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Center for Risk Science and Public Health
Hazard Identification
George Gray
Center for Risk Science and Public Health
Depa...
Center for Risk Science and Public Health
Actuarial vs Modeled Risks
•  Actuarial Risks
•  based on previous experience wi...
Center for Risk Science and Public Health
How is Risk Assessment
Done?
•  Hazard Identification
•  Dose-Response Evaluatio...
Center for Risk Science and Public Health
Hazard Identification Asks the
Questions:
•  What harmful effects is the agent c...
Center for Risk Science and Public Health
Hazard Identification and
Causality
•  Hazard identification is really about jud...
Center for Risk Science and Public Health
Some Definitions
•  “The purpose of hazard assessment is to review and
evaluate ...
Center for Risk Science and Public Health
Types of Adverse Effects
•  Acute toxicity
•  Irritation
•  Corrosivity
•  Sensi...
Center for Risk Science and Public Health
Determining Hazard
•  Epidemiology
•  Study of disease rates in human population...
Center for Risk Science and Public Health
Key Questions in
Epidemiology
•  Is an association different than would be expec...
Center for Risk Science and Public Health
Random Chance?
•  Usually accounted for through tests of statistical
significanc...
Center for Risk Science and Public Health
Coffee Drinking
Smoking
Pancreatic Cancer
Confounding
•  One of the most tricky ...
Center for Risk Science and Public Health
Biologically Plausible?
•  Is plausibility argument post hoc or part of hypothes...
Center for Risk Science and Public Health
Toxicity Testing
•  Tests conducted on animals (usually rodents) to
assess and s...
Center for Risk Science and Public Health
Key Questions for Toxicology
•  Are animals like humans? (and vice versa)
•  Can...
Center for Risk Science and Public Health
Animals to Humans: Cancer
Bioassays
Question 1 - Animal to Human Extrapolation o...
Center for Risk Science and Public Health
•  To maximize sensitivity, rodents are exposed to chemicals at
levels 1000 to 1...
Center for Risk Science and Public Health
What is an Adverse Response?
Rodent Cancer Bioassays
Question 3 - What is a carc...
Center for Risk Science and Public Health
Individual Tumor Rates Can
Increase
Dose
ProportionResponding
0.0
10.0
20.0
30.0...
Center for Risk Science and Public Health
Individual Tumor Rates Can
Decrease
Dose
ProportionResponding
0.0
10.0
20.0
30.0...
Center for Risk Science and Public Health
What if We Look at Total
Tumor Rate?
Dose
0.0
50.0
100.0
150.0
200.0
250.0
300.0...
Center for Risk Science and Public Health
Judging Hazard - Risk
Assessment
•  Risk assessment
•  Arose for use in setting ...
Center for Risk Science and Public Health
Choices in Hazard
Identification
Question
•  Which species best predicts
human r...
Center for Risk Science and Public Health
Potential Cancer Hazards
Identified by Animal Bioassays
Several hundred compound...
Center for Risk Science and Public Health
Using Hazard Data
•  U.S. EPA or IARC Carcinogen Classification
•  EU “List of D...
Center for Risk Science and Public Health
IARC Carcinogen
Classification
Category* Description Human Evidence Animal Evide...
Center for Risk Science and Public Health
EPA Hazard Descriptors
•  Carcinogenic to Humans
•  Likely to Be Carcinogenic to...
Center for Risk Science and Public Health
Uncertainty Does Exist
Center for Risk Science and Public Health
FDA
•  Although research is ongoing, the
Food and Drug Administration (FDA)
says...
Center for Risk Science and Public Health
International Agency for
Research on Cancer
•  "After reviewing all the evidence...
Center for Risk Science and Public Health
National Cancer Institute
•  Studies thus far have not shown a
consistent link b...
Center for Risk Science and Public Health
What is Going On?
•  Different questions
•  Could there be a relationship?
•  Is...
Center for Risk Science and Public Health
Take Away Messages
•  The hazards posed by an agent are identified through
physi...
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Hazard Identification

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Presentation by Prof. George Gray, Director of the Centre for Risk Science and Public Health, George Washington University, at the Workshop on Risk Assessment in Regulatory Policy Analysis (RIA), Session 9, Mexico, 9-11 June 2014. Further information is available at http://www.oecd.org/gov/regulatory-policy/

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Hazard Identification

  1. 1. Center for Risk Science and Public Health Hazard Identification George Gray Center for Risk Science and Public Health Department of Environmental and Occupational Health Milken Institute School of Public Health
  2. 2. Center for Risk Science and Public Health Actuarial vs Modeled Risks •  Actuarial Risks •  based on previous experience with the same risk •  predictions can be made with a great deal of precision •  examples include diseases, auto accidents, etc. •  Modeled Risks •  based on data and theory not direct observation of the risk •  predictions subject to considerable uncertainty •  examples include cancer risk from chemicals , global warming, etc.
