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TLV® Documentation Outline

GENERAL INSTRUCTIONS FOR PREPARING MAIN BODY OF THE TLV–TWA DOCUMENTATION

The primary purpose of the TLV® Documentation is to describe and analyze the scientific literature that specifically supports the derivation of a TLV and any associated notations. Although the Documentation is not intended to be a comprehensive review of the literature for a substance, it should describe the key literature studies that define the range of exposure information and animal and human health effects associated with a substance. To facilitate an organized description of this literature, the TLV Documentation template is divided into appropriate sections for description and analysis of the relevant studies. The review of the literature should not be just a recitation of the findings and conclusions of individual reports, but also must provide appropriate integrated analyses as to which study(ies) are most appropriate for consideration (i.e., weight-of-evidence analysis) in derivations of the TLV. When a study seems to suggest the TLV or any of its notations should be different from that selected, the reason for discounting this study should be provided.

Bibliographic references in the body of the draft Documentation should be presented as follows:
…text (Smith et. al., 1999; Smith and Jones, 1999; Smith, 1999)

If no studies are available for a major heading (e.g., Animal Studies, Human Studies, etc.), indicate this with the standard statement "No studies available"; if no data are available for a subheading (e.g., Oral, Dermal, Chronic, etc.), do not include the subheading in the outline. Any comprehensive literature reviews relevant to a major heading should be discussed first, before any subheadings. Information in reviews relevant to subheading topics should be summarized within the subheading section.

For each major heading and subheading, it is not necessary to describe all studies, but only those regarded as reliable and relevant to the TLV recommendation (for example: studies should include an adequate description of methodology, be reported in peer-reviewed literature, show evidence of reproducibility, etc.). Use of unpublished information requires that the entire study or communication be on file at ACGIH® headquarters and that full disclosure must be transferred to ACGIH® so the Committee may cite these data as necessary to be available for public release if requested. Unpublished data or reports should be used only if the methods follow standardized protocols.

The text of each section should first present those studies regarded as most relevant to the TLV derivation, followed by descriptions of studies deemed of lesser, but corroborative value. For studies that describe differential or contradictory findings, a brief rationale should be presented for discounting or devaluing their results (e.g., route of exposure, range of exposure or dose-response, study design, etc.).

Explanatory note: This template is constructed such that section headings of the actual Documentation are described in Times New Roman font and the associated instructions for completion of each section are described in Arial. These are the font families used by ACGIH® to construct the TLV Documentation. Where possible, make tables of data using the table-making feature of Microsoft Word or WordPerfect.

TLV DOCUMENTATION OUTLINE

CAS number: XX-XX-X. Provide CAS number(s) describing the substance

Synonyms: FUZZELENE; FUZZSTUFF; ETC. Provide listing of other chemical synonyms(s) attributed to substance

Molecular formula: C8H16O2 . Provide chemical equation (provided by staff)

Provide Chemical Structure on separate line from the Chemical Equation (required only if appropriate)

TLV–TWA, XX units. List current TLV–TWA expressed in appropriate units; if particulate, describe appropriate form

TLV-STEL, XX units. List current value in appropriate units; if no value assigned, do not list

TLV-C, XX units. List current value in appropriate units; if no value assigned, do not list

Skin; Sensitizer (SEN)

A3, Confirmed Animal Carcinogen. List notation as A1, A2, A3, A4, or A5 with corresponding descriptor, e.g., "Confirmed Animal Carcinogen"; if no notation assigned, do not list

Summary

The purpose of this section is to give an overview of the key issues raised in the Documentation. At a minimum, the summary should describe the critical health effects (animal and human) that serve as the basis for the TLV number, the relevant supporting exposure data and mechanism information and briefly summarize the rationale for the TLV and any associated notations. The summary should be limited to 250 words or less and may repeat all or portions of the TLV Recommendation section. The summary may contain more than just the TLV Recommendation and may touch on other critical effects that do not necessarily drive TLV.

