risk assessment – under the consumers’ and regulatory microscopeasq.org › fdc › 2015 › 11...

Risk Assessment – Under the Consumers’ and Regulatory Microscope

Dr. Clemens 1

Risk Assessment:Under the Consumers’ and

Regulatory MicroscopeRoger Clemens, DrPH, CFS, CNS, FIFT, FACN, FIAFST

Adjunct Professor, USC School of PharmacyInternational Center for Regulatory Science

[email protected]

Risk-Benefit in the News

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Daily aspirin therapy: Understand the benefits and risksMay 20, 2014

August 18, 2015

Wine may promote a longer lifespan, protect against certain cancers, improve mental health, and provide benefits to the heart. Yes, light to moderate drinking (<15 and <30 g of alcohol per day for women and men, respectively) was associated with minimally increased risk of overall cancer in both women and men.

Those who consumed 15 grams of nuts or peanuts daily were at a lower risk of death from numerous diseases compared with participants who did not consume them.June 11, 2015

Hazard vs Risk Analysis (video)

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Toxicity or hazard

Dose/timing matters

People differ

Things Change

Warfarin

CoumadinPolymorphismsAge, gender, health,

drugs

She used to drink turpentine (terebinth from Pistacia terbinthus?) to make her urine smell of violets

R = RiskI = is equal toT = Toxicity XE = ExposureRITE R = H x E


Dr. Clemens 2

Risk Analysis

"A process consisting of three components: risk management, risk assessment and risk communication." (World Health Organization, 2010)

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Risk Assessment Process

Risk assessment requires qualitative and quantitative information and consists of 4 key steps:1. Hazard identification

does the agent cause adverse effects?

2. Hazard characterization what is the relationship between the dose and the response?

3. Exposure assessment route(s) of exposure? level, frequency, and duration of exposure?

4. Risk characterization estimation of the incidence of health effects under the various

conditions of exposure to those affected

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Risk Management

The process, distinct from risk assessment, of weighing policy alternatives, in consultation with all interested parties, considering risk assessment and other factors relevant for the health protection of consumers and for the promotion of fair trade practices, and, if needed, selecting appropriate prevention and control options.(World Health Organization, 2010)

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Risk Communication

• Interactive information exchange

• Critical component of risk analysis

• Engagement with all interest groups from public, private and regulatory sectors

• Develop systematic approach(es)

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The interactive exchange of information and opinions throughout the risk analysis process concerning hazards and risks, risk-related factors and risk perceptions, among risk assessors, risk managers, consumers, industry, the academic community and other interested parties, including the explanation of risk assessment findings and the basis of risk management decisions.(World Health Organization, 2010)

Caramel

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• Other names: Caramel color or caramel coloring

• Chemistry: spectrum of polymers

• Source: Caramelized (heated) carbohydrate

• Label declaration: Yes

• Adverse events: 4-methylimidazole inconsistent link to cancer (see Murray FJ, Food Chem Toxicol 2011;49(1):320-2)

• Applications: – Food, Drugs, Dietary Supplements

4-methylimidazole (4-MEI)

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Dr. Clemens 3

4-methylimidazole (4-MEI)• Produced via Maillard Browning Reaction• National Toxicology Program (NTP)

– 2-yr study among rats and mice with diets at 0, 625, 1250 or 2500 ppm (males) and 0, 1250, 2500 or 5000 ppm (females)

– Female rats: • decreased tumors at mid and high doses (mammary, uterus,

clitoral gland, pituitary); • increased mononuclear cell leukemia (dose-related manner)

– Male rats: • decreased pituitary, adrenal medulla pheochromocytoma

– Among both sexes, actual tumor burden was lower than predicted (think about future modeling)

NTP, NTP Technical Report on the Toxicology and Carcinogenesis Studies of 4-Methylimidazole, 2007Chan et al., Arch Toxicol 2008;82(1):45-53Murray FJ Food Chem Tox 2011;49(1):320-2 13

Risk Assessment Objectives

Objectives of risk assessment: balance of risks and benefits

drugs (chemotherapy) - toxicity vs. life-threatening disease

pesticides – toxicity vs. protection of food crops

set target levels of risk food contaminants

water and air pollutants

establish program activities/policy to reduce risk regulatory agencies (FDA, EPA)

estimate effectiveness of action to reduce risk how effective was the action in reducing the risk?

