# Presentation: 335290

## Animal Cloning:  

**Larisa Rudenko,**** PhD DABT**
**Center for Veterinary Medicine**
**FDA/DHHS**

**Animal Cloning:  **
**A Risk Assessment**

**Conclusions for**
**Food Safety**

## The cloning risk assessment asked the following question: Are the edible products derived from animal clones and their progeny as safe to eat as the edible products derived from their conventional counterparts?

- Based on what we have presented, has the risk assessment adequately identified the hazards and characterized the risks related to food consumption?

## Criteria for Food Safety Evaluation

- Empiricisms, Biological Assumptions,
- Uncertainties, and Confidence

## Context for Data Evaluation: Two Pronged Approach

- Assume that regulations for
- conventional animals and food
- products apply to clones and their food products
**CBSA**
- Looking for subtle hazards
- Detailed examination of individual clones
**Composition Approach**
- Consideration of available data

## Interpretation of Conclusions from Qualitative Risk Assessments

- Qualitative, comparative risk assessment
- In science, certainty of safety approached, but never reached
- Strongest statement “likely to be as safe as”
- Comparator = conventional food animals
- What does it mean? As safe as food we eat every day.

## Presentation of Conclusions

- Species by species (except bovines)
- Weight of evidence evaluations
- Empirical observations for the species
- Consistency with other species
- Uncertainties
- Level of Confidence in conclusion

## Underlying Biological Assumptions for Clones and Progeny

- Food animals do not produce toxins
- No introduced genes from other sources
- Obviously malformed or diseased animals culled
- Subtle changes may pose hazards/risks
- Perinatal clones may fragile
- Gametogenesis naturally “clears” genome of inappropriate signals

## 
Species-Specific Analyses

- Species-Specific Analyses

**Conclusions for Food Safety**

## Comments on Developmental Node 1:  Cell fusion/ Fetal Development

**Probability of implanted embryo developing to viability low, but appears to be improving**
**High risk for developing animal**
**Lack of success likely due to two factors:**
**Technological ****(damage to o****ö****plast or donor)**
**Biological ****(incorrect reprogramming of donor genome)**
**Difficult to extrapolate from effects noted here to food consumption risks**

## CBSA: Perinatal Bovine Clones

**Perinatal clones may pose a limited risk for consumption as food.**
*Empirical:*
- Consistently reported relatively poor condition at birth; instability of physiological parameters
- Confidence in conclusions regarding safety of consumption of food from perinatal clones
- Moderate confidence with respect to risk in general, but individual animals may be healthy and similar to comparators
- Comments:
- Perinatal clones not likely intended as food source
- Economic drivers
- Rendering likely poses no feed risks

## CBSA: Juvenile Bovine Clones - 1

**Edible products from juvenile bovine clones are likely to be as safe to eat as those from non-clone juvenile cattle**.
*Empirical:*
- Cyagra survey and literature indicate
- Juvenile clones largely healthy and normal
- Exhibit appropriate physiological responses to developmental signals
- Early physiological instability resolves in this period
- No food consumption hazards detected in biochemical parameters

## CBSA: Juvenile Bovine Clones - 2

- Consistency with
- Underlying Biological Assumptions
- Other domestic livestock species
- Mouse model
- Uncertainties
- Very few
- Data set relatively large
- Consistent
- Confidence in Conclusions regarding health
- High
- Comments:
- Juvenile clones unlikely to be major producers of meat
- Economic drivers

## CBSA: Adult Bovine Clones - 1

**Edible products from adult bovine clones are likely to be as safe to eat as those from non-clone adult cattle**.
*Empirical:*
- Cyagra survey  healthy adult clones virtually indistinguishable from Comparators; earlier physiological instabilities resolved
- Literature results consistent (Chavatte-Palmer et al. 2002; Forsburg et al (2002), Pace et al. (2002)
- Information on reproductive function perfunctory, but indicates normal functionality

## CBSA: Adult Bovine Clones - 2

- Consistency with
- Underlying Biological Assumptions
- Other domestic livestock species
- Mouse model
- Uncertainties
- Very few; additional reproductive data could confirm cursory reports

## CBSA: Adult Bovine Clones - 3

- Confidence in Conclusions regarding health
- High
- Comments:
- Clones unlikely to be major producers of meat
- Economic drivers
- Milk from adult clones may enter food supply from lactating breeders

## Risk Statement for Adult Bovine Clones

- Initial position: Hypothesis 2
- Weight of Evidence   Hypothesis 1:
- Based on available evidence adult bovine clones do indeed appear to be biological copies of the donor
- Evidence confirming the health of clones is likely sufficient to show no additional risk from the consumption of clone edible products relative to  conventional comparators

## CBSA:  Swine Clones - 1

**Edible products from swine clones are likely to be as safe to eat as corresponding products from non-clone swine.**
*Empirical:*
- Data set more limited than for bovines
- Swine cloning appears difficult, but piglets appear healthy when born
- Behavior appears age appropriate and normal
- Health/physiological measures appear normal, and reflective of developmental function
- Animals not materially different from comparators

## CBSA:  Swine Clones - 2

- Consistency with
- Underlying Biological Assumptions
- Other domestic livestock species
- Uncertainties
- Additional data on reproductive function could confirm cursory reports
- Confidence in Conclusions regarding health
- Tempered by size of data set
- Archer et al. studies compelling; increase confidence
- Comments
- Clones unlikely to be major producers of meat

## Risk Statement for Swine Clones

- Initial position: Hypothesis 2
- Weight of Evidence   Hypothesis 1(minus):
- Relative high certainty that clones are not materially different from comparators, based on
- Biological consistency
- Small, but highly confirmatory data set