Chemical and Physical Properties

This section should provide a brief text description of the chemical and physical forms of the substance (e.g., solid, liquid, color, composition, contaminants, decomposition products, etc.). The text should also describe known odor or taste properties (e.g., what is odor/taste? odor/taste threshold?). The text section is followed by a specific listing of properties, some examples of which are provided below. If some of the specific data are not available, do not list the subheading.

Molecular weight: XXX.XX
Specific gravity: X.XXX at XX°C
Melting point: (Centigrade)
Boiling point: (Centigrade)
Vapor pressure: Use torr and specify temperature (Centigrade)
Flash point: (Centigrade)
Flammable limits: lower and upper
Autoignition temperature: (Centigrade)
Solubility:
Conversion factors at 25°C and 760 torr: 1 ppm = XX.X mg/m3, 1 mg/m3 = X ppm
Major Sources of Occupational Exposure

This section should describe the following information, when available, in text format:

  1. How the substance is produced (e.g., methods of manufacture, by-product of…)
  2. Uses
  3. Production volume and estimated number of worker exposures (from Chemical Selection Subcommittee)
  4. Major routes of exposure associated with manufacture and use (what forms are encountered during use, e.g., vapor, dusts, aerosol, liquid, etc.). Particle size issues and characterizations, if relevant
  5. Occupational exposure survey study(s), including information such as: job descriptions; monitored exposure levels (TLV–TWA, range of exposures, etc.); type of sampling (personal, area, duration, grab sampling, etc.); single vs. multiple surveys (optional)
  6. Historical exposure evaluation (optional)
Animal Studies

If review articles are used, describe and summarize them here, prior to any subheading sections.

The major section and subsections should describe the relevant in vivo and in vitro studies supporting assessment and derivation of the TLV–TWA.

Detailed descriptions of individual studies are generally not required. However, if known, the minimum information that should be reported for each study described in the subsection below is as follows:

  1. Species; sex; route and mode of administration (inhalation, oral gavage, oral diet, dermal, etc.); duration of dosing; specific doses tested; relevant toxic effects; No-Observed-Effect Levels (NOELs), Lowest-Observed-Effect Levels (LOELs), and toxic responses at higher dose levels
  2. Mechanistic studies (e.g., animal model and pharmacokinetic relevance) that provide perspective for appropriate extrapolation of animal findings to humans
  3. Published expert reviews (IARC, WHO, U.S. EPA, U.S. NIOSH, etc.) that offer analysis of human relevance of animal studies
  4. Structure-Activity Relationships (cross-reference to other TLVs — can create common tables to illustrate relationships)
Acute/Subacute (all studies less than 2 weeks duration)

ORAL

  • As available, incorporate minimum information noted above
  • Describe LD50 value(s) or equivalent indicator(s) of toxicity
  • Describe minimum lethal doses (LDLo, LC50) and any reported clinical signs
  • If no lethality found, indicate full range of doses, clinical observations, and NOEL and effect-level doses.
DERMAL
  • Same as oral above. Include description of nature of applied substance (neat, concentration of solutions and vehicles, formulations, etc.)
  • Describe systemic toxicity resulting from skin absorption
  • Describe specific toxicity to skin (irritation, burns, etc.); include assessment (classification) of toxic response (non-irritant, type of irritant — corrosive)
INHALATION
  • Same as oral above (LC50 values).
  • If relevant, include particle size characterization or lack thereof.
SENSITIZATION

Include:

  • species
  • doses
  • routes of administration
  • protocol used
  • ancillary information (adjuvants used, etc.)
  • end results (dose-response; NOEL, ancillary skin irritation, etc.)
  • classification (skin and/or respiratory sensitizer)
OTHER STUDIES

As available, include minimum information noted above for each of the relevant "other studies" described; examples of potentially relevant "other studies" include:

