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TLV ® Chemical Substances Committee. The Process for Decision Making Presented at the AIHce June 3, 2002, San Diego, CA Bill Wells PhD, CIH, CSP, Moderator Dennis Casserly, PhD, CIH & Marilyn Hallock, CIH Monitors. Forum Overview. Scott Merkle: ACGIH ® Structure

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tlv chemical substances committee
TLV® Chemical Substances Committee

The Process for

Decision Making

Presented at the AIHce

June 3, 2002, San Diego, CA

Bill Wells PhD, CIH, CSP, Moderator

Dennis Casserly, PhD, CIH & Marilyn Hallock, CIH Monitors

forum overview
Forum 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
acgih structure

ACGIH® Structure

Scott Merkle, CIH

National Institute of Environmental Health Sciences

Past-Chair, ACGIH®

forum on acgih exposure assessment guidelines
Forum on ACGIH® Exposure Assessment Guidelines
  • 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.
tlvs and beis
TLVs®and BEIs®
  • Threshold Limit Values for Chemical Substances
  • Threshold Limit Values for Physical Agents
  • Biological Exposure Indices for Chemical Substances
what is acgih
What 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
membership march 31 2002
MembershipMarch 31, 2002

Private Industry

& Others

Government

& Academia

slide9

Revenue Sources

Membership Dues

Other

Education

Technical Publications

2001 ACGIH®

Statement of Activities

slide10

Revenue From Technical Publications($2.2M)

Other House Pubs.

TLV®/BEI® Book & CD-Rom

Co-Op Sales

Bioaerosols

Ind. Vent. Manual & CD-Rom

TLV®/BEI®Documentation

OEV Guide

2001 ACGIH®

Statement of Activities

technical committees
Technical Committees

Committees provide the creativity, initiative, and technical expertise that has made ACGIH® what it is today and what it will be tomorrow.

.

acgih committees
ACGIH® 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
committees
Committees

May 2002

Merkle

core mission
Core Mission

May 2002

Merkle

topics of debate over the years
Topics of Debate Over the Years

1940s -

Present

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.

1960s -

Present

1980s - Present

topics of debate over the years16
Topics of Debate Over the Years

1990s –

Present

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).

1990s -

Present

1980s - Present

legal challenges of 2001
Legal Challengesof 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.
lessons
Lessons
  • 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 tlv in the overall context of risk management
Role of the TLV® in the Overall Context of Risk Management

Risk Management

Risk Assessment

Research

Development of regulatory options

Evaluation of social, economic & political

consequences

Regulatory decisions

and rulemaking

Toxicity assessment

Risk characterization

Exposure assessment

risk characterization
Risk Characterization

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

acgih statement of position
ACGIH® Statement of 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®.
acgih statement of position22
ACGIH®Statement of 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 tlv committee

Chemical Substances TLV® Committee

Lisa Brosseau, ScD, CIH

Associate Professor

University of Minnesota

Chair, TLV®-CS Committee

acgih committees24
ACGIH®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
a short historical perspective
A Short Historical Perspective
  • 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)
history
History
  • 1955 Written Documentation
    • TLV® Committee begins to write Documentation for each TLV® (207 completed by 1958)
    • Published 1st edition in 1962 (257 substances)
history27
History
  • 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
history28
History
  • 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 structure
Committee Structure
  • 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 subcommittees
Chemical Substance Subcommittees
  • Approximately 10 members on each
  • Membership from academia, government, unions, industry
  • Membership represents four key disciplines:
    • Industrial Hygiene
    • Toxicology
    • Occupational Medicine
    • Occupational Epidemiology
other subcommittees
Other Subcommittees
  • Chemical Selection
    • Recommendations to HOC, D&I, MISCO
  • Membership
    • Recruitment, screening, recommendations
  • Notations
    • Definitions, new proposals
  • Communications
    • Explaining our decisions
committee structure32
Committee Structure

Board of Directors

Staff

Chair of TLV® Committee

Administrative Subcommittees

(Membership, Chemical Selection)

Steering Committee

Dust & Inorganics Subcommittee(D&I)

Hydrogen, Oxygen, Carbon Subcommittee (HOC)

Miscellaneous Compounds Subcommittee

(MISCO)

tlv development process
TLV® Development Process

Draft

Doc.

