA, STEL, C) and reason for

selection– Notations

Other SourcesOther Sources• Kennedy GL, Brock JW Jr., Banerjee AK (1993)

Assignment of skin notation for threshold limit values of chemicals based on acute dermal toxicity. Appl Occup Environ Hyg 8:26-30.

• ECETOC Special Report No. 15. Examination of a proposed skin notation strategy. European Centre for Ecotoxicology and Toxicology of Chemicals, 1998.

• Spiritas R, Fleming LE, Demers PA, Weisburger EK (in press) TLV Carcinogenicity categories: Recent modifications. Appl Occup Environ Hyg

Other SourcesOther Sources

• Dean JH, Twerdok LE, Tice RR, Sailstad DM, Hattan DG, Stokes WS. ICCVAM Evaluation of the Murine Local Lymph Node Assay. II. Conclusions and Recommendations of an Independent Scientific Peer Review Panel. Regul Toxicol Pharmacol 34, 258-273 (2001).

• van Kampen V, Merget R, Baur X. Occupational Airway Sensitizers: An Overview on the Respective Literature. Amer J Ind Med 38, 164-218 (2000).

Current Issues of Interest Current Issues of Interest to theto the

TLVTLV®®-Chemical Substances -Chemical Substances CommitteeCommittee

Daniel J. Caldwell, Ph.D., CIH, DABT

ExxonMobil Biomedical Sciences, Inc.

Presentation Presentation OutlineOutline

•Mixtures

•Sensory Irritation

•Particulates Not Otherwise Specified

•Toxicology Issues

Mixtures

Appendix C, TLVs® for Mixtures

• Special case: atmospheric composition is similar to original material

• Application to hydrocarbon solvents using “Reciprocal Calculation Procedure”

Global interest: MAK, ACGIH®, IRSST

Mixtures: The Reciprocal Mixtures: The Reciprocal Calculation ProcedureCalculation Procedure

• Hydrocarbon Solvents are Well Defined

• Reciprocal Calculation Procedure

• Known Health Effects

• Group Guidance Values

• Mineral Spirits as an Example

• Conclusions

Mixtures - RCPMixtures - RCPObjective:

To develop a generic and harmonized method for setting exposure limits for hydrocarbon solvents.

Generic: • Include all hydrocarbon solvents

• Maximum advantage of existing data

• Minimize effects of minor differences

Harmonized: • Similar solvents have similar TLVs®

• Consistent health advice worldwide

Mixtures - RCPMixtures - RCP

KEY MESSAGE - Hydrocarbon solvents are a family of materialswhich contain constituents with similar chemical properties.

Properties of Hydrocarbon Solvents:• molecules composed only of hydrogen and carbon• n- / iso-paraffins, cycloparaffins and/or aromatics• may contain a single molecular type or be complex• boil between 35-320°C, although range is normally less• highly refined with specific technical properties• do not contain appreciable levels of benzene or

carcinogenic PAHs• olefins are not covered by method

Mixtures - RCPMixtures - RCP

Procedure To Set TLV® For Hydrocarbon Solvents:• applicable to all hydrocarbon solvents• consider the contributions of all constituents• ensure that no component exceeds its own TLV®

• produce changes in the TLV® which are proportional to changes in composition

• sound and transparent underlying scientific assumptions • readily adaptable to changes in the TLV® of any component

Mixtures - RCPMixtures - RCP

Determine Sum Of Fractional TLVs® :

1 =

Fractiona +Fractionb +

Fractionn

TLVmixture TlVa TLVb TLVn

Inputs Include: • TLVs® for single constituents e.g. cyclohexane, toluene• Guidance values for groups of hydrocarbons based on

structural and toxicological similarity

KEY MESSAGE - RCP is based on ACGIH® mixtures formula

1 Assumes similarity of vapor and liquid compositions.

Mixtures - RCPMixtures - RCP

Underlying Assumptions:• Similar chemistry similar toxicity• Health effects of components are additive• Vapor composition is similar to liquid composition• Exposure limits should be based on toxicological

properties

KEY MESSAGE - An RCP procedure can be used for complex substances if they contain constituents with similar physical and chemical properties

RCP – Group Guidance Values

or

What do you do when you don’t have a TLV®?

• Assigning Guidance Values for Hydrocarbon Groups– Divide hydrocarbon components into groups with

common health effects– Assign common guidance values to the groups– Calculate TLVs® for complex substances from individual

TLVs® and Group Guidance Values using the RCP

Group Guidance Values

KEY MESSAGE - If group values are developed, TLVs® can be calculated for hydrocarbon solvent mixtures using a RCP.

EuropeanGroup Guidance Values

C5-C8 Aliphatics/cycloaliphatics 1500 mg/m3

C9-C15 Aliphatics/cycloaliphatics 1200 mg/m3

C7-C8 Aromatics 200 mg/m3

C9-C15 Aromatics 100 mg/m3

Others: n-hexane 175 mg/m3

Naphthalene 50 mg/m3

Cyclohexane 350 mg/m3

RCP Example - Mineral Spirits

Generic Term Applied To Hydrocarbon Fractions:

• That boil between 140-215°C• Contain n- and iso-alkanes, cycloalkanes, and aromatics

in varying concentrations.• Contain < 1 - 30% aromatics.• Can be described by several CAS numbers.• Are often marketed in Europe under brand names, not

as “mineral spirit”.

KEY MESSAGE - Mineral spirits is a generic term for a range of hydrocarbon solvents..