## CBSA:  Ovine Clones

**Insufficient information on the health status of ovine clones to draw conclusions.**
- Unable to find relevant publicly available reports

## CBSA:  Caprine Clones - 1

**Edible products from caprine clones are likely to be as safe to eat as corresponding products from non-clone goats.**
- Empirical:
- Data set small, but consistent
- Goats appear “cloning friendly”
- Behavior appears age appropriate and normal
- Health/physiological measures appear normal, and reflective of developmental function
- One small, but detailed study of normal reproductive function

## CBSA:  Caprine Clones - 2

- Consistency with
- Underlying Biological Assumptions
- Other domestic livestock species
- Uncertainties
- Would be decreased if preliminary report of physiological status were confirmed and expanded
- Confidence in Conclusions regarding health
- Tempered by size of data set
- Comments
- Clones unlikely to be major producers of meat

## Risk Statement for Caprine Clones

- Initial position: Hypothesis 2
- Weight of Evidence   Hypothesis 1:
- Relative high certainty that clones are not materially different from comparators, based on
- Biological consistency
- Small, but highly confirmatory data set
- High weight placed on study of reproductive function

## Progeny -1

**Edible products from the progeny**
**of healthy clones are likely to be**
**as safe to eat as those from **
**conventional animals.**
*Biological Assumption*:	Gametogenesis naturally resets epigenetic signals.

## Progeny -2

*Empirical Support*:
- Often cursory, but always consistent observation of normal offspring in domestic livestock
- Compelling data from mouse model
- Limited report of comparability of bovine milk
- Limited reports of reproductive function of progeny (goats)

## 
Issues, Challenges,
Relative Merits

**Issues, Challenges,**
**Relative Merits**

**Meat and Milk Composition**

## Compositional Analysis of Bovine Milk

- One peer-reviewed study
- Consistent with prediction that animals that are virtually indistinguishable from comparators will likely produce milk that is similar to comparators
- One animal that is progeny of clone
- Small sample size
- Potentially confounded by breed and husbandry differences
- More data would increase confidence in judgments regarding whether material differences exist

## What is Milk?

**What is Milk?**

- What is milk?
- “[the] *lacteal secretion, practically free from colostrum, obtained by the complete milking of one or more healthy cows*” (21 CFR 131.110(a))

## What is Meat?

*(1) The part of the muscle of any cattle, sheep, swine, or goats, which is skeletal or...tongue,...diaphragm,...heart, or...esophagus, with or without the accompanying and overlying fat, and the portions of bone, skin, sinew, nerve, and blood vessels which normally accompany the muscle tissue... It does not include the muscle found in the lips, snout, or ears....” *
- 								(9 CFR 301.2)

## Milk and Meat Composition Issues

- No chemical formulas that “define” either commodity
- Can differ significantly from animal to animal, even within the same breed
- Season
- Climate
- Diet
- Age
- Lactation cycle
- Even for experimental purposes, very difficult to control conditions
- Exact compositional analysis is impracticable

## Meat and Milk Comparator Issues

- What comparators to choose?
- Genetically closely related animals (e.g., donor, half sibs) reared under identical conditions
- Could cast light on effect of cloning
- Accounting for normal epigenetic variability?
- Statistics?
- Commodity products (e.g., bulk tank milk, butcher shop)
- Provides comparator for “conventional counterparts”
- How to account for variability in comparators?
- Statistics?

## Meat and Milk Composition Issues

- Consider whether key constituents of milk or meat are within contemporary normal ranges of variability for that food product.
- Proximates, plus
- Vitamins/minerals (significant dietary sources)
- Fatty Acid Profiles
- Protein characterization
- Key proteins that make up meat, milk
- Essential amino acid profiles

## Compositional Analyses for Showing “No Material Differences” for Milk and Meat from Clones

**MILK**
**Proximates plus**
**Vitamins and minerals for which milk is a moderate to major source**
**Vit A, C, B-1,B-2, B-12, niacin, pantothenic acid**
**Ca, Fe, Ph**
**Fatty Acid Profiles**
**Saturated:  4:0, 6:0, 8:0, 10:0, 12:0, 14:0, 16:0, 18:0**
**Unsaturated:  18:1, 18:2, 18:3**
**Protein characterization (c****aseins, whey)**
**Amino acid profile**
**Somatic cell count**
**Estrogen (?)**

**MEAT**
**Proximates plus**
**Nutritionally important vitamins and minerals (for which meat is a moderate to major source)**
**Vit A, C, B-6, B-12, Niacin**
**Ca, Fe, Ph, Zn**
**Fatty Acid Profiles**
**Saturated: 10:0, 12:0, 14:0, 16:0, 18:0**
**Unsaturated:  18:1, 18:2, 18:3, 20:4**
**Cholesterol **
**Amino acid profile**

## Provocative Question

- Given the highly detailed physiological information on clones, what would be the additional scientific merit in obtaining compositional information on
- Milk?
- Meat?

## Concluding Comments

**Food Consumption Risks from Clones or their Progeny**

## Concluding Statement on Food Consumption Risks from Clones

- Edible products from normal, healthy clones or their progeny do not appear to pose increased food consumption risk relative to comparators
- Relatively high confidence in conclusion
- Empirical evidence from bovine clones
- Consistency of responses among other species

## Concluding Statement on Food Consumption Risks from Clone Progeny

- Edible products from clone progeny likely to be as safe to eat as products from non-clones
- Based on biological assumption
- Evidence from mouse model
- Limited, but consistent observations in domestic livestock
- Additional data on
- Health status of progeny
- Composition of milk and meat
- ........................would increase certainty(?)