Transcript The Nature of Judicial Processes (Plural) in the United States

Emerging Methods for
Controlling Chemicals
E. Donald Elliott
Professor (adj) of Law, Yale Law School
[email protected]
Gail Charnley Elliott PhD
HealthRisk Strategies
[email protected]
Current Regulatory Practice
NAS, Decision Making for
Regulating Chemicals in
the Environment (1975)
 Whole body animal tests
 High doses
 Uncertainty factors
Problems #1
• High Cost
– ~$500,000/bioassay
• Low Throughput
• Information Lacking on Safety of
Most Chemicals
Too Many Chemicals
Too Little Data (%)
9912
Judson, et al EHP (2009)
Is New Chemical Regulation
Technology-Forcing Toxicology?
 “Ambitious new testing programs such as REACH are
literally impossible without new methods for screening
and prioritizing.”
E. Donald Elliott, Needed: A Strategy for Implementing the Vision, 29 Risk
Analysis 482 (Feb., 2009).
 Conventional Implementation of REACH
 68,000 substances (vs. 29,000 predicted)
 54 million animals (ECHA: “only” 9 million)
 $13.5 billion
 “regulatory toxicology needs to move into the 21st century”
 “many core methods have remained unchanged for 40 years.”
Thomas Hartung & Costanza Rodiva, 460 Nature 1080 (Aug 27, 2009).
Problems #2
• Inter-species extrapolations
?
• High dose
low dose extrapolations
Problems #3
• Cruelty to Test Animals
The Solution?
•Automated
Micro-Arrays
•PathwayBased Risk
Assessment
•Computational
Toxicology
Toxicity Testing
in the 21st Century
National Academy of Sciences (2007)
“envisions a not-so-distant future in which virtually all
routine toxicity testing would be conducted in human
cells or cell lines in vitro by evaluating cellular responses
in a suite of toxicity pathway assays using high
throughput tests, implemented with robotic
assistance.”*
* M.Andersen & D.Krewski, Toxicol Sci. 2009 Feb;107(2):324-30
“toxicity pathway assays”
RNA
Normal
Protein
“toxicity pathway assays”
RNA
Perturbation
?
Protein
An (Imperfect) Analogy
http://en.wikipedia.org/wiki/Rabbit_test
ISCHEMIA REPERFUSION EVIDENCE
Source:
http://www.epa.gov/NCCT/practice_community/Andersen_EPA_CPCP_27mar2
008.pdf
Toxicity Testing
in the 21st Century
National Academy of Sciences (2007)
Overview
• How we got where we are now
• Why our current approach doesn’t
work well
• Proposal for a new approaches to
testing for the purpose of risk
assessment/regulatory decisionmaking
• Reaction so far
Qualitative statutory requirements
for public health protection
• reasonable certainty that no harm will
result
• provide an ample margin of safety to
protect public health
• no employee will suffer material
impairment of health
• safe
• significant risk of harm
• fulfill those requirements without being
arbitrary & capricious
Regulatory Risk Analysis
• Quantitative risk assessment: developed in
reaction to laws and judicial decisions calling for
limits on chemical exposures that protect public
health & to create a judicially reviewable record
Politics
Hazard identification
Social factors
Dose-response
assessment
Risk
characterization
Exposure assessment
Economics
Feasibility
Protect
public
health
Regulatory Risk Analysis
• Quantitative risk assessment: developed in
reaction to laws and judicial decisions calling for
limits on chemical exposures that protect public
health & to create a judicially reviewable record
Politics
Hazard identification
Social factors
Dose-response
assessment
Risk
characterization
Exposure assessment
Economics
Feasibility
Protect
public
health
Types of toxicity tests
•
•
•
•
•
•
•
Acute, single dose
Repeated dose (14 days, 90 days, 2 years)
Reproductive toxicity tests
Developmental toxicity tests
Neurological toxicity tests
Cancer bioassays
Mode-of-action studies
Traditional toxicity paradigm:
Exposure-response continuum
• Focus = adverse outcome
• Whole-animal based
The Problem (1)
• Tests are dated, expensive, timeconsuming, and animal-intensive
– Standard test methods date to 1930s
– $1 million+ per substance
– Low throughput: cancer bioassay takes 2
years to do, another year+ to evaluate results
– Cancer bioassay uses 800 animals
• Low sensitivity (false negatives)
• Poor specificity (false positives)
• Ethics
The Problem (2)
• Uncertain relevance of laboratory animal
tests to humans
– Interspecies extrapolation required
– High-to-low dose extrapolation required
High-to-low-dose extrapolation
DATA ARE
HERE
100
90
80
70
60
50
WE ARE
HERE
40
30
20
10
0
1
10
100
1000
The Problem (2)
• Uncertain relevance of laboratory animal tests to
humans
– Interspecies extrapolation required
– High-to-low dose extrapolation required
• Poor information on potential special sensitivities
– Life-stage, genetic, nutritional, etc.
