Doug Popken a & Tony Cox b Presented to the Nick Petry Workshop Dec 2013 a. Systems View b. Cox...
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The Good, the Bad, and the Ugly: Risk Analysis of Food Safety Doug Popken a & Tony Cox b Presented to the Nick Petry Workshop Dec 2013 a. Systems View b. Cox Associates
Doug Popken a & Tony Cox b Presented to the Nick Petry Workshop Dec 2013 a. Systems View b. Cox Associates
Doug Popken a & Tony Cox b Presented to the Nick Petry
Workshop Dec 2013 a. Systems View b. Cox Associates
Slide 3
Introduction Quantitative Risk Assessments provide an objective
means of evaluating risks in food safety and many other areas.
Ideally, by relying upon facts and data, rather than anecdotes,
emotions, and assumptions, they will guide policy makers to the
right decisions In reality, faulty methodology and hidden agendas
often distort conclusions.
Slide 4
The Ugly Ractopamine is used in a number of countries as a feed
additive to stimulate the production of muscle mass, reduce fat
mass, and improve feed efficiency in swine, cattle, and turkeys at
doses of 520 mg/kg of feed. Many (80) countries, including Russia
and the EU, currently ban the use of ractopamine as a feed additive
but it is allowed in 27 others, including the U.S., Canada, Mexico,
Japan, and South Korea under tight limits. The EU recently
developed new safe-use standards that are somewhat tighter than
those in the U.S. The U.S. and the EU would like to export more
pork to Russia. The Russians would like to prevent/stall this on
the grounds that foreign pork could be contaminated with
unacceptably high levels of ractopamine. We were asked by the
USDA/US Pork Board to evaluate the Russian risk assessment:
ASSESSMENT OF THE HEALTH RISK TO THE POPULACE FROM EXPOSURE TO
RACTOPAMINE FROM FOOD ANIMAL HUSBANDRY The Russian ractopamine
report argues for retaining a complete ban on animal products
containing any amount of ractopamine residue.
Slide 5
Russian Study Cites Carcinogenic Risk Based on a study of rats
fed ractopamine for 21 months at various levels The numbers of rats
that developed uterine hyperplasia (benign growths on uterine
lining) at each dosage level were observed. A dose-effect function
was developed from the data and extrapolated to cancer risk of
human dosages obtained from consuming pork.
Slide 6
Problem 1: Lack of Causal Link The induction of mesovarian
leiomyomas in mice and rats also appears to be a general feature of
b-adrenergic stimulants, as shown for various other b2-agonists
such as salbutamol [asthma, COPD relief] and terbutaline
[anti-contraction medication]* ..Ractopamine, like other
b-adrenerigic sympathomimetics, is therefore not a direct
carcinogen and the induction of leiomyomas is considered to be a
non-genotoxic event with a threshold, similar to other
toxicological end-points* What does this have to do with human
cancer risks? *JECFA. 2004. Toxicological evaluation of certain
veterinary drug residues in food. WHO Food Additive Series 53.
Ractopamine (Addendum). Prepared by the Sixty-second meeting of the
Joint FAO/WHO Expert Committee on Food Additives (JECFA).
http://whqlibdoc.who.int/publications/2004/9241660538_ractopamine.p
df
http://whqlibdoc.who.int/publications/2004/9241660538_ractopamine.p
df
Slide 7
Problem 2: Inappropriate Dose- Effect Model Raw Data Linear
Regression Model Dose, g/kg of body mass per day # rats Number of
response instances (uterine hyperplasia) Probability of developing
uterine hyperplasia in rats 06000 2,0006000 60,0006030.0500
200,00060170.2833 400,00060250.4167 Hint: In the U.S., the ADI
(Acceptable Daily Intake) is set at 1.24 g/kg body weight/day
Slide 8
Russian Study Cites Cardiovascular Risk Relies upon studies
from human volunteers that demonstrate heart rate increasing with
dosage. Parameters from the resulting dose-effect function are fed
into a system dynamics model that estimates cumulative effects The
model output provides # cases by age cohort, assuming lifetime
exposure
Slide 9
Problem 3: Inappropriate Dose- Effect Model (again) Raw Data
Linear Regression Fit Dose (mg)Dose (g/kg)* Ratio of Dose to U.S.
ractopamine ADI Change in bpm relative to control 0 0 00 5 67 53.60
10 133 106.40 15 200 16020 25 333 266.430 40 597 477.650
Slide 10
Problem 4: Fudging the Data Refer back to previous slide Note
that the regression is based on only 4 of 6 points, that is, the
groups with no effect for 5 and 10 mg doses were removed from the
regression. This was not justified or even mentioned in the study
but we verified the regression parameters result from a fit that
removes those two levels.
