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/

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. 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. Center for Risk Science and Public Health
How is Risk Assessment
Done?
• Hazard Identification
• Dose-Response Evaluation
• Exposure Assessment
• Risk Characterization

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Center for Risk Science and Public Health
Uncertainty Does Exist

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. 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. 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. 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. 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