TLV Chemical Substances Committee

1
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

2
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

3
ACGIH Structure

• Scott Merkle, CIH
• National Institute of Environmental Health
  Sciences
• Past-Chair, ACGIH

4
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.

5
TLVs and BEIs

• Threshold Limit Values for Chemical Substances
• Threshold Limit Values for Physical Agents
• Biological Exposure Indices for Chemical
  Substances

6
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

7
MembershipMarch 31, 2002
Private Industry Others
Government Academia
8
Membership by Profession, 2001
9
Revenue Sources
Membership Dues
Other
Education
Technical Publications
2001 ACGIH Statement of Activities
10
Revenue From Technical Publications (2.2M)
Other House Pubs.
TLV/BEI Book CD-Rom
Co-Op Sales
Bioaerosols
TLV/BEI Documentation
Ind. Vent. Manual CD-Rom
OEV Guide
2001 ACGIH Statement of Activities
11
Technical Committees
Committees provide the creativity, initiative,
and technical expertise that has made ACGIH what
it is today and what it will be tomorrow. .
12
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

13
Committees
May 2002 Merkle
14
Core Mission
May 2002 Merkle
15
Topics of Debate Over 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
16
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
17
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.

18
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 Cs of the TLV development process.
• Communication,
• Confidentiality,
• Conflict of Interest.

19
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 Regulat
ory decisions and rulemaking
Toxicity assessment
Risk characterization
Exposure assessment
20
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

21
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.

22
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.

23
Chemical Substances TLV Committee

• Lisa Brosseau, ScD, CIH
• Associate Professor
• University of Minnesota
• Chair, TLV-CS Committee

24
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

25
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)

26
History

• 1955 Written Documentation
• TLV Committee begins to write Documentation for
  each TLV (207 completed by 1958)
• Published 1st edition in 1962 (257 substances)

27
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

28
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

29
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 (DI)
• Hydrogen, Oxygen Carbon Compounds (HOC)
• Miscellaneous Compounds (MISCO)
• Staff Support (Liaison, Clerical, Literature
  Searching)

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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

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Other Subcommittees

• Chemical Selection
• Recommendations to HOC, DI, MISCO
• Membership
• Recruitment, screening, recommendations
• Notations
• Definitions, new proposals
• Communications
• Explaining our decisions

32
Committee Structure
Board of Directors
Staff
Chair of TLV Committee
Administrative Subcommittees (Membership,
Chemical Selection)
Steering Committee
Miscellaneous Compounds Subcommittee (MISCO)
Hydrogen, Oxygen, Carbon Subcommittee (HOC)
Dust Inorganics Subcommittee (DI)
33
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
34
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

35
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
36
The Essential Ingredients for Developing TLVs
Published / Peer Reviewed Science Dedicated
Volunteerism Professional Integrity Judgment
37
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

38
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

39
Policies and Processes for Limiting Conflict of
Interest

• Patrick N. Breysse, PhD, CIH
• Johns Hopkins University
• Bloomberg School of Public Health
• Vice-Chair, ACGIH

40
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

41
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

42
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

43
Membership

• Regular member
• professional whose primary employment is with a
  government agency or an educational institution
• Associate member
• Student member
• Retired member
• Organizational member

44
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.

45
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

46
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.

47
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

48
Conflict of Interest (NAS definition)

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

49
Conflict of Interest

• Basis for Conflicts of Interest
• Employment
• Financial benefit
• Personal
• Professional
• Avoid perceived as well as real conflict of
  interest

50
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

51
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

52
COI Process at ACGIH
53
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

54
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?

55
Conflict of Interest

• It is each Members 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

56
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

57
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

58
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

59
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.

60
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

61
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

62
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

63
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

64
TLV Notations and Designations

• Philip Bigelow, PhD, CIH
• Associate Professor
• Florida AM University
• Institute of Public Health
• TLV-CS Committee

65
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

66
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

67
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

68
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

69
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

70
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)

71
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

72
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

73
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

74
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

75
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

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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

77
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.

78
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

79
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.

80
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 gt300 mg/kg
• Male rat kidney cancer alpha-2-urinary globulin
  mechanism
• Other animal bioassays equivocal findings
• No human cancer studies

81
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.

82
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

83
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.

84
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

85
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

86
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 826-30.
• 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

87
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).

88
Current Issues of Interest to theTLV-Chemical
Substances Committee
Daniel J. Caldwell, Ph.D., CIH, DABT ExxonMobil
Biomedical Sciences, Inc.
89
Presentation Outline

• Mixtures
• Sensory Irritation
• Particulates Not Otherwise Specified
• Toxicology Issues

90
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

91
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

92
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

93
Mixtures - RCP

• 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 35-320C, 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.
94
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

95
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.
96
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
97
RCP Group Guidance Values

• or
• What do you do when you dont have a TLV?

98
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.
99
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
100
RCP Example - Mineral Spirits

• Generic Term Applied To Hydrocarbon Fractions
• That boil between 140-215C
• Contain n- and iso-alkanes, cycloalkanes, and
  aromatics in varying concentrations.
• Contain lt 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..
101
RCP - Analysis Of A Typical Mineral Spirit

• Boiling range 150-200C
• Flash Point 38C
• 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

102
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
103
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

104
RCP - Conclusions

• The RCP approach is
• Application of special case of the mixtures
  formula
• Accepted by ACGIH, and some EU member states

105
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

106
Sensory Irritation

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

107
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

108
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

109
Sensory 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

110
Nasal Chemesthesis

• 2-alternative forced choice design
• Simultaneous sniff from 2 vessels, one containing
  test substance, the other a blank
• 14 trials per session

111
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

112
Sensory Irritation

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

113
Sensory Irritation
114
Sensory Irritation

• Invited presentations
• Pam Dalton, Monell Institute
• Bill Cain, Univ. California

115
Sensory Irritation

• Useful Guidelines
• Threshold for sensory irritation 32 of Cs
• Acceptable human exposure 0.03 x RD50
• Odor threshold lt Lateralization threshold lt
  Irritation threshold

116
Sensory Irritation

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

117
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)

118
Particulates Not Otherwise Specified

• Airborne concentrations should be kept
• lt 3 mg/m3, respirable particles
• lt 10 mg/m3, inhalable particles
• until such time as a TLV is set.

119
Toxicology Issues

• Reproductive Toxicity
• Separate repro notation?
• Seminar presented by MAK Commission
• Neurotoxicity
• Differentiation of neurotoxicity from
  neurobehavioral effects
• Seminar presented

120
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
121
Questions?

• Scott Merkle
• Lisa Brosseau
• Patrick Breysse
• Philip Bigelow
• Dan Caldwell