  • Eye irritation
  • Respiratory irritation RD50 studies
  • etc.
Subchronic (> 2 weeks <= 3 months)
  • Same information as above, organized by route of exposure
Chronic/Carcinogenicity (> 3 months <= animal lifetime)
  • Same information as above, organized by route of exposure
  • Include any carcinogenicity classification determinations published by internationally recognized review bodies (IARC, U.S. NTP, U.S. EPA, MAK, etc.)
Genotoxicity
  • Organized by in vitro and in vivo
  • Describe test systems (bacterial, mammalian cell, etc), final study conclusions (positive/negative; with/without activation). Test systems should not be described in detail.
  • If possible, an integrated assessment of the combined genotoxicity findings should be described. These include such observations as:
    1. positive findings noted only in vitro studies with negative findings in in vivo studies;
    2. potency of response relative to study positive control agents;
    3. dose/concentration responses;
    4. etc.
Reproductive/Developmental Toxicity
  • Present reproductive studies first, followed by developmental toxicity studies
  • Same information as above, organized by route of exposure
Absorption, Distribution, Metabolism, and Excretion
  • Describe animal studies first, followed by human studies
  • If available, key information to be described may include: amount absorbed (percent of applied dose); metabolites formed; estimated half-lives and clearance routes (urine, exhaled air, feces); dose–response evaluations and overall relevance to developing a TLV.
Human Studies

If there are many human studies with similar designs in multiple populations, make tables of data where possible to summarize the key information listed below. In general, little detail is warranted concerning case reports, with the exception of sensitization. Studies among occupationally exposed populations should be given priority in those studies receiving detailed description.

For key studies, include the following information:

  • Type of study (e.g., cross sectional, case control, cohort, experimental, or other);
  • Description of study population (include location of study, number of participants, and pertinent demographic information);
  • Measurements of disease or death (e.g., death certificates, physical examination, laboratory analyses, questionnaires, etc);
  • Measurements of exposure (e.g., laboratory analyses, air measurements, etc);
  • Measurements of health effect using tools such as odds ratio, relative risk, standardized mortality/morbidity ratio [SMR], proportional mortality/morbidity ratio [PMR], etc. (e.g., cross shift change in physiologic measurement). Include confidence intervals or p values and whether data were adjusted for other causes of effect and disease;
  • Other potential causes of effect and disease (e.g., age, smoking, ethanol, socio-economic class, gender, location), and other exposures present.
Other considerations that may be used in evaluating human studies include Hill's criteria of causation (e.g., exposure prior to disease, dose response, biological plausibility, strength of effect, consistency of findings with other studies, etc). (We need a reference for these criteria.)

Recommended Order:

  • Case reports and case studies; disease clusters;
    • Occupational only
    • Accident reports
    • Summarize observed toxicity; include doses or exposure estimates
      • Hierarchy of reports to be described:
        • exposure information is available,
        • chemical information is specific (no other chemicals present),
        • adverse effect(s) potentially attributable to chemical exposure (e.g., irritation, sensitization, CNS responses, etc.)
  • Experimental (e.g., chamber studies, cross over)
    • Controlled experiments (all exposure routes)
    • Do not include PK (see above)
    • In vitro studies
  • Epidemiology
    • General
      • Occupational studies are of primary importance (include general population studies only if relevant to TLV derivation)
      • Describe:
        • type of study (case-control; cohort, etc.)
        • key endpoints reported
        • dose–response characterization
    • Types of Epidemiology Studies
      • Cross sectional and related (e.g. Panel studies, cytotoxicity studies in humans);
      • Case–Control;
      • Cohort (e.g., retrospective, prospective, SMR);
      • Other (e.g., PMR, ecological, meta-analysis and pooled).
TLV Recommendation

Focus only on that (those) study(ies) providing the rationale for deriving the TLV recommendation. For example:

  • human study(ies) in relevant settings with relevant exposures
  • animal study(ies) expressing most relevant route of exposure, doses, and appropriate responses
Include the relevant bibliographic references (e.g., Smith, 1999). The results of these studies should not be repeated in detail; provide only the key conclusion(s) as they support the rationale for the TLV recommendation.