  3. 3. Center for Risk Science and Public Health How is Risk Assessment Done? •  Hazard Identification •  Dose-Response Evaluation •  Exposure Assessment •  Risk Characterization
  4. 4. Center for Risk Science and Public Health Hazard Identification Asks the Questions: •  What harmful effects is the agent capable of causing? •  At what doses are the effects seen? •  Is there additional information which can help us understand the hazard posed by the agent?
  5. 5. Center for Risk Science and Public Health Hazard Identification and Causality •  Hazard identification is really about judging the weight of evidence for a causal relationship between an agent and an outcome •  All of our sources of information have uncertainty •  Epidemiology – bias, confounding, conflicting data •  Toxicology – relevance of animal models, relevance of high doses, what is adverse response?
  6. 6. Center for Risk Science and Public Health Some Definitions •  “The purpose of hazard assessment is to review and evaluate data pertinent to two questions: (1) whether an agent may pose a carcinogenic hazard to human beings and (2) under what circumstances an identified hazard may be expressed. US EPA - Proposed Guidelines for Carcinogen Risk Assessment EPA/600/ P-92/003C •  “Hazard Identification is the identification of the adverse effects which a substance has the inherent capacity to cause” Commission Directive 93/67/EEC, Article 2
  7. 7. Center for Risk Science and Public Health Types of Adverse Effects •  Acute toxicity •  Irritation •  Corrosivity •  Sensitization •  Repeated dose toxicity •  Mutagenicity •  Carcinogenicity •  Toxicity for reproduction Source: Commission Directive 93/67/EEC, Annex I
  8. 8. Center for Risk Science and Public Health Determining Hazard •  Epidemiology •  Study of disease rates in human populations with, and without exposure to chemical under study •  Can discover a statistical association between exposure and disease •  Rarely can establish causal relationship or mechanism of disease causation •  Toxicology •  Tests in animals •  Measure many potential types of toxicity •  Well controlled experiments •  Have to generalize results across species and to different exposures
  9. 9. Center for Risk Science and Public Health Key Questions in Epidemiology •  Is an association different than would be expected by random chance? •  Have relevant confounders been ruled out? •  Is the association biologically-plausible?
  10. 10. Center for Risk Science and Public Health Random Chance? •  Usually accounted for through tests of statistical significance •  Beware multiple comparisons •  Hypothesis testing or hypothesis generating study?
  11. 11. Center for Risk Science and Public Health Coffee Drinking Smoking Pancreatic Cancer Confounding •  One of the most tricky and contentious issues in interpretation of epidemiological studies •  Often “controlled” through statistical methods - questions about adequacy
  12. 12. Center for Risk Science and Public Health Biologically Plausible? •  Is plausibility argument post hoc or part of hypothesis testing? •  Plausible doesn’t mean right •  Important factor in weight of evidence for causality based on epidemiology
  13. 13. Center for Risk Science and Public Health Toxicity Testing •  Tests conducted on animals (usually rodents) to assess and study adverse effects •  Rodents chosen for short life, small size and relatively easy care •  Tests can address acute (1-7 days), subchronic (3-6 months), or chronic (1-2 years) toxicity •  Other tests look at isolated tissues, cells or biomolecules
  14. 14. Center for Risk Science and Public Health Key Questions for Toxicology •  Are animals like humans? (and vice versa) •  Can effects be extrapolated from different exposure levels? •  What is an adverse response?
  15. 15. Center for Risk Science and Public Health Animals to Humans: Cancer Bioassays Question 1 - Animal to Human Extrapolation of Effect •  How well does carcinogenesis translate across species? •  all known human carcinogens are carcinogenic to some animal species under some conditions •  concordance between rats and mice is 71% - very rarely same type of cancer •  concordance between mice and rats is 75% •  male rat to female rat concordance is 87% •  male mouse to female mouse concordance is 89% •  Is there reason to believe that there may be species specific carcinogenic responses? •  d-limonene •  human specific responses?
  16. 16. Center for Risk Science and Public Health •  To maximize sensitivity, rodents are exposed to chemicals at levels 1000 to 10,000 times higher than environmental exposures •  Question 2: Are Carcinogenic effects observed at high doses in animal tests relevant to human responses at low doses? •  Yes •  Mutational theory of carcinogenesis •  Assumption of no threshold for carcinogenic effects •  No •  All toxicological effects have thresholds •  Mechanisms of high dose carcinogenesis will not apply to low dose exposure Dose Extrapolation: Cancer Bioassays
  17. 17. Center for Risk Science and Public Health What is an Adverse Response? Rodent Cancer Bioassays Question 3 - What is a carcinogenic response in an animal bioassay? •  Response in any tested animals? •  In National Toxicology Program bioassays, of all positive studies •  28 % of tests are positive in all 4 sex/species •  16 % are positive in 3 out of 4 •  35 % are positive in 2 out of 4 (usually same species) •  21 % are positive in 1 out of 4 •  What about tumors in rodent organs with no human equivalent? •  Focus on specific tumor types or overall cancer rate?
