National Toxicology Program NTP: Evaluating Chemical Agents for Potential Hazards to Reproduction Ja

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National Toxicology Program (NTP)Evaluating
Chemical Agents for Potential Hazards to
Reproduction Jack B. Bishop, PhD Reproductive
and Developmental Genetic ToxicologyLaboratory
of Molecular Toxicology NIEHS/NTP, RTP, NC
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• The NIEHS mission is to reduce the burden of
  human illness and dysfunction due to
  environmental causes through a better
  understanding of interrelationships between the
  interactive elements of environment, genetics
  (susceptibility) and time (age).
• The NTP strives to safeguard public health by
  identifying and characterizing the toxic effects
  of environmental chemicals.

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Overview

• NIEHS/NTP Missions
• NTP Reproductive Tox Tests
• TRCT
• DLT
• RACB
• RDGT
• TER
• Summary of NTP Test Results
• Discussion of Animal Model Test Needs

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TRCT Chemicals
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Male DL Bleomycin
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Female DL Bleomycin
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Confirmation of Female DLT Effects

• Reciprocal Transfer Experiments
• Cytogenetic Analyses
• Oocytes MI and MII
• Zygotes 1st cleavage metaphase
• Ovarian Histology

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RACB Study Design
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Adverse Female Reproductive Effects

• Decreased number of litters per fertile pair
• Decreased number of pups per litter
• Decreased pup weight
• Altered pups sex ratio
• Malformations (mostly RDGT)

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RACB Female Positives
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Length of PregnancyMeasures

• Average Gestation Length
• Average Time to Litter
• Cumulative Time to Litter

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30 RACB/RDGT Studies Reviewed
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Teratology (TER)

• Standard Segment II study
• Conducted with two species mouse,
• rat,rabbit, hamster or guinea pig

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Summary/Conclusions

• Currently, our animal model reproductive tests
  are inadequately designed to capture information
  on chemically induced alterations of gestation
  length
• Rodent models have numerous limitations including
  relative development time-line and various
  factors in parturition

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Acknowledgements

• Walderico M. Generoso
• Lori A. Hughes
• Oak Ridge National Laboratory, Oak Ridge, TN
• Richard W. Morris
• Analytical Sciences, Inc., RTP, NC
• John C. Seely
• PATHCO, Inc., RTP, NC

• Gary W. Wolfe
• TherImmune Research Corporation, Gaithersburg, MD
• Robert E. Chapin
• DuPont Pharmaceuticals Company, Newark, DE
• Michael D. Shelby
• Cana L. Gyongyos
• NIEHS, RTP, NC

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