Selecting an appropriate TLV:

  1. Decide critical health effects.
    1. Those that occur at the lowest exposure levels and will drive the TLV number
  2. Decide which kind of TLV (TWA, STEL, C).
    1. Review the definitions to elucidate the appropriate form of a TLV.
    2. Although the type of available data may affect this, in general:
      1. Chronic effects → TWA
      2. Acute effects → STEL
        1. In some cases, STEL may be selected when it is thought that short, high-level exposures lead to chronic effects.
      3. Severe, acute effects → Ceiling
    3. Some substances may fit into more than one category of TLV.
    4. In exceptional cases, other schemes may be chosen, if clearly described and supported in the Documentation.
  3. Decide the TLV number and appropriate units.
    1. It may be useful to pull together a table of key studies and findings as they relate to the TLV. From this information, select a point at which it appears no health effects are likely to occur in workers.
    2. Describe the relationship of the recommended number to known human or animal toxicity responses.
    3. Describe how the TLV reflects uncertainties in the available data. Using professional judgment, adjust the TLV to reflect an appropriate degree of conservatism.
      1. Uncertainty considerations include:
        1. When animal data are the primary source
        2. The quality of the studies
        3. Available exposure information
      2. Use language that avoids referring to these adjustments as "factors."
      3. The TLV number should have only one significant figure, unless your data are very precise.
    4. Use language such as the following:
      1. A TLV-Ceiling of ____is recommended to minimize the acute irritation associated with occupational exposure to ABC. Remember to provide the citation(s) from the discussion in the body of the Documentation.
    5. This section should have a clear explanation about each of the items described below. That is, a description of the key health effects, a discussion of why particle size fraction was selected for the TLV (for aerosols), and the reasoning for the selection of a number. Adjustments do not need to be quantified, but rather explained. Notations and other relevant information should also be described and explained.
  4. Consider whether the substance may occur or be generated in the form of an aerosol.
    1. If so, it may be necessary to develop a TLV for the aerosol form in addition to the vapor form.
      1. It may be necessary to determine separate TLVs for these two forms.
      2. If the TLV number is the same for both forms, then a designation of both vapor and aerosol must be made.
    2. If the TLV may refer to an aerosol, one of the three Particle Size Selective (PSS)-TLV designations must be selected. In general, the following relationship will determine which one:


        PSS   In which part of the respiratory system can deposition or absorption lead to health effects?

      i.
      ii.
      iii.
      Inhalable
      Thoracic
      Respirable
        Throughout respiratory system
      Lung airways and gas exchange
      Gas exchange areas

    3. Exposure data that include particle size distributions may be useful in helping identify the appropriate PSS fraction.
    4. Use language such as the following:
      1. A TLV–TWA of __ mg/m3, measured as inhalable particulate mass, is recommended for occupational exposure to ________. This recommendation will minimize the particle clearance alterations that have been demonstrated to occur in both animals and human subjects after exposure to _______.
      2. One of the characteristics of _____is _______, which are apparently caused by the deposition of particles containing _____ on the alveolar walls. Accordingly, it would be appropriate to state the TLV in terms of respirable particulate mass. Respirable particulate in a dust cloud is only a small fraction of the airborne material and the numerical value of the fraction depends on the process that generated the dust.
      3. When the TLV is measured as "aerosol and vapor, add the following sentence to the Recommendation section:
      Because the estimated saturated vapor concentration may significantly contribute to the exposure at the TLV–TWA and evaporative losses of collected particulate may occur during sampling, both the particulate and vapor phase concentrations should be considered and summed to determine total airborne concentration.
  5. Identify appropriate notations and explain reasoning for their selection
    1. Carcinogenicity designation (see Appendix A in the TLVs/BEIs Handbook). Use language such as the following:
      1. ACGIH® selected an A2, Suspected Human Carcinogen, notation because -ABC has been demonstrated to be carcinogenic to experimental animals by mechanisms considered relevant to worker exposures and because there is sufficient epidemiological evidence indicating that it is a suspected human carcinogen. (Cite specific data and provide the citation from the body of the Documentation.)
      2. Therefore, to protect against all effects including cancer, a TLV–TWA of _____ with an A3, Confirmed Animal Carcinogen with Unknown Relevance to Humans, notation is assigned to ABC (cite specific data and provide the citation from the body of the Documentation.)
      3. On the basis of this evidence, the TLV Committee is proposing a carcinogen classification of A4, Not Classifiable as a Human Carcinogen, for ABC. An A4 category is appropriate on the basis that no epidemiological cancer studies have been conducted in connection with exposure to ABC.
    2. SEN (see future Appendix in TLVs/BEIs Handbook). Use language such as the following:
      1. Available data on sensitization from exposure to ABC warrants the addition of the SEN (sensitization) notation. (Cite specific data and provide the citation from the body of the Documentation.)
    3. Skin (see future Appendix in TLVs/BEIs Handbook). Use language such as the following:
      1. Based on _______ studies a skin notation is warranted. (Cite specific data and provide the citation from the body of the Documentation.)
    4. The TLV Documentation has been updated and revised to reflect new scientific data, but the TLV recommendation has not been changed.
    5. Language for "delete", e.g., STEL

