New Approaches to Adversity Assessment in
Food Safety Evaluation
Daniel Krewski, PhD, MHA
McLaughlin Centre for
Population Health Risk Assessment
University of Ottawa [email protected]; www.mclaughlincentre.ca
&
Risk Sciences International [email protected]; www.risksciences.com
Declaration of Interest Statement
Scientific Director of the McLaughlin Centre for Population
Health Risk Assessment at the University of Ottawa,
supported by the R. Samuel McLaughlin Foundation
Natural Sciences and Engineering Research Council of
Canada Industrial Research Chair in Risk Science at the
University of Ottawa
Chief Risk Scientist at Risk Sciences International, a
Canadian company established in 2006 in partnership with
the University of Ottawa
Outline
• Traditional and Future Approaches
• Determining Adversity: Past and Future
• Severity Scoring Based on Degree of Adversity
• Evidence Integration
• Summary
Subchronic
Toxicity &
Reproduction
U
+
Accept
Reject
Defined
Test
Material
Exposure
Assessment
Acute
Toxicity
Reject
+ Genetic
Toxicology
-
Metabolism &
Pharmokinetics
+
Reject
-
Accept
S
Reject
+ -
?
Reject
Chronic
Toxicity
Accept
+
-
Traditional Approaches to Food Safety Assessment
Food Safety Council (1980)
Case Study: Sodium Saccharin
1981: Saccharin banned as a direct food additive on
the basis of urinary bladder tumours induced
in male rats in two-generation cancer bioassay
2010: Saccharin removed from US EPAs hazardous
substances list following re-evaluations of
the scientific data by the US NTP and by
the International Agency for Research on
Cancer in the 1990s
Two-Generation Lifetime Bioassay of Sodium Saccharin
Concentration Incidence of Percent
in Diet (%) Bladder Tumours Response
0.00 0/324 0
1.00 5/658 1
3.00 8/472 2
4.00 12/189 6
5.00 15/120 13
6.25 20/120 17
7.50 37/118 31
5.00 (through gestation) 0/122 0
5.00 (following gestation) 12/120 10
International Research and Development Corporation (1985)
Mechanism of Saccharin Induced Rat Bladder Tumours
National Toxicology Program Report on Carcinogens (1991), p. 91
“When sodium saccharin is fed to male rats at high dietary levels
(about 2.5%), the concentration of urinary sodium is increased and
the pH level is elevated (above 6.5). Under these conditions, binding
of saccharin and male rat α2u-globulin results in the formation of
silicon containing crystallized precipitate in the bladder
After binding, the precipitate enters the bladder urothelial walls and
is cytotoxic. Acting as microabrasives, the silicate and precipitate
particles irritate the mucosa and cause focal necrosis.
The loss of urothelial cells results in regenerative hyperplasia and
increased cell proliferation which, when sustained over a lifetime,
provides the basis for urinary bladder tumorigenesis.”
The Next Generation of Risk Science
• New paradigm for toxicity testing, as
described in Toxicity Testing in the 21st
Century (NRC, 2007)
• Advanced risk assessment
methodologies, including those
addressed in Science and Decisions (NRC, 2009)
• Population health approach,
incorporating multiple health
determinants and multiple interventions (Krewski et al., 2007, HERA, 13:1288-1312)
Krewski et al. (2014): http://ehp.niehs.nih.gov/1307260/
Toxicity Testing in the 21st Century
www.nas.edu
Future Approaches to Food Safety Assessment
Krewski et al. (2011), ARPH: 32:161-178.
Motivation for Change
Increased throughput, reduced costs
Early screening of potential new food chemicals
Test directly in human cells and human cell lines
Test directly at lower dose levels
Understand toxicity pathways and pathway
perturbations
Characterize interactions among toxicity pathways
Characterize interactions between test agent and
concomitant exposures
Compatibility of New Approaches with Existing Statutes?
“Agency rulemaking provides
the legal flexibility to
implement a new toxicity
testing program using existing
laws.”
The Environmental Forum (2008), pp. 46-51.
Implementing the New Paradigm: Selected Methodological Issues
1. Adversity
2. Dose-response
3. Variability
4. Susceptible populations
5. Dose and species extrapolation
6. Mixtures and multiple stressors
7. Uncertainty analysis
Determining Adversity: Past and Future
Issue Current
Approach
NexGen Approach
Adverse
outcomes
Apical outcomes in
mammalian systems,
or precursors to
these outcomes,
serve as the basis
for risk assessment.
In vitro assays identify
critical toxicity pathway
perturbations, which
serve as the basis for
risk assessment, even
in the absence of a
direct link with an apical
outcome.
