# Presentation: 830542

## Harvard Risk Assessment of Bovine Spongiform Encephalopathy (BSE)

- Joshua T. Cohen, Ph.D.
- The Center for the Evaluation of Value and Risk
- Institute for Clinical Research and Health Policy Studies
- Tufts New England Medical Center (NEMC)
- For the U.S. Department of Agriculture
- July 25, 2006

## Background

- Work conducted by Harvard Center for Risk Analysis (HCRA) using the Harvard BSE simulation model
- History of the Harvard BSE simulation model
- Delivered to USDA in November 2001
- Underwent a technical review by scientists outside of USDA*
- Finalized in October 2003*
- USDA Food Safety Inspection Service (FSIS) asked HCRA to
- Update the Harvard BSE model*
- To assess risks associated with introduction of BSE into the U.S.
- To assess the impact of risk management measures
- Analysis underwent formal independent peer review in Fall 2005 according to OMB information quality guidelines*

- *Reports, peer review comments, and response to comments available on the USDA/FSIS website

## Overview

- Model structure and enhancements
- Scenarios considered
- Base case
- Measures either taken or proposed to mitigate BSE risks
- Measures adopted by USDA after December, 2003
- Regulations considered by the Food and Drug Administration (FDA)
- Proposals advanced by the International Review Subcommittee
- Sensitivity analyses
- Results
- Conclusions

## 1.  Model Structure and Enhancements

## Harvard Model – October 2003 Risk Assessment

- Contamination

- Mislabeling

- Misfeeding

- Blood meal

- Other animals

- Rendering

- Export

## Model is Probabilistic

- Initialize Model

## Model Revisions - Motivation

- Update assumptions to represent conditions in the U.S. in December 2003, just prior to the discovery of the BSE-positive animal in Washington State
- Accommodate evaluation of additional risk mitigation measures
- Account for data on the presence of the BSE agent in cattle tonsils

## Updates

- How *Antemortem* (AM) inspection works
- Addition of tonsils as a tissue that can harbor the BSE agent
- Specified risk material (SRM) inspection allows for removal of tissues from dead animals, not just those that go to slaughter
- Feed control compliance estimates updated
- Contamination of bone-in-beef revised

## Update #1Antemortem Inspection

| Detect BSE Signs | AM Condemn | Human Food | Animal Feed |
| --- | --- | --- | --- |
| None Identified | Pass | OK | OK |
|  | Condemn | No | OK |
| Detected | Pass | No | No |
|  | Condemn | No | No |

- October 2003 Model

## Antemortem InspectionRevised Model

| Detect 
BSE Signs | AM Condemn | Ambulatory Status | Human Food | Animal Feed |
| --- | --- | --- | --- | --- |
| None Identified | Pass | Normal | OK | OK |
|  |  | Non-Amb | OK | OK |
|  | Condemn | Normal | No | OK |
|  |  | Non-Amb | No | OK |
| Detected | Pass | Normal | No | No |
|  |  | Non-Amb | No | No |
|  | Condemn | Normal | No | No |
|  |  | Non-Amb | No | No |

- Clinical
- Status

- Animal
- Age

## Detection of BSE Clinical Signs

- BSE clinical signs more likely to be detected among ambulatory animals
- Ambulatory – AM inspection detects 95% of animals with BSE clinical signs
- Non-ambulatory – AM inspection detects 85% of animals with BSE clinical signs
- Fraction of animals that are non-ambulatory
- For animals that have not reached clinical status: 0.5%
- For animals that have reached clinical status: 8%

## Update #2BSE Infectivity in Tonsils

- October 2003 model
- No infectivity in tonsils
- Revised model
- Assumes 0.2% of total carcass infectivity is in cattle tonsils

## Update #3SRM Inspection

- October 2003 Model
- SRM inspection removes tissues only from animals that are sent to slaughter
- 2005 revised model for FSIS
- Revised model assumes SRM tissues are also removed from animals that die prior to slaughter

## Update #4Ruminant Feed Control Compliance Rates

- Mislabeling of meat and bone meal (MBM) or feed known to have ruminant protein as “non-prohibited”
- Cross-contamination of non-prohibited production lines in plants that process both prohibited and non-prohibited materials