TLV Basis — Critical Effects

This section should briefly list the critical health effects that support derivation of the TLV. This description will be used to complete the "TLV Basis — Critical Effect(s)" column in the ACGIH® TLVs/BEIs Handbook. Example descriptors include: Cancer; Irritation; Lung; Neurotoxicity; CNS; Reproductive; etc.

List of Health Effects (NOTE: This is a dynamic list; may change periodically)

TLV Chronology

The purpose of this section is to describe only the historical and/or pending/actionable activities (dates) associated with the TLV Documentation. It is not intended to describe the detailed history of actions completed on the Documentation. See example below:

19XX proposed: TLV–TWA, XX ppm
19XX-present: TLV–TWA, XX ppm
20XX: Documentation revised. Describes current Documentation revision efforts; use only when Documentation is revised but TLV is not changed
20XX proposed: TLV–TWA, XX ppm; notation(s). If necessary, describe proposed published (NIC) TLVs and associated notations that have not been adopted by ACGIH®.
20XX proposed: TLV–TWA, XX ppm; notation(s). Describe proposed TLV recommendation and associated notations under active review and consideration by ACGIH®

References

List in alphabetical order.

Unlike the reference style of the past, use a modified MedLine style, e.g., all extraneous punctuation and capitalization are eliminated in journal citations (e.g., article titles are treated as a sentence).

Journal Articles
List all authors when there are four or less. If five or more, list the first three, followed by "et al.:"

Davies CN: Dust sampling and lung disease. Br J Ind Med 9:120–122 (1952).

Deskin R; Bursain SJ; Edens FW: The effect of chronic manganese administration on some neurochemical and physiological variables in neonatal rates. Gen Pharmacol 12:279–280 (1981).

Wagner WD; Fraser DA; Wright PG; et al.: Experimental evaluation of the threshold limit of cristobalite — calcined diatomaceous earth. Am Ind Hyg Assoc J 29:211–221 (1968).

Online Citations
U.S. National Library of Medicine: Substance name. In: Hazardous Substances Data Bank. Toxicology Data Network (TOXNET). Online at: http://toxnet.nlm.nih.gov/

U.S. Environmental Protection Agency: Integrated Risk Information System (IRIS) Substance File: Substance name. U.S. EPA, Washington, DC (1996). Online at: http://www.epa.gov/iris/subst/0373.htm

U.S. National Toxicology Program: Substance name. In: Testing Information and Study Results, Results and Status. Online at: http://ntp-server.niehs.nih.gov/main_pages/NTP_ALL_STDY_PG.html

Federal Agency Publications

U.S. National Toxicology Program: Toxicology and carcinogenesis studies of manganese (II) sulfate monohydrate (CAS No. 10034-96-5) in F344/N rats and B6C3F1 mice (feed studies) Technical Report No. 428. DHHS (NIH) Pub. No. 94-3159. NTP, Research Triangle Park, NC (1993).

