TLV Notations and Designations Philip Bigelow Ph D

TLV® Notations and Designations Philip Bigelow, Ph. D, CIH Associate Professor Florida A&M University Institute of Public Health TLV®-CS Committee

TLVs® – More than a number ! – Core principles focus on protection of workers – Use threshold concepts to protect against: • Chronic effects • Acute effects • Freedom from irritation, stress, other effects – Numerical values are important • TLV®-TWA • TLV®-STEL • TLV®-Ceiling – Notations are also part of the TLV®

Why Notations and Designations? – To aid in worker protection by: • Identifying agents for which the cutaneous route is important • Identifying agents that have potential to produce sensitization • Identifying agents that have been studied to assess their carcinogenicity potential • Identifying agents that have a Biological Exposure Index • Note: other notations may be added to reflect contemporary occupational health practice

Guidance for Interpreting Notations • INTRODUCTION TO THE CHEMICAL SUBSTANCES – – Guidelines and philosophy for using TLVs® SKIN notation SENsitizer notation Biological Exposure Indices (BEI®) notation • See also INTRODUCTION TO THE BIOLOGICAL EXPOSURE INDICES • Appendix A: Carcinogenicity • NOTE: Absence of a notation may reflect absence of scientific evidence not “no effect”

Guidance for Interpreting the SKIN Notation • Significant contributions to overall exposure by cutaneous route, mucous membranes or eyes by vapor or direct skin contact • Evidence that dermal absorption may be important in expressed toxicity • Biological monitoring should be considered • Notation not related to skin irritation, dermatitis or skin sensitization

SKIN Notation Example • 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

Guidance for Interpreting the SEN Notation • Refers to the potential for the agent to produce significant sensitization, as confirmed by human or animal data • May or may not be critical effect • TLV® values not intended to protect those workers already sensitized (goal is to prevent sensitization) • May reflect risk of dermal and/or inhalation sensitization (must consult Documentation)

SEN Notation Example • Formaldehyde TLV®-Ceiling 0. 3 ppm; SEN; A 2 (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

• Human Other Evidence Used to Assess Sensitization Risk – Human Repeat Insult Patch Test – In vitro immunological tests • Animal – Guinea pig maximization test – Murine local lymph node assay – Mouse ear swelling test – No current suitable test for respiratory allergens

Guidance for Interpreting the BEI® Notation • Refers to existence of a Biological Exposure Index (BEI®) for the agent • Biomonitoring serves as a complement to exposure assessment by air sampling • Most BEIs® based on direct correlation to TLV® (conc. of determinant at TLV® exposure) • BEIs® used as guidelines in evaluation of potential hazards

BEI® Notation Example • Methanol TLV® 200/250 ppm; SKIN; BEI® (neuropathy; vision; CNS) – BEI® • Methanol in urine – 15 mg/L • End of workshift • Notations – B – background – Ns – nonspecific

Guidance for Interpreting the Carcinogenicity Notation • 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 A 1 agents with a TLV® and for A 2 and A 3 agents exposure by all routes should be controlled • For agents with no designation – no human or animal data available to assign

A 1 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

A 2 Suspected Human Carcinogen • Human data are accepted as adequate in quality but are conflicting or insufficient to classify the agent as A 1, 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.

A 2 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

A 3 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.

A 3 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

A 4 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.

A 4 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

A 5 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.

A 5 Not Suspected as a Human Carcinogen Example • Nickel (elemental/metallic) – Extensive human epidemiologic findings are negative – Genotoxicity studies negative – Chronic bioassays negative • Trichloroethylene – Extensive animal bioassays negative but initial studies did evoke concern; genotoxicity tests mixed – Human epidemiology studies negative

The Documentation • TLV® — more than just “THE NUMBER” • Documentation describes: – Critical health effects – Quality of the data relied upon and areas of uncertainty – Possible sensitive subgroups – Type of TLV® (TWA, STEL, C) and reason for selection – Notations

Other Sources • Kennedy GL, Brock JW Jr. , Banerjee AK (1993) Assignment of skin notation for threshold limit values of chemicals based on acute dermal toxicity. Appl Occup Environ Hyg 8: 26 -30. • ECETOC Special Report No. 15. Examination of a proposed skin notation strategy. European Centre for Ecotoxicology and Toxicology of Chemicals, 1998. • Spiritas R, Fleming LE, Demers PA, Weisburger EK (in press) TLV Carcinogenicity categories: Recent modifications. Appl Occup Environ Hyg

Other 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).