## FDA Compliance Data

|  | Inspected | Cited for Mislabeling |  | Cited for Comingling |  |
| --- | --- | --- | --- | --- | --- |
| Facility Type | (N) | (N) | % | (N) | % |
| Renderers | 171 | 4 | 2.3% | 3 | 1.8% |
| Feed mills |  |  |  |  |  |
|      Licensed mills | 370 | 8 | 2.2% | 2 | 0.5% |
|      Non-licensed mills | 1224 | 55 | 4.5% | 28 | 2.3% |
|      Total mills | 1594 | 63 | 4.0% | 30 | 1.9% |

## Assumptions for Mislabeling and Cross-Contamination

|  | MBM Production |  | Feed Production |  |
| --- | --- | --- | --- | --- |
|  | Base Case 2003 | Base Case Revised | Base Case 2003 | Base Case Revised |
| Contamination probability | 14% | 1.8% | 16% | 1.9% |
| Proportion of prohibited material transferred to non-prohibited per contamination event | 
0.1% | 
0.1% | 
0.1% | 
0.1% |
| Mislabeling probability | 5% | 2.3% | 5% | 4% |

## FDA Compliance Data May Overstate Non-Compliance 

- Data indicate proportion of _facilities_ with at least 1 rule violation, which can be greater than proportion of _material_ processed in violation of rules
- Data from September 2003 and earlier are likely to overstate feed control _non_-compliance rates after identification of the BSE positive animal in Washington State in December 2003

## Update #5Bone-in-Beef Contamination

- Both models
- For animals 12 months and older
- 30% of infectivity in spinal cord ends up in bone-in beef if the spinal cord is not removed prior to splitting
- October 2003 Model
- Bone-in beef cuts (like T-bone steaks) are restricted to animals under the age of 24 months
- Hence, model _effectively_ assumed 30% of spinal cord infectivity deposited in bone-in-beef for animals of age 12-23 months
- Revised model
- When spinal cord not removed, 30% of spinal cord infectivity deposited in bone-in-beef for animals extended to animals 24 months and older

## 2.  Scenarios Considered

- Base case
- “What-if” scenarios
- Sensitivity analyses

## Base Case

- October 2003 assessment
- Introduction of 10 infected animals
- Simulate 20 years post introduction
- 5,000 simulation trials
- Current assessment
- Same base case with 750,000 simulation trials
- Run time: 4 weeks

## Achieving Precision in Less Time

- Introduce 500 infected animals at the beginning of each trial and conduct 50,000 trials
- Arithmetic mean for original base case results can be estimated
- Divide inflated base case results by 50
- Why it works
- The introduction of each infected animal is an independent event
- Total events scale linearly with the number of infected animals introduced

## Empirical Evidence of Linear Scaling

| Statistic | 10 Animals | 500 Animals | Ratio |
| --- | --- | --- | --- |
| Epidemic statistics
Total infected
Total infected w/o imports
Total clinical | 
14
3.5
4.3 | 
680
180
210 | 
49
51
49 |
| Mode of infection
Maternal
Protein
Blood | 
0.54
3.0
0.010 | 
27
150
0.53 | 
50
50
53 |
| ID50 Sources
From slaughter
From death on farm | 
7,400
34,000 | 
370,000
1,800,000 | 
50
53 |
| Disposition of ID50s
Total to cattle
Total potential humans | 
65
75 | 
3,400
3,800 | 
52
51 |
| Human exposure
Brain
Advanced meat recovery
Tonsils | 
14
32
0.028 | 
710
1,600
1.5 | 
51
50
54 |

- Note: Reported statistics are rounded to 2 sig. figures

## Rationale for the Inflated Base Case

- Precision and speed
- Precision depends on total number of infected animals introduced
- Execution time depends mostly on number of trials

| Infected Animals Introduced | Trials | Total Infected Animals Introduced | Execution Time on a 2.8 GHz PC |
| --- | --- | --- | --- |
| 10 | 750,000 | 7.5 million | ~ 28 days |
| 500 | 50,000 | 25 million | ~ 3 days |

- Note – Percentiles do not scale.