Boiling range 150-200°C

Flash Point ~38°CCarbon number range 8-12Average molecular weight 141%w/w n-/iso-cyclo-Alkanes (C5-C8) 7.4% w/w n-iso-cyclo-Alkanes (C9-C15) 76.5% w/w Aromatics 16.1 comprising C7/C8 aromatics 2.0

C9 aromatics 8.3Non-listed aromatics 5.8

RCP - Analysis Of A RCP - Analysis Of A TypicalTypical Mineral SpiritMineral Spirit

RCP Example -RCP Example - Mineral Spirits Mineral Spirits

Using the proposed guidance values for mineral spirits and substituting these values in the RCP formula:

__1__ = __Fra_+ ___Frb__ + ..... _Frn__

TLV sol TLVa TLVb TLVn

= 0.074 + 0.765 + 0.020 + 0.141 1500 1200 200 100= 0.000049 + 0.00064 + 0.0001 + 0.00141

= 0.00219

RCP Example – RCP Example – Mineral SpiritsMineral Spirits

• 1/TLV = 0.00219 • TLV = 456 mg/m3

• Using the rounding procedure this becomes

500 mg/m3 • Comparable to TLV® for Stoddard Solvent of

600 mg/m3

RCP - ConclusionsRCP - Conclusions

The RCP approach is:

• Application of special case of the mixtures formula

• Accepted by ACGIH®, and some EU member states

Group Guidance Values can be used to calculate TLVs® because:

• Solvents do not contain highly toxic constituents• A substantial toxicology database exists• Acute CNS effects are the endpoint of greatest

concern • Preventing acute CNS effects will prevent

chronic effects

RCP – Conclusions RCP – Conclusions (cont.) (cont.)

Sensory IrritationSensory Irritation

• What is Sensory Irritation?

• What data are used in developing TLVs®?

• Differentiating irritation from odor

• Conclusions

Sensory IrritationSensory Irritation

Background Information:• Undesirable temporary effect on the eyes and

upper respiratory tract• Acute, concentration dependent effect• Critical effect upon which to base a TLV®

• Nearly 50% of TLVs® set to prevent irritation• Confounding of irritation response by odor

Sources of Data

• Animal models (RD50)

• Physical/Chemical properties • Worker experience

Social Expectations• Irritation is an adverse effect• “Nearly all” workers should be protected

Sensory IrritationSensory Irritation

Mechanism of Sensory Irritation - Human Chemosensory System

• olfactory (first cranial nerve) - smell• trigeminal (fifth cranial nerve) - irritation

Perception of Irritation Impacted By• psychological context• exposure duration• inter- and intra- individual variability

Sensory IrritationSensory Irritation

Nasal Chemesthesis

• 2-alternative forced choice design

• Simultaneous sniff from 2 vessels, one containing test substance, the other a blank

• 14 trials per session

Ocular Chemesthesis

• 3-alternative forced choice design

• Air flow of 4 L/min to displace headspace vapor into eye cup

• 5 sec exposure with 10 trials per session

Current Research Areas• Sensory scaling• Stimulus lateralization• Variation in sensitivity• Adaptation• Attitude and expectations• Differentiation of odor from irritation

Sensory IrritationSensory Irritation

Sensory IrritationSensory Irritation

S T R E S S R E L A T E DH E A L T H E F FE C T S

A N N O Y A N C E

A V O ID A N C EB E H A V IO R

H A B IT U A T IO N

A P P R A IS A L A D A P T A T IO N

P E R C E P T IO N

E X P O S U R E

O D O R S O U R C E

Sensory IrritationSensory Irritation

Invited presentations:

• Pam Dalton, Monell Institute

• Bill Cain, Univ. California

Useful Guidelines• Threshold for sensory irritation: ~ 32% of Cs

• Acceptable human exposure: ~ 0.03 x RD50• Odor threshold < Lateralization threshold <

Irritation threshold

Sensory IrritationSensory Irritation

Conclusions:• Remains an active research area• Effect with multiple causes• Committee seeking reliable data on irritant

effects

Sensory IrritationSensory Irritation

Particulates Not Otherwise Specified

Appendix E: Particulates (insoluble or poorly soluble) Not Otherwise Specified

• Do not have an applicable TLV® Insoluble or poorly soluble in water (preferably in aqueous lung fluid)

• Have low toxicity (i.e., not cytotoxic, genotoxic, or otherwise chemically reactive with lung tissue)

Particulates Not Otherwise Specified

Airborne concentrations should be kept:

• < 3 mg/m3, respirable particles

• < 10 mg/m3, inhalable particles

until such time as a TLV® is set.

Toxicology Issues

Reproductive Toxicity

• Separate “repro” notation?

• Seminar presented by MAK Commission

Neurotoxicity

• Differentiation of neurotoxicity from neurobehavioral effects

• Seminar presented

Neurobehavioral Effects of Neurobehavioral Effects of Hydrocarbon Solvents:Hydrocarbon Solvents:

Research Strategy Research StrategyHUMAN BEHAVIORAL

AND

PK STUDIES

RAT BEHAVIORAL

AND

PK STUDIES

HUMAN BEHAVIORAL

AND

PK STUDIES

RAT BEHAVIORAL

AND

PK STUDIES

RAT BEHAVIORAL

AND

PK STUDIES

Validation Complete

ETOH

“STODDARD SOLVENT”/CYCLOHEXANE

RAT

SUBCHRONIC

STUDIES

OTHER REPRESENTATIVE HYDROCARBON SUBSTANCES

Questions?Questions?

• Scott Merkle

• Lisa Brosseau

• Patrick Breysse

• Philip Bigelow

• Dan Caldwell