  18. 18. Center for Risk Science and Public Health Individual Tumor Rates Can Increase Dose ProportionResponding 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 0 1 10 100 liver tumors pulmonary tumors
  19. 19. Center for Risk Science and Public Health Individual Tumor Rates Can Decrease Dose ProportionResponding 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0 0 1 10 100 mammary gland tumors uterus tumors
  20. 20. Center for Risk Science and Public Health What if We Look at Total Tumor Rate? Dose 0.0 50.0 100.0 150.0 200.0 250.0 300.0 0 1 10 100 total tumors
  21. 21. Center for Risk Science and Public Health Judging Hazard - Risk Assessment •  Risk assessment •  Arose for use in setting standards and limits •  Needs to operate in the face of scientific uncertainty •  “as an Agency policy, risk assessment procedures, including default options that are used in the absence of scientific data to the contrary, should be health protective.” “Use of health protective risk assessment procedures as described in these cancer guidelines means that estimates, while uncertain, are more likely to overstate than understate hazard and/or risk.” U.S. EPA Risk Assessment Forum (2005) Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F
  22. 22. Center for Risk Science and Public Health Choices in Hazard Identification Question •  Which species best predicts human response? •  Which sex best predicts human response? •  Are carcinogenic effects in animals exposed to levels of chemical 10,000 time higher than human exposure relevant? Regulatory Risk Assessment Choice ⇒  The most sensitive ⇒  The most sensitive ⇒  Yes
  23. 23. Center for Risk Science and Public Health Potential Cancer Hazards Identified by Animal Bioassays Several hundred compounds have been found to increase some type of tumor in rodents in a standard 2 year bioassay Agent Animal Evidence Human Evidence Acrylamide sufficient inadequate Chloroform sufficient inadequate Carbon Tetrachloride sufficient inadequate 1,4-Dioxane sufficient inadequate Naphthalene sufficient no adequate data Ochratoxin A sufficient inadequate Phenytoin sufficient no adequate data PCBs sufficient inadequate/conflicting Source: U.S. DHHS 12th Report on Carcinogens
  24. 24. Center for Risk Science and Public Health Using Hazard Data •  U.S. EPA or IARC Carcinogen Classification •  EU “List of Dangerous Substances” •  FDA “Bad Bug Book” •  May trigger labeling requirements - e.g., •  Directive 67/548/EEC and amendments •  US EPA Pesticide labels
  25. 25. Center for Risk Science and Public Health IARC Carcinogen Classification Category* Description Human Evidence Animal Evidence 1 carcinogenic sufficient none, inadequate, to humans limited or sufficient 2A probably limited sufficient 2B possibly none or inadequate sufficient 3 not classifiable none or inadequate inadequate or limited 4 probably not suggests not suggests not carcinogenic carcinogenic carcinogenic *All categories can be modified with sufficient supporting mechanistic information
  26. 26. Center for Risk Science and Public Health EPA Hazard 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 •  Multiple descriptors allowed for single compound (i.e., route specific or dose-dependent carcinogenicity) •  Accompanied by 1-2 page Hazard Characterization
  27. 27. Center for Risk Science and Public Health Uncertainty Does Exist
  28. 28. Center for Risk Science and Public Health FDA •  Although research is ongoing, the Food and Drug Administration (FDA) says that available scientific evidence —including World Health Organization (WHO) findings released May 17, 2010—shows no increased health risk due to radio- frequency (RF) energy, a form of electromagnetic radiation that is emitted by cell phones. •  Despite the dramatic increase in cell phone use, occurrences of brain cancer did not increase between 1987 and 2005.
  29. 29. Center for Risk Science and Public Health International Agency for Research on Cancer •  "After reviewing all the evidence available, the IARC working group classified radiofrequency electromagnetic fields as possibly carcinogenic to humans," panel chairman Jonathan Samet, MD, chair of preventive medicine at the USC Keck School of Medicine, said at a news teleconference. "We reached this conclusion based on a review of human evidence showing increased risk of glioma, a malignant type of brain cancer, in association with wireless phone use."
  30. 30. Center for Risk Science and Public Health National Cancer Institute •  Studies thus far have not shown a consistent link between cell phone use and cancers of the brain, nerves, or other tissues of the head or neck. More research is needed because cell phone technology and how people use cell phones have been changing rapidly. •  Although there have been some concerns that radiofrequency energy from cell phones held closely to the head may affect the brain and other tissues, to date there is no evidence from studies of cells, animals, or humans that radiofrequency energy can cause cancer.
  31. 31. Center for Risk Science and Public Health What is Going On? •  Different questions •  Could there be a relationship? •  Is the evidence sufficient to say cell phones causally related to cancer? •  Scientific uncertainty •  Conflicting studies •  Hard for science to prove a negative
  32. 32. Center for Risk Science and Public Health Take Away Messages •  The hazards posed by an agent are identified through physical/chemical properties, epidemiology or toxicologic studies •  All sources of information have inherent uncertainty in the ability to determine a causal relationship between exposure and outcome •  Many risk assessment processes use “conservative” assumptions in the face of this uncertainty •  Uncertainty may be important when estimating benefits in RIA

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