U.S. Food and Drug Administration

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U.S. Food and Drug Administration

• Notice Archived Document
• The content in this document is provided on the
  FDAs website for reference purposes only. It was
  current when produced, but is no longer
  maintained and may be outdated.

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Animal Safety

• Amey L. Adams, PhD
• Center for Veterinary Medicine
• Food and Drug Administration
• November 4, 2003

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Context for Consideration of Animal Health Risks

• Do the risks experienced by animals involved in
  the cloning process differ qualitatively from
  those experienced by animals undergoing other
  assisted reproductive technologies?

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Critical Biological Systems Approach Animal
Safety
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Overview

• Surrogate Dams of Clones
• Neonatal Clones
• Juvenile to Prepuberty Clones
• Puberty through Reproductive Maturity
• Maturity and Aging
• Progeny of Clones

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Surrogate Dams
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Cattle and sheep

• Studies indicate increased risk of mid- to late-
  gestational complications
• Hydrops (edema of fetus or fetal membranes)
• Dystocia (difficulty giving birth)
• Other complications

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Hydrops

• A collective term referring to excessive build-up
  of fluids in fetus or fetal membranes
• May be detected as early as the sixth month of
  pregnancy in cattle (clone producers)

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Hydrops (continued)

• Degree varies from mild to severe (clone
  producers)
• Severe hydrops - death of the dam and/or fetus
  (Heyman et al. 2002)
• Incidence highly variable among laboratories
• Data indicate risk higher in clone pregnancies
  vs. IVF (Pace et al. 2002 (some transgenic
  30/178), clone producers (1/300))

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Dystocia

• Causes
• fetal oversize compared to pelvic opening
• malpresentation of the fetus
• multiple fetuses presenting simultaneously
• Also in conventionally bred animals bearing
  single, large fetus (Lucy 2001, Dwyer 2003)

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Dystocia in Clone Pregnancies

• Often result from fetal oversize (i.e. Large
  Offspring Syndrome)
• May cause damage to the reproductive tract and
  musculo-skeletal system
• Incidence varies with LOS, management decisions
  (clone producers)

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Less Frequent Complications

• Also observed in cattle and sheep surrogate dams
  (Hammer et al. 2001, Wells et al. 1998 1999,
  Ptak et al. 2002)
• Poor or absent mammary development
• Absent or atypical signs of labor (uterine
  inertia)
• Agalactia (failure to lactate)
• Impaired maternal behavior
• Frequency of these anomalies were not reported

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Goats and Swine

• No reported complications in surrogate goats
• No reports of hydrops or LOS in either species
• Some reports indicate lack of mammary
  development, agalactia, uterine inertia in swine
  (Carter et al. 2002 (transgenic), clone
  producers) (Frequency not reported)

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Neonatal Clones
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Cattle and Sheep

• Large Offspring Syndrome (LOS)
• Reported in IVF, BNT, SCNT-derived cattle and
  sheep (Kruip and de Daas 1997, Knight et al.
  2001, Chavatte-Palmer et al 2002, Ptak et al.
  2002)
• Fetus or newborn gt20 above average weight
• Respiratory complications
• Internal organ defects (heart and kidney)
• Musculo-skeletal defects
• Poor or absent suckle reflex

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LOS (continued)

• Increases risk of dystocia
• Dystocia - stress neonatal calf or lamb, increase
  risk of mortality and morbidity (Moore et al.
  2002, Kato et al. 1998)
• Premature separation of placenta
• Inhalation of amniotic fluid - respiratory
  complications

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LOS continued

• Some complications reversible, depending on
  severity
• Incidence variable among labs for SCNT (8 to 50)
  (Miyashita et al. 2002, Kato et al. 2000)
• LOS in IVF calves 7 to 31 (Hasler et al. 1995,
  Kruip and den Daas 1997)

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Neonatal Survival

• Critical survival period first 48 hours (Cyagra)
• Neonatal death rate 20 in clone cattle (Pace
  et al. 2002 (some transgenic), Cyagra)
• Death rate in early IVF cattle studies 14 to 16
  (Hasler et al. 1995, Kruip and den Daas 1997)

