June 16-19, USEPA Cancer Guidelines: Mode of Carcinogenic Action 1 ICABR – Impacts of the Bioeconomy on Agricultural Sustainability, the Environment and Human Health

United States Environmental Protection Agency The mission of EPA is to protect human health and the environment. EPA's purpose is to ensure that all Americans are protected from unreasonable risks to human health and the environment where they live, learn and work. 2

Risk Assessment Paradigm: Hazard vs. Risk 3

Office of Pesticide Programs Evaluating Potential New Pesticides and Uses Federal law requires that before selling or distributing a pesticide in the United States, a person or company must obtain a registration, or license, from EPA. registration Before registering a new pesticide or new use for a registered pesticide, EPA must first ensure that the pesticide, when used according to label directions, can be used with a reasonable certainty of no harm to human health and without posing unreasonable risks to the environment. To make such determinations, EPA requires more than 100 different scientific studies and tests from applicants. Where pesticides may be used on food or feed crops, EPA also sets tolerances (maximum pesticide residue levels) for the amount of the pesticide that can legally remain in or on foods. 4

Federal Insecticide, Fungicide, and Rodenticide Act and Federal Food Drug and Cosmetic Act FIFRA defines “unreasonable adverse effects on the environment” as (1) any unreasonable risk to man or the environment, taking into account the economic, social, and environmental costs and benefits of the use of any pesticide, or (2) a human dietary risk from residues that result from a use of pesticide in or on any food inconsistent with the standard under [FFDCA] section 408… FFDCA authorizes EPA to set maximum residue levels, or tolerances, for pesticides used in or on foods or animal feed The safety standard for setting a tolerance is a "reasonable certainty of no harm" 5.

Available Data for Review of Carcinogenicity Registrant generated 40 CFR Part 158 Data – GLP/OECD –In vitro Genotoxicity studies –Mechanistic Data – not required –Sub-chronic rodent studies –Chronic rodent and non-rodent studies –Cancer bioassays in rat and mouse Open Literature Studies – Peer Reviewed –Quantitative use in risk assessment –Qualitative use in weight of evidence –Unacceptable or inappropriate for use in risk assessment Regulatory Authorities’ current risk assessments 6

2005 USEPA Cancer Guidelines Transition from categories to descriptors –Carcinogenic to Humans, –Likely to Be Carcinogenic to Humans, –Suggestive Evidence of Carcinogenic Potential, –Inadequate Information to Assess Carcinogenic Potential, and –Not Likely to Be Carcinogenic to Humans Consideration of Mode of Action: Threshold vs. Non-Threshold –Biological Plausibility and Coherence –Dose Response Concordance –Temporal Concordance 7

Weight of Evidence Assessment Integrative Weight of Evidence – –Incidence and type of tumor findings, or lack thereof, in humans and laboratory animals; –an agent’s chemical and physical properties; –its structure-activity relationships (SARs) as compared with other carcinogenic agents; and –studies addressing potential carcinogenic processes and mode(s) of action, either in vivo or in vitro. –Data from epidemiologic studies are not generally available but would be considered when characterizing human cancer hazard and risk. 8

Mode of Action and Adverse Outcome Pathway 9

Mary Ko Manibusan Senior Managing Scientist, Human Health Toxicologist/Risk Assessor Exponent, Inc. Tel