## “What-if” Scenarios

- USDA/FSIS
- FDA
- The International Review Subcommittee

## USDA/FSIS Scenarios

- Prohibit for use as human food of all non-ambulatory cattle
- Prohibit the use of SRMs for human consumption
- Brain, skull, eyes, trigeminal ganglia, spinal cord, vertebral column, dorsal root ganglia from cattle 30 months and older
- Small intestines and tonsils from all cattle
- Prohibit the use for human food of
- Meat collected from vertebral column using advanced meat recovery (AMR) from cattle 30 months of age or older
- Mechanically separated meat from all cattle

## FDA Scenarios

- Prohibit the use of ruminant blood in ruminant feed
- Requirement of dedicated lines for production of animal feeds or meat and bone meal in facilities that also produce materials designated for non-prohibited uses

## International Review Subcommittee Scenarios

- Prohibit the use of SRMs for human consumption or animal feed
- Cattle 12 months of age or older: brain, spinal cord, vertebral column
- All cattle: Intestine
- Assume applicability of rule to both slaughtered and animals that die prior to slaughter
- Assume perfect compliance
- Results provide an upper bound on impact of strategy
- Prohibit the use of _any_ MBM in ruminant feed

## Sensitivity Analyses

| Scenario | Parameter | Base Case | Sensitivity Analysis |
| --- | --- | --- | --- |
| 1 | Renderer – contamination probability
Renderer – mislabel probability
Feed producer – contamination probability
Feed producer – mislabel probability | 1.8%
2.3%
1.9%
4% | 14%
5%
16%
5% |
| 2 | Proportion of correctly labeled prohibited feed administered to cattle (misfeeding) | 1.6% | 15% |
| 3 | Rendering technology - %
Batch (3.1 log reduction)
Continuous – fat added (2 log reduction)
Continuous – no fat added (1 log reduction)
Vacuum (no reduction) | 
5%
45%
45%
5% | 
5%
20%
70%
5% |

## Sensitivity Analyses

| Scenario | Parameter | Base Case | Sensitivity Analysis |
| --- | --- | --- | --- |
| 4 | Proportion of bone-in-beef consumed
Cattle 0 to 23 months
Cattle 24 to 29 months
Cattle 30 months and older | 
70%
50%
25% | 
100%
90%
45% |
| 5 | Probability of detecting BSE clinical signs at antemortem inspection
Normal ambulatory status
Nonambulatory | 

95%
85% | 

50%
25% |
| 6 | BSE incubation period
Median incubation period (months) | 
~ 50 | 
~ 100 |

## Sensitivity Analyses

| Scenario | Parameter | Base Case | Sensitivity Analysis |
| --- | --- | --- | --- |
| 7 | Proportion of cattle that are non-ambulatory
Pre-clinical cattle
Clinical cattle | 
0.5%
~ 8% | 
0%
~ 8% |
| 8 | Proportion of cattle that are non-ambulatory
Pre-clinical cattle
Clinical cattle | 
0.5%
~ 8% | 
0.5%
100% |

## 3.  Results

- Key output statistics
- Base case
- Measures to mitigate BSE risks
- Sensitivity analyses

## Key Output Statistics

- Question 1 – To what extent are humans potentially exposed to the BSE agent?
- Simulation output: Potential human exposure to the BSE agent, quantified in terms of cattle oral ID50s
- Value represents _potential_ human exposure
- Question 2 – To what extent does BSE spread among cattle in the U.S.?
- Number of cattle that become infected with BSE _after_ the initial introduction
- The disease reproductive constant, designated “R0.”

## Key Output StatisticsR0: Disease Reproductive Constant

- R0 is the average number of new BSE cases resulting from each incident BSE case
- For R0 = 2
- Initial condition – Introduce 1 case
- Generation 1 – 2 more cases
- Generation 2 – 4 more cases
- Generation 3 – 8 more cases
- ...