Defining Adversity in the Absence of Apical Outcomes
Dose-Response Analysis: Signal-to-Noise Crossover Dose (SNCD)
Sand, Portier & Krewski, Environmental Health Perspectives (2011), pp. 1766-1774.
Application to High-Throughput Screening Data
Dose-response models fit to
over 10,000 datasets for over
1,400 chemicals tested as
part of the Tox21 program
44 nuclear receptor assays,
23 cytotoxicity assays, 12
stress response assays
Analysis used to calibrate
SNCD against traditional BMD
Exposure Science in the 21st Century
http://www.nap.edu/openbook.php?record_id=13507
Human Biomonitoring
National Health and Nutrition Examination Survey
Canadian Health Measures
Survey (CHMS)
NHANES
Establishing Biomonitoring Equivalents
Biomonitoring Equivalents
• 2,4-D
• Acrylamide
• Cadmium
• Cyfluthrin
• Di(2-ethylhexyl)phthalate
• Phthalate Esters: Diethyl phthalate Di-n-butyl phthalate Benzylbutyl phthalate
• Polychlorinated dibenzo-p-dioxins and dibenzofurans
• Toluene
• Trihalomethanes: Chloroform Dibromochloromethane Bromodichloromethane Bromoform
http://www.biomonitoringequivalents.net/html/chemical_specific_bes.html
High-Throughput Biomonitoring
Jones, D.P. (2016), Toxicol. Rep. 3, 29-45.
Combining High-Throughput In Vitro Testing with High-Throughput Exposure Assessment
Comparison of Bioactivity Patterns for 163 ToxCast Chemicals
with High-Throughput Exposure Modeling Results
Evidence Required for Establishing Dietary Reference Intakes
U-Shaped Dose-Response for Essential Nutrients
Dose (Concentration)
Essentiality
Excess Deficiency
Homeostasis
Zone
of
conflict
Zone
of
conflict
Very Low Very High
Resp
on
se
Highly
Abnormal
Normal
Resp
on
se
Highly
Abnormal
Normal
Joint Model for Excess and Deficiency (JMED)
Copper Toxicity Database: Severity Scoring of Adverse Events
Copper Toxicity Database
Optimal Intake of Copper
xMINDUE = 2.73 mg/day
For humans, a daily oral intake of 2.73 mg will minimize the probability of a departure
from a non-normal response attributed to excess or deficiency. The 95% confidence
interval for xMINDUE is (1.57, 4.46) and is analogous to an acceptable range of oral intakes.
Application to Manganese . . .
. . . with Incorporation of Pharmacokinetics
Evidence Integration
Review of EPA’s Integrated Risk Information System (NRC, 2014)
Systematic Review: Objective and Reproducible
Quantitative Synthesis Using Meta-Analysis
Summary
• New paradigm for toxicological assessment of chemicals based on:
− Toxicity Testing in the 21st Century (NRC, 2007)
− Exposure Science in the 21st Century (NRC, 2012)
− Using 21st Century Science to Improve Risk-Related Evaluations (NRC,
2017)
• Need for change motivated by
− Increased throughput and lower cost
− Greater human relevance
− Obtain evidence directly at human exposure levels
• New paradigm presents challenges in re-defining adversity, and
adaptation of regulatory practice to reflect new evidence of adversity
• New approaches to evidence integration and synthesis will ensure
consideration of all relevant data in food safety assessment
Further Reading
Barton-Maclaren, T., Darshan, S. and Mattison, D.R. [Eds]. Risk Science in the 21st Century.
International Journal of Risk Assessment and Management 20 (1/2/3):1-283.
Council of Canadian Academies (2012). Integrating Emerging Technologies into Chemical
Safety Assessment. Council of Canadian Academies, Ottawa.
I. Cote, M. E. Andersen, G. T. Ankley, et al. The next generation of risk assessment
multiyear study- highlights of findings, applications to risk assessment and future directions.
Environmental Health Perspectives DOI:10.1289/EHP233, 2016.
D. Krewski, M. Westphal, M. E. Andersen, G. M. Paoli, W. A. Chiu, M. Al-Zoughool, M. C.
Croteau, L. D. Burgoon, and I. Cote. A framework for the next generation of risk science.
Environmental Health Perspectives 122 (8):796-805, 2014.
National Research Council (2007). Toxicity Testing in the 21st Century: A Vision and a
Strategy. National Academy Press, Washington, D.C.
National Research Council (2012). Exposure Science in the 21st Century. National Academy
Press, Washington, D.C.
National Research Council (2014). Review of EPA's Integrated Risk Information System
(IRIS) Process. National Academy Press, Washington, D.C.
National Research Council (2017). Incorporating 21st Century Science into Risk-Related
Evaluations. National Academy Press, Washington, D.C.