1. TLV ® Chemical Substances Committee The Process for Decision Making 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. Membership March 31, 2002 Government & Academia Private Industry & Others

8. Membership by Profession, 2001 Industrial Hygienist42% Administrator/Manager11% OH&S Professional6% Environmental Professional4% Safety Professional3% Other (Engineer, Scientist, Toxicologist, Professor, etc.) ~33%

9. Revenue Sources Technical Publications Other Membership Dues Education 2001 ACGIH ® Statement of Activities

10. Revenue From Technical Publications ($2.2M) 2001 ACGIH ® Statement of Activities TLV ® /BEI ® Book & CD-Rom TLV ® /BEI ® Documentation Ind. Vent. Manual & CD-Rom OEV Guide Bioaerosols Co-Op Sales Other House Pubs.

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 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

17. Legal Challenges of 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 C’s” of the TLV ® development process. –Communication, –Confidentiality, –Conflict of Interest.

19. Role of the TLV ® in the Overall Context of Risk Management Research Risk Assessment Risk Management Development of regulatory options Evaluation of social, economic & political consequences Regulatory 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 (D&I) –Hydrogen, Oxygen & Carbon Compounds (HOC) –Miscellaneous Compounds (MISCO) Staff Support (Liaison, Clerical, Literature Searching)

30. 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

31. Other Subcommittees Chemical Selection –Recommendations to HOC, D&I, MISCO Membership –Recruitment, screening, recommendations Notations –Definitions, new proposals Communications –Explaining our decisions

32. Committee Structure 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

33. TLV ® Development Process Under Study List Draft Doc. Committee & Board Approval NIC Committee Review & Revision External Input Adopted Value Committee Review & Revision Committee & Board Approval

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 individual’s 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 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

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 A&M 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 LD 50 reported –Human study showed absorption rate up to 8.0 microgram/min/cm 2 –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

76. 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 >300 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 a Human 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 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

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 the TLV ® -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 KEY MESSAGE - Hydrocarbon solvents are a family of materials which 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

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 = Fraction a + Fraction b + Fraction n TLV mixture TlV a TLV b TLV n 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 don’t have a TLV ® ?

98. 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.

99. European Group Guidance Values C5-C8Aliphatics/cycloaliphatics1500 mg/m 3 C9-C15Aliphatics/cycloaliphatics1200 mg/m 3 C7-C8Aromatics 200 mg/m 3 C9-C15Aromatics 100 mg/m 3 Others:n-hexane 175 mg/m 3 Naphthalene 50 mg/m 3 Cyclohexane 350 mg/m 3

100. 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..

101. Boiling range150-200°C Flash Point~38°C Carbon number range8-12 Average molecular weight141 %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 comprisingC7/C8 aromatics 2.0 C9 aromatics 8.3 Non-listed aromatics 5.8 RCP - Analysis Of A TypicalMineral Spirit RCP - Analysis Of A Typical Mineral Spirit

102. RCP Example - Mineral Spirits Using the proposed guidance values for mineral spirits and substituting these values in the RCP formula: __1__=__Fr a _+___Fr b __+..... _Fr n __ TLV sol TLV a TLV b TLV n =0.074 +0.765 + 0.020 + 0.141 15001200 200 100 = 0.000049 + 0.00064 + 0.0001 + 0.00141 = 0.00219

103. RCP Example – Mineral Spirits 1/TLV = 0.00219 TLV =456 mg/m 3 Using the rounding procedure this becomes 500 mg/m 3 Comparable to TLV ® for Stoddard Solvent of 600 mg/m 3

104. RCP - Conclusions The RCP approach is: Application of special case of the mixtures formula Accepted by ACGIH ®, and some EU member states

105. 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 (cont.)

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. Sources of Data Animal models (RD 50 ) Physical/Chemical properties Worker experience Social Expectations Irritation is an adverse effect “Nearly all” workers should be protected Sensory Irritation

109. 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 Irritation

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

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

115. Useful Guidelines Threshold for sensory irritation: ~ 32% of C s Acceptable human exposure:~ 0.03 x RD50 Odor threshold < Lateralization threshold < Irritation threshold Sensory Irritation

116. Conclusions: Remains an active research area Effect with multiple causes Committee seeking reliable data on irritant effects Sensory Irritation

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: < 3 mg/m 3, respirable particles < 10 mg/m 3, 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 HUMAN 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

121. Questions? Scott Merkle Lisa Brosseau Patrick Breysse Philip Bigelow Dan Caldwell