## R0: Disease Reproductive Constant

- Whether R0 > 1 is critical

## R0 - Continued

- R0 is estimated as “N” divided by “D” where
- N = Number of newly infected BSE cases over the course of the simulation (i.e., excluding cases introduced)
- D = Number of BSE cases that die during the course of the simulation

## Model is Probabilistic

- Initialize Model

## Other Statistics Reported by Simulation

- Mode of infection – maternal, spontaneous
- protein, blood, imports

- Epidemic statistics – Cattle infected,
- clinical cases, R0

- Mode of death – Slaughter, on farm

- ID50 sources – from slaughter or from
- animals that die on the farm

- Disposition of ID50s – How they
- are processed and whether they are
- administered to cattle or are
- potentially available for human
- consumption

- BSE agent in human food by tissue

## Other Statistics Reported by Simulation:Evolution of Agricultural System Over Time

## Base Case Results**

|  | Mean |
| --- | --- |
| New Cattle Infected | 3.5 |
| Potential Human Exposure | 75 |

- Introduce 10 infected animals – 750,000 simulation trials

- Introduce 500 infected animals – 50,000 simulation trials

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| New Cattle Infected | 180 | 33 | 98 | 160 | 240 | 400 |
| Potential Human Exposure | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,700 |

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| New Cattle Infected | 3.5 | 0 | 0 | 0 | 1 | 11 |
| Potential Human Exposure | 75 | < 0.01 | 0.07 | 2.6 | 46 | 320 |

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| New Cattle Infected | 3.5 | 0 | 0 | 0 | 1 | 11 |
| Potential Human Exposure* | 75 | < 0.01 | 0.07 | 2.6 | 46 | 320 |
| R0 | 0.087 | 0 | 0 | 0 | 0.091 | 0.52 |

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| New Cattle Infected | 180 | 33 | 98 | 160 | 240 | 400 |
| Potential Human Exposure | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,700 |
| R0 | 0.24 | 0.062 | 0.16 | 0.24 | 0.33 | 0.45 |

|  | Mean |
| --- | --- |
| New Cattle Infected | 180 |
| Potential Human Exposure* | 3,800 |

- * Potential human exposure expressed as cattle oral ID50s over 20 years
- ** Results rounded to 2 significant digits

## Precision500 Animals Introduced – 50,000 Trials*

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| Lower 2.5% Bound | 178 | 33 | 97 | 154 | 241 | 396 |
| Central Estimate | 179 | 33 | 98 | 156 | 243 | 400 |
| Upper 97.5% Bound | 180 | 34 | 99 | 158 | 246 | 403 |

- 95% Confidence Interval – Number of New BSE Infections

- 95% Confidence Interval – Potential Human Exposure

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| Lower 2.5% Bound | 3,760 | 1,580 | 2,390 | 3,180 | 4,410 | 8,580 |
| Central Estimate | 3,780 | 1,590 | 2,400 | 3,190 | 4,440 | 8,660 |
| Upper 97.5% Bound | 3,800 | 1,610 | 2,410 | 3,210 | 4,470 | 8,770 |

- *Results rounded to 3 significant digits to make evident distinction between central and bounding
- estimates

## Measures to Mitigate BSE Risks:New BSE Cases

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| BASE CASE | 180 | 33 | 98 | 160 | 240 | 400 |
| USDA/FSIS |  |  |  |  |  |  |
|    No non-ambulatory to food | 180 | 33 | 98 | 160 | 240 | 400 |
|    No SRMs (30 mo+) to food | 180 | 33 | 98 | 160 | 250 | 400 |
|    No AMR (30 mo+) to food | 180 | 33 | 97 | 160 | 240 | 400 |
| FDA |  |  |  |  |  |  |
|    No cattle blood to cattle feed | 180 | 33 | 98 | 160 | 240 | 400 |
|    Dedicated prohibited prod. lines    | 180 | 33 | 97 | 160 | 240 | 400 |
| Int. Review Subcomm. |  |  |  |  |  |  |
|    No SRMs (12 mo+) to food/feed | 35 | 19 | 25 | 30 | 38 | 71 |
|    No MBM to cattle feed | 170 | 32 | 92 | 150 | 230 | 390 |

## Measures to Mitigate BSE Risks:Potential Human Exposure (Cattle Oral ID50s)*

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| BASE CASE | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,700 |
| USDA/FSIS |  |  |  |  |  |  |
|    No non-ambulatory to food | 3,700 | 1,600 | 2,400 | 3,100 | 4,400 | 8,500 |
|    No SRMs (30 mo+) to food | 11 | 2.7 | 5.8 | 8.6 | 12 | 20 |
|    No AMR (30 mo+) to food | 2,200 | 450 | 960 | 1,600 | 2,600 | 7,000 |
| FDA |  |  |  |  |  |  |
|    No cattle blood to cattle feed | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,600 |
|    Dedicated prohibited prod. lines    | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,600 |
| Int. Review Subcomm. |  |  |  |  |  |  |
|    No SRMs (12 mo+) to food/feed | 9.8 | 2.7 | 5.7 | 8.5 | 12 | 22 |
|    No MBM to cattle feed | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,600 |