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Food Defect Action Levels(May 1995; Revised March 1997; Revised May 1998)

21CFR§110.110

• In order to qualify as U.S. No. 1 Grade, the commodities listed below cannot exceed the following limits of contamination: – Ketchup -- 30 fruit fly eggs / 100 g

– Canned corn -- 2 insect larvae / 100 g

– Blueberries -- 2 maggots / 100 berries

– Peanut butter -- 50 insect fragments / 100 g

– Curry powder -- 100 insect fragments / 100 g

– Wheat -- 1% of grains infested

– Sesame seed -- 5% of seeds infested

– Coffee -- 10% of beans infested

15http://www.cfsan.fda.gov/~dms/dalbook.html

A grain elevator owned by the Frontier Cooperative loads rail cars with corn

by N

atiH

arni

k, A

P

Risks vs Benefits

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Health Statistics• Measurement: DALY

– DALY = Disability-Adjusted Life Year

– DALY = one lost year of “healthy” life; measurement across the population (burden of disease) assesses gap between current health status and an ideal health situation (population is disease and disability free, lives to advanced age)

– DALY = YLL (Years of Life Lost) + YLD (Years Lost due to Disability)

• YLL = N (number of deaths) x L (standard life expectancy at age of death in years)

• YLD = I (number of incident cases) x DW (disability weight) x L (average during of the case until remission or death [years])

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http://www.who.int/healthinfo/global_burden_disease/metrics_daly/en/Accessed August 19, 2015

• Compares and ranks risks from multiple combinations of foods and contaminants (microbial and chemical)

• Predicts effectiveness of interventions at any step of food-supply chain, from farm to consumer

• Calculates public-health outcomes of food production, processing or handling practices, and interventions

• Is useful for prioritizing, decision-making, resource allocation

18http://www.fda.gov/downloads/Food/FoodScienceResearch/UCM316705.pdfAccessed August 19, 2015


Dr. Clemens 4

Quantitative Predictive Risk Assessment Model (QPRAM)

• UC Davis-based studies– Multi-year study in Salinas Valley

– Collected real-world data on E. coli O157:H7 contaminated lettuce

– Data indicated 5-day interval between final irrigation and harvest plus removal of outer leaves significantly reduced microbial contamination

– Data contributed to development of transfer coefficients – rates of pathogen transfer from soil to crops – to inform Produce Risk model for CFSAN

19http://wcfs.ucdavis.edu/current_research.phpAccessed: August 19, 2015

Virtual Deli

• Scenarios– Worker Behaviors, Sanitation and Cross

Contamination (16)

– Temperature Control and Growth Inhibition (6)

20Interagency Retail Listeria monocytogenes Risk Assessment Workgroup, May 2013

Virtual Deli

21Interagency Retail Listeria monocytogenes Risk Assessment Workgroup, May 2013

• Effect of various sanitation mitigation scenarios on the mean risk per serving and relative risk in the susceptible population in a retail deli with multiple niches.

• The bottom graphs show the prevalence of L. monocytogenes in RTE products and the estimated risk of listeriosis.

• The top graphs present the relative change (%) in estimated prevalence per serving and in the estimated risk of listeriosis per serving relative to the baseline.

• The absence of sanitation greatly increases the estimated prevalence of L. monocytogenes in the sold RTE product

• No sanitation increases estimated risk by 41%

BRAFO (Benefit-Risk Analysis of Foods)

• Developed a framework to quantitatively compare human health risks with the benefits of foods and food compounds

• Assessment scale based on quality-adjusted life years (QALY)- or disability-adjusted life years (DALY)-like methodology

• Initial study groups– Natural foods like oily fish and soy – Macronutrient replacement agents

e.g. sweeteners, fat substitutes – The impact of heat processing on foods

22Hoekstra et al., Food Chem Toxicol 2012;50:S684-98



• Tier 1 – risk and benefit assessed independently

• Tier 2 – risks and benefits compared without common metric

• Tier 3 – risks and benefits integrated quantitatively in a common metric by a deterministic approach

