IDENTIFICATION OF CHEMICALS OF CONCERN WITH RESPECT TO CARCINOGENICITY

Vicki L. Dellarco, Ph.D.Office of Pesticide ProgramsU.S. Environmental Protection Agency

2nd McKim Workshop on Reducing Data Redundancy in Cancer Assessment

May 8-10, 2012

Disclaimer: This presentation does not represent the views and policies of the EPA.

Carcinogenicity Information

Data rich: more reliance on in vivo data requirements Most pesticides and drugs are tested in two species,

two-year carcinogenicity bioassays, generally rats and mice. Genotoxicity data also required

Data limited: more reliance on alternative methods Most industrial chemicals, pesticide inerts &

metabolites/degradates (Q)SAR, Read across/bridging, in vitro (genotoxicity),

exposure information Consider human information and epidemiology

when available

Topics

Tumor profiles in rodents & humans Mode of action approach to evaluate the

human relevance of animal tumor 2005 EPA Cancer Assessment

Guidelines: Cancer Likelihood Characterization

Directions in Toxicology: 21st Century Initiatives to develop nonanimal (in vitro, in silico) pathway based approaches

Tumor profiles in rodents & humans

Topics

2nd McKim Workshop on Reducing Data Redundancy in Cancer Assessment

Ten Most Prevalent Tumor Sites in Rodents (http://potency.berkeley.edu/pathology.table.html

Rats (N=564 carcinogens)Mice (N=442 carcinogens)

Site

No. of Positive Chemicals

% SiteNo. of Positive

Chemicals %

Liver 222 40 Liver 254 57

Mammary gland 107 19 Lung 121 27

Kidney 94 17 Stomach 69 16

Stomach 88 16 Vascular system 64 14

Hematopoietic system 57 10 Hematopoietic 54 12

Lung 58 10 Kidney 27 6

Urinary bladder 52 9 Mammary gland 22 5

Nasal cavity / turbinates 50 9 Thyroid gland 21 5

Ear / Zymbal’s gland 42 7 Urinary bladder 12 3

Esophagus 37 7 Uterus 12 3

2008

RodentTumor Distribution (219 Pesticides)

Liver

Lung

Thyroid

Testes

Liver

Mouse

Rat

Ten Most Prevalent Tumor Sites in Humans (NCI SEER Cancer Statistics Review 1975-2005)

Site Incidence/100,000

Prostate (male) 163

Breast (female) 126

Lung & Bronchus 79

Colon and rectum 59

Urinary bladder 37

Skin melanoma 25

Lymphoma** 24

Corpus uteri (female) 23

Kidney & Renal pelvis (male) 18

Oral cavity and pharynx16

***Non-Hodgkin's lymphoma; 1 age-adjusted to 2000 US population

How Do We Assess Human Health Risks?

Relies heavily on laboratory animal data Relies on extrapolations, inference

methods, safety factors, etc Animal Biology = Human Biology Effects found at high animal doses predict

effects at environmental levels of exposure Current animal assays provide adequate

coverage for predicting effects on human health including susceptible groups

Mode of action (MoA) analysis approach to evaluate the human relevance of animal tumor response

Topic

How Do You Determined the Weight of Evidence (WoE) for Establishing a MoA?

Postulated MoA (theory of the case) Experimental support for key events

Concordance of dose-response relationships Temporal association Strength, consistency and specificity of association of

toxicological effect with key events Biological plausibility and coherence

Other possible MoAs Uncertainties, inconsistencies, & data gaps

Comparison of “Key Events” & relevant biology between animals & humans (qualitative; quantitative)

USEPA 2005; IPCS, see www.who.int/ipcs/methods/harmonization/areas/cancer_mode.pdf

Chemical-Induced Tumorigenesis: Modes of Action

DNA-reactive carcinogens Chemicals can induce tumors by a variety of MoAs

unrelated to DNA damage Experience from pesticides and/or drugs, e.g.,

Sustained cytotoxicity & regenerative proliferation Nuclear receptor activation (e.g., PPARa, CAR) & mitogenic

proliferation Renal neoplasms in male rats related to alpha-2-u-globulin Urinary bladder neoplasms secondary to mineralization or

disruption of normal urinary biochemistry Exaggerated pharmacological effects Immune suppression Hormonal imbalance

2005 EPA Cancer Assessment Guidelines: Cancer Likelihood Characterization

Topic

Highlights of 2005 EPA Cancer Guidelines

Hazard assessment emphasizes analysis of all biological information, particularly related to agent’s mode of action