Under Study

List

Committee Review

& Revision

External

Input

Committee Review

& Revision

Committee

& Board

Approval

NIC

Committee

& Board

Approval

Adopted

Value

tlvs defined
TLVs® 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 tlv principles
Core TLV® 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

slide36

The Essential Ingredients for Developing TLVs®

Published / Peer Reviewed Science

+

Dedicated Volunteerism

+

Professional Integrity

& Judgment

warnings
Warnings
  • 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
summary
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

Summary
policies and processes for limiting conflict of interest

Policies and Processes forLimiting Conflict of Interest

Patrick N. Breysse, PhD, CIH

Johns Hopkins University

Bloomberg School of Public Health

Vice-Chair, ACGIH®

background
Background
  • 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 cont
Background (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 cont42
Background (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
membership
Membership
  • Regular member
    • professional whose primary employment is with a government agency or an educational institution
  • Associate member
  • Student member
  • Retired member
  • Organizational member
associate member
Associate 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 policy and procedures development
Conflict of Interest Policy and Procedures Development
  • 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 nas definition
BIAS (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.”

slide47
BIAS
  • 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 nas definition
Conflict of Interest (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 interest
Conflict of Interest
  • Basis for Conflicts of Interest:
    • Employment
    • Financial benefit
    • Personal
    • Professional
  • Avoid perceived as well as real conflict of interest
conflict of interest50
Conflict 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 interest51
Conflict 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
conflict of interest53
Conflict 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 interest54
Conflict 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 interest55
Conflict 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 conflict
High Degree of Conflict
  • 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 conflict cont
High Degree of Conflict (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 conflict examples
High Degree of Conflict 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 conflict
Medium Degree of Conflict
  • 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 conflict examples
Medium Degree of Conflict 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 conflict examples cont
Medium Degree of Conflict Examples (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 conflict
Low Degree of Conflict
  • 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 evolution
Continuing 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
tlv notations and designations

TLV® Notations and Designations

Philip Bigelow, PhD, CIH

Associate Professor

Florida A&M University

Institute of Public Health

TLV®-CS Committee

tlvs more than a number
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 designations
Why Notations and 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 interpreting notations
Guidance for Interpreting 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 the skin notation
Guidance for Interpreting the 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 example
SKIN 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 for interpreting the sen notation
Guidance for 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 example
SEN 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 to assess sensitization risk
Other Evidence Used to Assess Sensitization 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 the bei notation
Guidance for Interpreting the BEI® 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
bei notation example
BEI® 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 the carcinogenicity notation
Guidance for Interpreting the 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 human carcinogen
A1 Confirmed Human 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 human carcinogen
A2 Suspected Human 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 carcinogen examples
A2 Suspected Human Carcinogen 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 carcinogen with unknown relevance to humans
A3 Confirmed Animal Carcinogen with Unknown Relevance 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 carcinogen with unknown relevance to humans examples
A3 Confirmed Animal Carcinogen with Unknown Relevance 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 a human carcinogen
A4 Not Classifiable as a 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 not classifiable as a human carcinogen example
A4 Not Classifiable as aHuman 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 not suspected as a human carcinogen
A5 Not Suspected as a Human 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 not suspected as a human carcinogen example
A5 Not Suspected as a Human 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 documentation
The Documentation
  • 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 sources
Other 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 sources87
Other 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).
slide88

Current Issues of Interest to theTLV®-Chemical Substances Committee

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

ExxonMobil Biomedical Sciences, Inc.

presentation outline
Presentation Outline
  • Mixtures
  • Sensory Irritation
  • Particulates Not Otherwise Specified
  • Toxicology Issues
mixtures
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

slide91

Mixtures: The Reciprocal Calculation Procedure

  • Hydrocarbon Solvents are Well Defined
  • Reciprocal Calculation Procedure
  • Known Health Effects
  • Group Guidance Values
  • Mineral Spirits as an Example
  • Conclusions
mixtures rcp
Mixtures - RCP