• Tier 4 – risks and benefits are integrated quantitatively in a common metric by a probabilistic approach




Dr. Clemens 5


• Common sources of uncertainty– Those affecting problem formulation (e.g., intake,

population(s))

– Those affecting hazard and benefit identification (e.g., relevant nutrients, contaminants, health endpoints)

– Those affecting intake assessment (e.g., concentration, report bias, extrapolation from unmeasured foods, degree of uptake, compliance)


Benefit-Risk Analysis of FoodsFarmed Salmon – Tier 1

Health Effect ChangeQuality of Evidence

Strength of Evidence

PopulationHealth Impact

Incidence of death from CHD

Reduced incidence or fatal MI or CVA

Convincing Strong Adults > 50yo Beneficial

Healthy infant development

Increase IQ and visual acuity

Possible Small Infants Beneficial

Cancer incidence

No effect on incidence

Probable Small AdultsBeneficial or adverse

Improved cognitive functions

Reduced incidence of dementia/Alzheimer’s disease

Possible Small Adults Beneficial

Prevention of AMD

Reduced incidence of AMD

Possible Small Adults Beneficial

Impaired infant development

Decrease in IQ Possible Small Infants Adverse

26Watzl et al., Food Chem Toxicol 2012;50:S699-709

Benefit-Risk Analysis of FoodsAcrylamide – Tier 1

Health Effect ChangeQuality of Evidence

Strength of Evidence

PopulationHealth Impact

Reduced probable cancer risk

Acrylamidereduction by 30‐50%

Medium Medium Mostly > 50 yo Beneficial

Kidney issuesIncreased Ca intake

LowNegligible (intakelow relative to background)

Total population

None

Improved bone health

Increased Ca intake

HighLow (intake low

relative to background)

Total population

Beneficial

Increased risk of HTN and associated CVD

Increased Na intake

Medium – High Increase Mostly > 50 yo Adverse

Increased probably cancer risk

Increased 3‐MCPD* intake

Medium(animal data

only)

Negligible (increase will not exceed current

TDI)

Total population

None

* 3‐MCPD: 3‐monochloropropane‐1,2‐diol27

Schütte et al., Food Chem Toxicol 2012;50:S724-35

• Most of the major countries of the world have advised consumers to follow the dietary recommendations for a balanced diet issued by their food regulatory and public health agencies.

• The data available to date have been insufficientto warrant any recommendation for a significant change in the dietary recommendations because of acrylamide.

• Current epidemiological and toxicological evidence are insufficient to indicate that the amounts of acrylamide consumed in the normal diet are likely to result in adverse human health effects, particularly cancer.

Acrylamide in Foods

Lineback et al., Ann Rev Food Sci Technol 2012;3:15-3528

“HEATOX” (Heat-Generated Food Toxicants) Report

• Conclusions– Current knowledge does not allow for a risk-benefit

assessment of cooking with respect to acrylamide or other heat-induced toxicants

– Risk-benefit assessments should be performed; therefore, there is a need or harmonized protocols

• Current Understanding– Health-protective compounds are also produced by

heating foods– Health benefits of the heated foods

themselves• Confronting Health

– “Protective” health effects must be considered in the risk-benefit evaluation process

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IFT Expert Report• Examined US and international Legal and

Regulatory Frameworks governing the safety of the food supply

• Evaluated the process by which the nature and size of real or potential risks are determined, especially when data are incomplete

• Evaluated consumer exposure assessments• Evaluated spectrum of risk-benefits

of whole foods (e.g., methyl Hg vs seafood benefits; Maillard products [acrylamide, coffee])

• Approaches to Risk Communication

30Bidlack et al., Comp Rev Food Sci Food Safety 2009;8:269-303


Dr. Clemens 6

• Risk Communication– Develop best practices for active engagement of

multiple audiences in effective communications prior to, during and after potentially catastrophic food bioterrorism incidents

