identification of chemicals of concern with respect to carcinogenicity
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Identification of Chemicals of Concern with respect to Carcinogenicity. Disclaimer: This presentation does not represent the views and policies of the EPA. Vicki L. Dellarco, Ph.D. Office of Pesticide Programs U.S. Environmental Protection Agency. - PowerPoint PPT PresentationTRANSCRIPT
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
20
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”
Chemicals Molecular Target
Cellular Response
Tissue Organ Individu
alPopulationPharmaco
- kinetics
In vitro studies
Biomonitoring
Structure Activity Relationships
Toxicity Pathways
In vivo studies
Greater Toxicological Understanding Greater Risk Relevance
Adverse Outcome Pathway
22
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
Hum
an D
rug
Appr
oval
Char
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hem
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at
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ite to
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Listin
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Drin
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ntam
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and
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colle
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Regi
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oval
for A
gricu
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se
ComprehensiveData
Requirements
Data-LimitedSituations
Qualitative Quantitative
Ground Truthing to Apical Toxicity
Lower Higher
Adverse Outcome Pathway
Sorti
ng/P
riorit
y Se
tting
for E
DSP
25
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