Objective:

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 rcp93
Mixtures - RCP

Properties of Hydrocarbon Solvents:

  • molecules composed only of hydrogen and carbon
  • n- / iso-paraffins, cycloparaffins and/or aromatics
  • may contain a single moleculartype 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

KEY MESSAGE - Hydrocarbon solvents are a family of materials

which contain constituents with similar chemical properties.

mixtures rcp94
Mixtures - 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 rcp95
Mixtures - 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 rcp96
Mixtures - 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
RCP – Group Guidance Values

or

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

group guidance values
Group Guidance Values
  • 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

KEY MESSAGE - If group values are developed, TLVs® can be

calculated for hydrocarbon solvent mixtures using a RCP.

european group guidance values
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
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..

rcp analysis of a typical mineral spirit
RCP - Analysis Of A TypicalMineral Spirit

Boiling range 150-200°C

Flash Point ~38°C

Carbon number range 8-12

Average 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 8.3

Non-listed aromatics 5.8

rcp example mineral spirits102
RCP Example - 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 mineral spirits103
RCP Example – Mineral 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 conclusions
RCP - Conclusions

The RCP approach is:

  • Application of special case of the mixtures formula
  • Accepted by ACGIH®, and some EU member states
rcp conclusions cont
RCP – Conclusions (cont.)

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
sensory irritation
Sensory Irritation
  • What is Sensory Irritation?
  • What data are used in developing TLVs®?
  • Differentiating irritation from odor
  • Conclusions
sensory irritation107
Sensory 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
slide108

Sensory Irritation

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 irritation109
Sensory Irritation

Mechanism of Sensory Irritation - HumanChemosensory 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
nasal chemesthesis
Nasal Chemesthesis
  • 2-alternative forced choice design
  • Simultaneous sniff from 2 vessels, onecontaining test substance, the other a blank
  • 14 trials per session
ocular chemesthesis
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
sensory irritation112
Sensory Irritation

Current Research Areas

  • Sensory scaling
  • Stimulus lateralization
  • Variation in sensitivity
  • Adaptation
  • Attitude and expectations
  • Differentiation of odor from irritation
sensory irritation114
Sensory Irritation

Invited presentations:

  • Pam Dalton, Monell Institute
  • Bill Cain, Univ. California
sensory irritation115
Sensory Irritation

Useful Guidelines

  • Threshold for sensory irritation: ~ 32% of Cs
  • Acceptable human exposure: ~ 0.03 x RD50
  • Odor threshold < Lateralization threshold < Irritation threshold
sensory irritation116
Sensory Irritation

Conclusions:

  • Remains an active research area
  • Effect with multiple causes
  • Committee seeking reliable data on irritant effects
particulates not otherwise specified
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 specified118
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
Toxicology Issues

Reproductive Toxicity

  • Separate “repro” notation?
  • Seminar presented by MAK Commission

Neurotoxicity

  • Differentiation of neurotoxicity from neurobehavioral effects
  • Seminar presented
neurobehavioral effects of hydrocarbon solvents research strategy
Neurobehavioral Effects of Hydrocarbon Solvents: Research Strategy

RAT BEHAVIORAL

AND

PK STUDIES

HUMAN BEHAVIORAL

AND

PK STUDIES

ETOH

HUMAN BEHAVIORAL

AND

PK STUDIES

RAT BEHAVIORAL

AND

PK STUDIES

RAT

SUBCHRONIC

STUDIES

“STODDARD SOLVENT”/CYCLOHEXANE

Validation Complete

RAT BEHAVIORAL

AND

PK STUDIES

OTHER REPRESENTATIVE HYDROCARBON SUBSTANCES

questions
Questions?
  • Scott Merkle
  • Lisa Brosseau
  • Patrick Breysse
  • Philip Bigelow
  • Dan Caldwell