1. Carcinogen Classification Criteria Patricia Richter Ph.D., DABT Tobacco Products Scientific Advisory Committee June 8, 2010

2. National Toxicology Program Multiple U.S. government agencies participate in the NTP, including the NIH, CDC and FDA In the United States, the NTP releases the Report on Carcinogens (RoC) every 2 years The RoC identifies 2 groups of agents: –"Known to be human carcinogens" –"Reasonably anticipated to be human carcinogens“ The RoC does not list substances that have been studied and found not to be carcinogens

3. National Toxicology Program CategoryCriteria Clear evidence of carcinogenic activity Dose-related 1) increase of malignant neoplasms, 2) increase of a combination of malignant and benign neoplasms, or 3) marked increase of benign neoplasms if there is an indication from this or other studies of the ability of such tumors to progress to malignancy

4. National Toxicology Program CategoryCriteria Some evidence of carcinogenic activity A chemical-related increased incidence of neoplasms (malignant, benign, or combined) in which the strength of the response is less than that required for clear evidence Equivocal evidence of carcinogenic activity A marginal increase of neoplasms that may be chemically related

5. National Toxicology Program CategoryCriteria No evidence of carcinogenic activity No chemical-related increases in malignant or benign neoplasms. Inadequate study of carcinogenic activity Major qualitative or quantitative limitations cannot be interpreted as valid for showing either the presence or absence of carcinogenic activity

6. International Agency for Research on Cancer (IARC) Part of the World Health Organization (WHO). Has evaluated over 900 likely carcinogens over 30 years. Classification system: –Group 1: Carcinogenic to humans –Group 2A: Probably carcinogenic to humans –Group 2B: Possibly carcinogenic to humans –Group 3: Unclassifiable as to carcinogenicity in humans –Group 4: Probably not carcinogenic to humans

7. IARC: Carcinogenicity in Humans Sufficient evidence Causal relationship Limited evidence Positive association, causal interpretation is credible Inadequate evidence Available studies are of insufficient quality, consistency or power to assess causal relationship Lack of carcinogenicity Several adequate studies covering full range of human exposures fail to show positive associations

8. IARC: Carcinogenicity in Animals Sufficient evidence Causal relationship Limited evidence Data suggestive of carcinogenic effect Inadequate evidence Available studies are insufficient to assess causal relationship Lack of carcinogenicity Adequate studies involving at least two species fail to demonstrate carcinogenicity

9. IARC: Mechanistic Data May include data on –Preneoplastic lesions –Tumor pathology –Genetic effects –Structure-activity relationship –Metabolism and toxicokinetics –Physiochemical parameters

10. IARC: Classification Group 1Sufficient evidence in humans or sufficient evidence in animals and strong mechanistic data in humans Group 2ALimited evidence in humans and sufficient evidence in animals Group 2BLimited evidence in humans and less than sufficient evidence in animals Group 3Inadequate in humans and inadequate or limited in animals Group 4Lack of carcinogenicity in humans and in animals

11. Environmental Protection Agency The US EPA maintains the Integrated Risk Information System (IRIS), an electronic database that contains information on human health effects from exposure to various substances in the environment. Rating system: –Group A: Carcinogenic to humans –Group B: Likely to be carcinogenic to humans –Group C: Suggestive evidence of carcinogenic potential –Group D: Inadequate information to assess carcinogenic potential –Group E: Not likely to be carcinogenic to humans

12. EPA Classification Criteria Weight of evidence approach: –Epidemiological human data –Results of long-term experimental animal bioassays –Other key data, including physiochemical properties, structure-activity relationships, comparative metabolism and toxicokinetics, and mode of action

13. California EPA The CA Safe Drinking Water and Toxic Enforcement Act requires that the state publish a list of chemicals known to cause cancer or reproductive toxicity. Inclusion criteria: –Recommendation by the state's qualified experts. The state Science Advisory Board includes two subcommittees that review toxicity data and identify carcinogens and reproductive toxicants. – Identification by recognized authoritative bodies, including the U.S. EPA, FDA, National Institute for Occupational Safety and Health, NTP or IARC. –Requirement by state or federal government agencies that the chemical be labeled or identified as a carcinogen or reproductive toxicant.