Hazard, dose-response, and exposure characterization

Weight of evidence narrative and standardized descriptors

Major default assumptions are discussed Framework for judging mode of action

information is provided

Weight of Evidence

Narrative: a short summary (one to two pages) that explains an agent's human carcinogenic potential and the conditions that characterize its expression

Descriptors: provide some measure of clarity and consistency in an otherwise free-form narrative Based on weight of evidence Are a matter of judgment and cannot be

reduced to a formula Examples are illustrative, NOT a checklist

Weight-of-Evidence Descriptors

Carcinogenic to humans Likely to be carcinogenic to humans Suggestive evidence of carcinogenic

potential Inadequate information to assess

carcinogenic potential Not likely to be carcinogenic to humans

Some remarks about the descriptors

Not a check list For example, when an agent has not been

tested in a cancer bioassay, conclusions can still be drawn by scientific inference from toxicokinetic or mode-of-action data The agent operates through a mode of action

for which cancer data are available. The agent’s effects are caused by a human

metabolite for which cancer data are available.

Directions in Toxicology: 21st Century Initiatives to develop non-animal (in vitro, in silico) pathway based approaches

Topic

Regulatory Safety Assessment

Meeting Common Needs A faster, more predictive (relevant) and

reliable, and less expensive testing and assessment paradigm that allows focus on chemicals and effects of concern.

Move from Empirical to Mechanistic

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Enhanced Integrated Approaches to Testing and Assessment

Combine existing exposure and toxicity data including information from new technologies (in silico, in vitro and –omics) to:

Formulate hypotheses about the toxicity potential of a chemical or a chemical category.

Target further data needs specific to a chemical or members of a chemical category for a given exposure.

Progressive, Tiered-Evaluation Approach: “Integrate, Formulate, Target”

ChemicalsMolecular

TargetCellular

ResponseTissue Organ

Individual

PopulationPharmaco- kinetics

In vitro studies

Biomonitoring

Structure Activity Relationships

Toxicity Pathways

In vivo studies

Greater Toxicological Understanding Greater Risk Relevance

Adverse Outcome Pathway

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Biologicinputs

“Normal” BiologicalFunction

AdverseOutcomes

(e.g., mortality, ReproductiveImpairment)

Cell inury, Inability to

regulate

AdaptiveResponses

Early cellularchanges

Exposure

Uptake-Delivery to Target Tissues

Perturbation

Cellular response pathway

Molecularinitiating event

Perturbed cellular response pathway

Adverse outcomerelevant to

risk assessment

Toxicity Pathway

Adverse Outcome Pathway

II. Adverse Outcome Pathways – definition and example

Modified From NRC 2007

Pathway-Based Assessment to Predict Adversity

Fit for Purpose

Safety Evaluations Agricultural chemicals Antimicrobials and

Consumer products Industrial chemicals Pesticide inert ingredients

Data Availability/Quality Varies Extensively

Different decisions Chemical prioritization Screening level assessment Quantitative risk

assessment Cumulative risk assessment

For Regulatory Purposes

Chemical Domain of ApplicabilityEndpoints

Duration & RouteDecision Context

Uncertainty

Level of Confidence(Uncertainties Acceptable?)

Decision (Regulatory) Context

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Data-LimitedSituations

Qualitative Quantitative

Ground Truthing to Apical Toxicity

Lower Higher

Adverse Outcome Pathway

Sor

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Set

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21st Century Methods: Moving Forward

• Predicted endpoint is defined.• Mechanistic interpretation associated

with predictions, if possible.• Defined chemical domain of

applicability for the model.• Appropriate measures of goodness of

fit, robustness, ability to predict.• An unambiguous algorithm.

OECD Principles for QSAR Validation:Transparency & Utility for a Specified

Application

21st Century Methods: Moving Forward

Incremental application to decision making. continuous process of learning and refinement.

In concert with regulatory dialogue. regulatory frameworks allows the nature of

information to evolve in managing chemical risks to ensure effectiveness and efficiency in decision-making process.

understanding the type and degree of uncertainty tolerated in the decision making context will help chart research and incremental application.

Flow from expert peer review and transparency International harmonization using common

frameworks and principles

21st Century Methods: Moving Forward

Public Outreach transparency and public participation is

mandatory, science necessary but not sufficient public trust that approach is as good or better

than current incorporation of any new methods would flow

from peer review, public participation and transparency

Stakeholder support is critical to moving forward