Slide 11
Problem 5: Unrealistic Evaluation Scenario The Russian models
for cancer and cardiovascular risk require an assumed input level
for ractopamine consumption The level chosen in their study was
based on the assumption that all meat products consumed by all
Russians over their entire life time will contain ractopamine
residue at the maximum regulatory limit (as set by the European
Codex Alimentarius Commission ).
Slide 12
Problem 6: Inconsistent Logic Note that even the extreme usage
scenario (previous slide) results in an average daily dose of only
0.0371 g/kg versus the U.S. ADI of 1.24 g/kg. The U.S. ADI is based
on a safety factor of 54 times below the computed No Effects Level
of the human volunteer study. The Russian RA rejects using the
results from the human volunteer study for computing a safety
factor (not enough data, not enough time, improper methodology,
etc). Note that the computed Russian average daily dose is
equivalent to a safety factory of 1806, but its still not enough
for them. However, their entire cardiovascular analysis is based on
a dose-effect parameter they derived from that same study.
Slide 13
The Bad Tetracycline antibiotics are used in the treatment and
prevention of bacterial infections of both human and animals. In
animal husbandry, they are used as therapeutic and veterinary
drugs, and also as a feed additive for disease prevention and feed
efficiency. Used as a feed additive in the U.S. since the early
50s. Sub- therapeutic use banned in the EU in 2006 under the
precautionary principle. We were asked by the USDA/US Pork Board to
review a risk assessment performed by Kazhakstan: "Materials for
Human Health Risk Assessment of Tetracycline Intake with Food The
report argues for a lower limit on maximum tetracycline residues in
food animals than other international authorities and scientists
have considered prudent.
Slide 14
Problem 1: Lack of knowledge and effort About 80% of the KZ
risk assessment was a virtual cut and paste from a Russian risk
assessment we evaluated last year (Lesson: Know your subject).
Slide 15
Problem 2: Association does not equal Causation Normal
microflora are critical to the function of the human body. The
proportion of the intestinal microflora may change under the
influence of tetracycline. A number of diseases (irritable bowel
syndrome, diarrhea, constipation, inflammatory bowel disease,
duodenitis, food allergies, atopic dermatitis, anemia,
immunodifficiency, etc.) are related to imbalance of the intestinal
microflora. Therefore, tetracycline residues cause a number of
human diseases. Their core logic:
Slide 16
Problem 3: Rejecting Accepted Scientific Findings with Weak
Rationale WHO recommends an ADI for tetracylines of 30 g/kg of body
weight. The KZ tetracycline assessment advocates using an earlier
standard of 3 g/kg of body weight. The new standard is based on the
results from relatively recent in-vitro studies. As was the case
with Russia, KZ bucks the international consensus by claiming that
the in-vitro studies are invalid and cannot be extrapolated to
humans.
Slide 17
Problem 4: Undefined, Non-validated Model Results presented
without describing how they were produced We know this was lifted
from a Russian RA completed last year They are outputs of a
simulation model The underlying system dynamics equations came from
a Russian PhD thesis. Figure 1 - The dependence of the relative
abundance of the intestinal microflora (%) on the concentration of
tetracycline
Slide 18
Problem 5: No defined hazard The KZ report stops after
presenting the simulation results. Apparently this graph of
dysbiosis is all the proof that is needed. Even the Russian RA went
on to tie a model of disease generation rates to the bacterial
(dis)proportions, based on Russian population studies to quantify
effects. Lacking a similar study for KZ, their RA merely stops and
jumps right to the conclusions.
Slide 19
The Good Cox Associates and Systems View performed a risk
assessment for the USDA/Pork Board quantifying the human health
risk from MRSA in pork. Human MRSA is typically spread in
hospitals, and causes damaging, hard to treat infections, with a
high mortality rate. A new strain of MRSA, ST398, was detected in
U.S. swine and swine farm workers in 2008, and some years prior in
Europe. Alarms were raised! MRSA is in our food!
Slide 20
KATIE COURIC RIPS INTO AG FOR OVERUSE OF ANTIBIOTICS Katie
Couric took down big livestock farming last night on CBS, with that
simple, explain-it-to-me cheeriness with which she took down Sarah
Palin last year. In the first of a two part series on
antibiotic-use in American agriculture, Couric repeatedly linked
routine livestock antibiotics to the rise of drug-resistant staph
(MRSA): A University of Iowa study last year, led by the brilliant
Tara C. Smith, found a new strain of MRSA in nearly three-quarters
of hogs (70 percent), and nearly two-thirds of the workers (64
percent) on several farms in Iowa and Western Illinois. All of them
use antibiotics, routinely. On antibiotic-free farms no MRSA was
found. [Since then, high levels of ST398 has been found on numerous
antibiotic-free farms] And with this anecdote: Former hog worker,
Kim Howland took CBS News inside a factory farm in Oklahoma where
she worked two years ago. They administer drugs, you know,
constantly, constantly, constantly, Howland said. Thats their fix
for everything. She said drugs like Tylan, Keflex, and Baytril, the
same classes used to treat everything from skin to respiratory
infections in humans were given regularly to pigs that were not
sick. Her husband contracted MRSA and almost died. [Turns out it
was not ST398 see next slide]
http://fairfoodfight.com/2010/02/10/katie-couric-rips-ag-overuse-
antibiotics / Public perception
Slide 21
Do: Take a Deep Breath Hospital deaths with ST398 MRSA U.S.