• Need to regulate with incomplete information
– Default assumptions
– Uncertainty factors
Setting chemical exposure limits
Highest
non-toxic
dose in rats
People might be
more sensitive
than rats
Some people
might be more
sensitive than
others
Safe dose
10x
100x
The Problem (3)
• Test large numbers of existing chemicals,
many of which lack basic toxicity data
• Test the large number of new chemicals
and novel materials, such as
nanomaterials, introduced each year
Toxicity Testing in
the 21st Century
A Vision and a Strategy
The National Academies Press
www.nap.edu
Goals
•
•
•
•
•
Minimize animal use
Increase throughput
Reduce time & expense
Replace assumptions with data
Produce toxicity in a way that provides
information useful for risk assessment
– identify conditions of use that are unlikely to
produce toxicity = “safety”
Vision
• Transform routine toxicity testing and human
health risk assessment & management
– Computational toxicology
– High & medium-throughput screening assays
• in vitro human cell lines
• toxicogenomics & other -omics
– Physiologically based pharmacokinetic models
– Pathway-based, not adverse-outcome-based
• Identify critical pathways that when perturbed can lead
to adverse health outcomes
Pathway-based toxicity testing:
Intersection of exposure and biologic function
Example: Perchlorate & thyroid function
I-
thyroid cell
thyroid
hormones
I-
thyroid
hormones
metabolism &
organ function
fetal/childhood
growth & development
Example: Perchlorate & thyroid function
I-
thyroid cell
thyroid
hormones
thyroid
hormones
metabolism &
organ function
I-
compensate
fetal/childhood
growth & development
Example: Perchlorate & thyroid function
I-
thyroid
hormones
I-
thyroid cell
thyroid
hormones
lower metabolism &
impaired organ function
abnormal fetal/childhood
growth & development
Pathway-based toxicity testing: Intersection
of exposure and biologic function
• Exposure leads to perturbation of normal
biologic pathways
• Biologic function is compromised if host is
unable to adapt because:
– Perturbation is sufficiently large
– Underlying nutritional, genetic, life-stage, or
disease status
• Compromised biologic function leads to
toxicity & disease = mode of action
Source: NAS/NRC (2006) Health Implications of Perchlorate Ingestion
ISCHEMIA REPERFUSION EVIDENCE
Source: William Pennie, Pfizer
Challenges
• Identifying normal biologic pathways
• Validation: determining whether
perturbations, such as a particular pattern
of changes in gene expression, are
adverse
– Changes may not indicate adverse effect
– Multiple/complex etiologies of most diseases
– Support tort liability arguments without rigor
• Regulatory guidance development
Bimodal reactions so far
Chemical
industry
We’ll have the means to identify
safer substances & to reduce
risks more effectively
We’ll get sued every time
a chemical perturbs something
We’ll be able to identify low-dose
& cumulative effects, synergies,
& people with special sensitivities
Uncertainty factors might be
replaced by data, leading to
less stringent exposure limits
Environment
NGOs
Balancing the Risks of
False Positives and False Negatives
The classic case in American
law is International Harvester
Co. v. Ruckelshaus, 478 F.2d
615 (D.C. Cir. 1973).
Judge Leventhal held the extent
of proof required should be a
function of the consequences of
an error in one direction or
another.
“Extraordinary conclusions require extraordinary proof” - Carl Sagan
• Aaron Wildavsky,
Searching for Safety
(New Brunswick, N.J.: Transaction Books, 1988)

improve resilience vs.
improve anticipation
Uses of Pathway-Based
in vitro Assays
•
•
•
•
•
Validation
Private use to eliminate candidates _
Screening/setting agency priorities
Requiring additional testing
Public information
Considered in weight of evidence
in standard-setting/rulemaking
• Material basis for approval
• Admissible in damage cases
+
• Material basis for regulation