TLV Notations and Designations

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TLV Notations and Designations

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

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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

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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

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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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.

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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

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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.

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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

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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.

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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

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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.

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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

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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

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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

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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).