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Neonatal Goats and Swine

• Two reports of neonatal mortality in goat clones
  (Keefer et al. 2001 (1/6), Keefer et al. 2002
  (2/9))
• Few reports of complications in neonatal swine
  clones
• Low birth-weight (Polejaeva et al. 2000, Walker
  et al. 2002) (actual frequency not reported)
• One report of physical deformity (anal atresia)
  in non-transgenic clone pig (1/28) (Walker et al.
  2002)

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Juvenile to Prepuberty
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Juvenile Clones

• Most reports indicate normal growth and
  development following the neonatal period
• Behavioral studies in cattle and swine note no
  abnormalities (Savage et al. 2003, Archer et al.
  2003)
• Results of blood tests indicate cattle and swine
  in this age group are mostly within the range of
  conventionally bred animals of the same age
  (Cyagra, Archer et al. 2003 Chavatte-Palmer et
  al. 2002, Kato et al. 2000)

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Juvenile Cattle

• A few individual animals reported to have health
  problems which may stem from LOS (Cyagra, n134)
• Non-resolving musculo-skeletal (2)
• Failure to thrive (1)
• Umbilical surgeries (29)
• GI tract problems (2)
• Heart abnormalities (1)
• Some of these animals had more than one anomaly

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Juvenile Goats and Swine

• One report of respiratory infections in growing
  goat clones (2/6) (Keefer et al. 2001)
• One report of hyperkeratosis in a swine clone
  (1/9) (Archer et al. 2003)

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Other Complications

• Cryptorchidism (3/134) (Cyagra) (all from one
  cell line)
• Dwarfism (1/134) (Cyagra)
• Hyperkeratosis (Archer et al. 2003) (1/9)
• Cryptorichidism and dwarfism may be related to
  genetics of nuclear donor
• Hyperkeratosis (dermatitis vegetans) rarely a
  recessive gene

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Puberty through Reproductive Maturity
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Pubertal Cattle

• No health problems noted blood chemistries
  normal (Cyagra)
• Most reports indicate heifers reach puberty,
  conceive and deliver healthy calves (Lanza et al.
  2001 (transgenic), Pace et al. 2002 (some
  transgenic), Enright et al. 2002)
• One report of clone heifers achieving puberty
  slightly later than controls, but within the
  normal range for their breed (actual frequency
  not reported) (Enright et al. 2002)
• No detailed information on bulls (Forsburg et al.
  2002, Kato et al. 2000, Kubota et al. 2000)

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Other Species

• One report each on fertility of ram and buck
  clones, indicating normal age at puberty,
  fertility, and sperm quality (Wells et al. 1998,
  Gauthier et al. 2001)
• One report of goat doe clones conceiving and
  delivering normal offspring (Reggio et al. 2001)
• No reports on reproduction in swine clones

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Maturity and Aging

• Insufficient time to evaluate aging in farm
  animal species
• Aging study in mice observed shorter lifespans,
  increased health problems (Ogonuki et al. 2002)
• Studies of telomeres conflicting not good
  predictor of lifespan (Betts et al. 2001, Lanza
  et al. 2000, Tian et al. 2000, Miyashita et al.
  2002, Kubota et al. 2000)

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Offspring of Clones

• Several cursory reports state offspring are
  normal and healthy
• No details available in farm animal species
• Reports from mice indicate offspring do not
  inherit clone-associated abnormalities of parents
  (Shimazowa et al. 2002, Tamashiro et al. 2002)

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Conclusions
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Cattle and Sheep

• Critical period late gestation - first
  post-natal days (surrogate dams and clones)
• Risk of perinatal morbidity and mortality higher
  in clone pregnancies compared to other ARTs
• Most clones that survive perinatal period appear
  healthy and similar to conventional counterparts
• No abnormalities reported in offspring

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Swine

• A few reports of complications in surrogate sows
• One report of deformity in a clone pig
• Anal atresia also noted in conventionally bred
  swine
• No reports on reproductive maturity of clones or
  health of offspring

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Goats

• No complications noted for surrogate does
  carrying goat clones
• Very few health problems noted in goat clones
• Two deaths during labor, three deaths due to
  respiratory infection
• Appear to mature normally and produce healthy
  offspring

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Overall Conclusions

• No qualitative differences from other ARTs or
  natural breeding
• Frequency of anomalies increased even relative to
  IVF
• Adverse outcomes observed more frequently in
  cattle and sheep than swine and goats

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VMAC Question

• Question 1 Based on what we have presented, has
  the risk assessment adequately identified the
  hazards and characterized the risks relating to
  animal health?