cases = 0 Worldwide cases = 1 possible (Lozano, 2011) Hospital
outbreaks of ST398 MRSA 1 instance (maybe), in Netherlands (Wulf et
al., 2007) Community outbreaks of ST398 MRSA 0 instances reported
worldwide Invasive infections with ST398 MRSA U.S. cases = 0 EU
cases < 10
Slide 22
Do: Clearly Define the Potential Hazard Colonization among meat
handlers and swine handlers, followed by infection, is the main
risk of practical concern. ST398 Colonization ST 398 Infection is
hypothesized (worst-case assumption) but not observed This project:
Quantify how large these human health risks could be for Pig
farmers Professional meat handlers Consumers in general public
Slide 23
Do: Define a stochastic causal model: (workers) Swine herd
colonization rate Number of Swine Herds Swine workers Colonized
workers P(worker colonization |swine colonization) Workers Per Herd
Infected workers P(infection| colonization
Slide 24
Do: Define a stochastic causal model (consumers) Number of US
families Colonization among Dutch meat handlers Colonization among
US meat handlers Colonized consumers Pork attributable fraction
Infected P(infection| colonization US/Netherlands ratio of MRSA on
pork US/Netherlands ratio of pork processing Handler/consumer pork
contact ratio Pork handlings/ family/year
Slide 25
Do: Populate model with conservative distributions based on
real data Assume transmission (arrows) may occur even if not
specifically observed Develop probability distributions from known
data (scientific reports, surveillance data, etc.) Use
conservative, bayesian distributions with noninformative priors,
e.g. betabinomial(s+1,n-s+1), mean = (s+1)/(n+2) [Note: this is
very handy when there have been no observations (s=0)]
Slide 26
Do: Develop output distributions via simulation Perform large
numbers of simulations of the stochastic model Each run utilizes a
new random value for each distribution. Final output is a
probability distribution of the conservative estimate Mean
infections in U.S. = 1.00/yr (.968 pig farm workers,.024 food
handlers,.008 consumers)
Slide 27
The Good Cox Associates and Systems View performed a risk
assessment for the USDA/Pork Board quantifying the human health
risk from Toxoplasma Gondii (T. gondii) in pork. Commonly found in
pork until the 90s. Most infected adult humans suffer few or no
detectable ill effects from toxoplasmosis (carried by ~ 9% of U.S.
adults). However, infection can be deadly for AIDS patients and
devastating for the unborn children of pregnant women (blindness,
retardation, chronic illness) Spread via cat feces to livestock
(and humans) Poultry and pork in open (e.g. free range) production
systems have greatly increased risk of T. gondii infection
Slide 28
Do: Clearly Define the Potential Hazard Infection risk is from
eating raw/undercooked pork (in the case of newborns, it is
transmitted from the mother). Risk is proportional to the
prevalence of T. gondii in pork. Numerous studies have shown that
the prevalence of T. gondii in pork is proportional to the fraction
of U.S. pork not raised in confinement.
Slide 29
Do: Define a stochastic causal model Prevalence among hogs in
confinement Prevalence among unconfined hogs Current Fraction of
unconfined hogs Number Infected Tuner Fraction of unconfined hogs
Population Size Prevalence in Pork P(Infection | Prevalence)
Slide 30
Do: Populate model with conservative distributions based on
real data Variety of papers and USDA studies on prevalence of T.
gondii in confined and/or unconfined hog populations Medical
articles on illness, hospitalization, and mortality rates Key
research article allowed us to convert numbers of illness by group
(adult, newborn) to potential QALYs lost (Quality Adjusted Life
Years)
Slide 31
Do: Perform simulations to obtain a range of possible outcomes
Outcome (Equation) Mean5%95% Total Cases
(3)37,027.0821,128.7556,698.22 Hospitalizations
(4)1904.72962.803173.62 Deaths (5)138.4071.07226.88 Congenital
Cases (6)40.4520.6666.55 Total QALYs (7)4036.722091.796587.93
Current T. gondii Annual Impacts Incremental QALYs Lost versus
Fractional Increase in Unconfined Hogs Equates to an average of 1
QALY lost per 676 hogs moved out of confinement (note approx. 6.5M
hogs are consumed/year)
Slide 32
Summary While many now at least give lip service to the value
of performing quantitative risk assessments, these can still be
done badly. You will often see association confused with causation,
even by scientists and analysts who should know the difference.
Facts and data are the best counters to fear and uncertainty