- *Over a 20 year period

## Sensitivity Analyses:New BSE Cases

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| BASE CASE | 180 | 33 | 98 | 160 | 240 | 400 |
| 1.  Cross contam. + mislabeling | 200 | 38 | 110 | 180 | 270 | 440 |
| 2.  Misfeeding | 2,600 | 1,200 | 1,900 | 2,500 | 3,200 | 4,400 |
| 3.  Render technology | 240 | 38 | 130 | 210 | 330 | 530 |
| 4.  Bone-in-beef consumption | 180 | 33 | 97 | 160 | 240 | 400 |
| 5.  Antemort. detect of clinicals | 190 | 36 | 100 | 170 | 260 | 420 |
| 6.  BSE incubation period | 43 | 6 | 13 | 24 | 60 | 130 |
| 7.  Non-amb. proportion (low) | 180 | 33 | 97 | 160 | 240 | 400 |
| 8.  Non-amb. proportion (high) | 180 | 33 | 97 | 160 | 240 | 400 |

## Sensitivity Analyses: Potential Human Exposure (Cattle Oral ID50s)*

|  | Mean | 5th Pctl | 25th Pctl | Median | 75th Pctl | 95th Pctl |
| --- | --- | --- | --- | --- | --- | --- |
| BASE CASE | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,700 |
| 1.  Cross contam. + mislabeling | 3,800 | 1,600 | 2,400 | 3,300 | 4,500 | 8,700 |
| 2.  Misfeeding | 9,000 | 4,200 | 6,300 | 8,300 | 11,000 | 16,000 |
| 3.  Render technology | 4,000 | 1,700 | 2,500 | 3,400 | 4,700 | 8,800 |
| 4.  Bone-in-beef consumption | 4,500 | 2,000 | 3,000 | 3,900 | 5,300 | 9,400 |
| 5.  Antemort. detect of clinicals | 6,600 | 3,000 | 4,300 | 5,700 | 7,900 | 13,000 |
| 6.  BSE incubation period | 1,900 | 650 | 1,100 | 1,600 | 2,200 | 4,400 |
| 7.  Non-amb. proportion (low) | 3,800 | 1,600 | 2,400 | 3,200 | 4,400 | 8,700 |
| 8.  Non-amb. proportion (high) | 3,800 | 1,600 | 2,400 | 3,200 | 4,500 | 8,800 |

- *Over a 20 year period

## Conclusions (1)

- Under the base case:
- The model predicts that introduction of BSE into the U.S. will result in a minimal spread of disease
- R0 << 1
- Human exposure over 20 years < 100 cattle oral ID50s
- Human exposure in the UK likely to have been millions of cattle oral ID50s

## Conclusions (2)

- Risk mitigation measures
- The USDA/FSIS ban on SRM use in food (mostly for animals 30 months of age and older) has a substantial impact on potential human exposure
- Neither measure considered by FDA has a large impact on either human exposure or the spread of disease among cattle
- The International Review Subcommittee’s ban on the use of specified risk materials in either food or feed has a substantial impact on both potential human exposure and animal health

## Conclusions (3)

- Sensitivity analyses
- The most influential assumption in this analysis is the misfeeding rate
- R0 can reach 1.0 or more with 5% probability if the most pessimistic value is used for this assumption
- Even so, total human exposure remains relatively limited over the 20-year period
- Other parameters have a much smaller influence on the model-predicted outcomes

## Conclusions (4)

- In the absence of adopting any additional measures
- The U.S. agricultural system is able to limit the spread of BSE, if imperfectly
- Human exposure is limited
- A ban on use of specified risk materials has the biggest impact on the spread of BSE among cattle and human exposure
- The assumed misfeeding rate is the most important source of uncertainty in this analysis.