U.S. Agency for Toxic Substances and Disease Registry, Toxicological profile for manganese (update). U.S. Department of Health and Human Services, ATSDR, Atlanta, GA (September 2000).

With Author(s)
Anderson HA; Dally KA; Hanrahan LP; et al.: The epidemiology of mobile home formaldehyde vapor concentration and residents' health status. Pub. No. EPA 905/1 83 001. U.S. Environmental Protection Agency, Washington, DC (1983).

Books
Sections/Chapters with Specific Author(s)

Beliles RP: The metals. In: Patty's Industrial Hygiene and Toxicology, 4th ed., Vol. 2C, Toxicology, pp. 2106–124. G.D. Clayton and F.E. Clayton, Eds. John Wiley & Sons, New York (1994).

Matanoski GM: Risk of cancer associated with occupational exposure in radiologists and other radiation workers. In: Cancer Achievements, Challenges, and Prospectives for the 1980s, Vol. 1, pp. 241–254. J.H. Burchenal, Ed. Grune and Stratton, New York (1981).

With Editor(s) Only

Hathaway GJ; Proctor NH; Hughes JP (Eds.): Substance name. In: Proctor and Hughes' Chemical Hazards of the Workplace, 4th ed. Van Nostrand Reinhold, New York (1996).

Lide DR; Frederikse HPR (Eds.): Substance name. In: Handbook of Chemistry and Physics, 77th ed. CRC Press, Boca Raton, FL (1996).

Proceedings

Andersen I: Formaldehyde in the indoor environment — health implications and the setting of standards; and discussion. In: Indoor Climate: Effects on Human Comfort, Performance and Health in Residential, Commercial, and Light Industry Buildings, pp. 65–87. PO Fanger and O Volbjorn, Eds. Proceedings of the First International Indoor Climate Symposium, Copenhagen, August 30–September 1, 1978. Danish Building Research Institute, Copenhagen (1979).

Failing A; Knecht U; Woitowitz HJ: Biological monitoring of a standardized tetrahydrofuran exposure (in German). In: Proceedings of the 34th Meeting of the German Society of Occupational and Environmental Medicine in Wiesbaden, pp. 375–376. R Kessel, Ed. Gentner Verlag, Stuttgart (1994).

Boyle MJ: Tropic of Capricorn — assessing hot process conditions in northern Australia. In: Proceedings of 14th Annual Conference, pp. 54–57. Australian Institute of Occupational Hygienists, Adelaide (1995).

Budd GM: Stress, strain and productivity in Australian wildfire suppression crews. In: Proceedings of the Society of American Foresters National Convention, San Francisco, pp. 119–123. SAF, Bethesda, MD (1991).

Industrial Health Foundation: Proceedings of a Symposium on an Industry Approach to Chemical Risk Assessment: Caprolactam and Related Compounds as a Case Study. IHF, Arlington, VA (1984).

CD-ROMs

U.S. National Institute for Occupational Safety and Health: Criteria for a Recommended Standard: Occupational Exposure to Substance name. DHEW (NIOSH) Pub. No. Fill in the number from original reference; 19??. In: NIOSH Criteria Documents Plus CD-ROM. DHHS (NIOSH) Pub. No. 97-106; NTIS Pub. No. PB-502-082. National Technical Information Service, Springfield, VA (1997).

Merck & Co., Inc.: Substance name. In: The Merck Index, 12th edition on CD-ROM, Version 12:1. S Budavari, M O'Neil, A Smith, et al., Eds. Chapman & Hall, New York (1996).

Lewis Sr, RJ (Ed.): Hawley's Condensed Chemical Dictionary, 13th ed. In: Comprehensive Chemical Contaminants Series CD-ROM. Van Nostrand Reinhold, New York (1997).


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