– Understand characteristics that influence behavior

– Establish real-time, data-based feedback through national media tracking and social networking

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https://www.ncfpd.umn.edu/research/risk-analysis/risk-communication-resources/Accessed: August 19, 2015

Single Toxic Substance Communications

• Consumer confidence in food is eroded by media scares• Scarce resources do not always go to the most critical

risks (e.g., trace chemicals vs microbial or nutrient threats)

• Disruption of business and international trade• Analytical advances drive detection levels to near “zero”• High-dose animal testing identifies potential problems

following unrealistic exposure by humans• Insufficient resources to chase all substances in food

(natural or otherwise)• Need toxicological harmonization to some biologically

insignificant level of a substance and the benefits of the whole food

32Courtesy of J. Coughlin

Window of Benefit Assessment

33Palou et al., Crit Rev Food Sci Nutr 2009;49:670-80

• The window of benefit integrates nutritional optimization and safety considerations. Its optimal adequacy will vary between individuals and within an individual during his/her lifetime, depending on age, sex, lifestyle and genetic constitution.

• It holds on to threshold values, but introduces two new values: the lower level of additional benefit (LLAB) and the upper level of additional benefit (ULAB).

• No further detectable benefit can be seen from intakes below or above these thresholds, respectively.An increase in the intake of a food or food component

will result in the following subsequent physiological conditions: deficient, adequate, beneficial, adequate, and toxic.

Characteristics of Regulatory Benefit

Characteristic Benefit Assessment Risk Assessment

Study design Experimental (observational may be accepted)

Experimental (observational may be accepted)

Study population Human Animal (human is possible)

Widely accepted methodology In development (see ICH guidelines)

Yes

Widely accepted endpoints In development; measured as reduction in adverse endpoint(s)

Yes

Exposure Usually few doses in experimental study; physiologicaldoses/observational design may be accepted

Usually few doses in experimental study

Study duration Usually short (weeks/days) in experimental design; longer periods in observational studies

Usually lifetime of animal until adverse endpoint occurs

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Tijhuis et al., Food Chem Toxicol 2012;50:5-25

Characteristics of Regulatory Benefit

Characteristic Benefit Assessment Risk Assessment

Evidence required Grading “convincing” (sometimes “probable” admitted in weight of evidence approach

Strongest effect (steepest slope in positive evidence approach)

Desired outcome in benefit‐risk assessment setting

Benefit characterization, including low dose‐response information

Risk characterization, including low dose‐response information

Desired outcome in regulatorysetting

Benefit/no benefit Safe/unsafe or acceptable/non‐acceptable

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Tijhuis et al., Food Chem Toxicol 2012;50:5-25

Risk-Benefit Evaluation

• Health benefits of whole foods may outweigh effects of trace levels of animal carcinogens and other toxicants in these foods

• Need methods to quantitatively assess the benefits of whole foods

• Global action steps for public health and regulatory authorities– Use improved risk assessment methodologies

– Assess whole foods, not just individual food chemicals

– Consider health benefits of foods, especially heated foods

– Keep major focus on nutritional and microbial risks

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Courtesy of J Coughlin


Dr. Clemens 7

Questions?

• What are the three major components of risk analysis?

• What are the four steps in the risk assessment process?

• What are the four key elements of risk management?

• What is a critical component in risk communications?

• What is the current position with the FDA regarding risk-benefit analysis?

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Questions?• What are the three major components of risk analysis?

Assessment, Management, Communications• What are the four steps in the risk assessment process?

Hazard Identification, Hazard Characterization, Exposure Assessment, Risk Characterization

• What are the four key elements of risk management? Conduct preliminary risk management activities, Identify and select risk management options, Implement risk management decisions, Monitor and review risk management actions

• What is a critical component in risk communications? Active engagement and exchange of information among all stakeholders

• What is the current position with the FDA regarding risk-benefit analysis? Primary outcome is consumer safety; FDA has several draft guidance documents on this topic. Key elements include type, magnitude and duration of benefits while weighing the uncertainties among intended populations

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risk assessment – under the consumers’ and regulatory microscopeasq.org › fdc › 2015 › 11...

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