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Assessment of a short-term reproductive and developmental toxicity screen
M W Harris1, R E Chapin, A C Lockhart
1Developmental and Reproductive Toxicology Group, NIEHS, Research Triangle Park, North Carolina 27709.
Abstract:
Short-term tests for reproductive and developmental toxicity are needed to provide preliminary data on the toxicity of chemicals about which little or no data exist. An ideal design would test all aspects of reproduction and identify the target process in a short time period. One potential design has been evaluated using four chemicals of varying reproductive/developmental toxicity. Swiss mice were mated for 3 days prior to chemical exposure to produce time-mated females for gestational exposure and to ascertain fertility of the untreated males. The group of time-mated females was treated during Gestation Days 8-14 and allowed to litter for observations through Postnatal Day (PND) 4. Endpoints observed included pup number and body weights on PND 0, 1, and 4 and number of uterine implantation sites on PND 4. A second group of females was dosed daily for 19 days. After 7 days, these females (n = 10/group) were cohabited with male mice who had been treated for 5 days prior to this second mating. Daily chemical dosing continued during the 5-day cohabitation. This second group of females was killed after 19 days of treatment and the number of live and dead fetuses and implantation sites was recorded. After 17 days of dosing, male mice were killed and the reproductive system evaluated by organ weights, total epididymal sperm counts and motility, and testicular histology. All four chemicals tested, boric acid, ethylene glycol, ethylene glycol monomethyl ether, and theophylline, were found to be toxic to development or reproduction when tested previously by conventional developmental toxicity or continuous breeding protocols. This short-term (21 day) design correctly identified three of these four chemicals as reproductive and developmental toxicants and distinguished the potent toxicants from the less effective compounds. This design can be used to prioritize chemicals for further study, or to delineate the relative toxicities of structurally related chemicals, and to identify the proper dose range for subsequent toxicity studies.
Insights
A new 21-day test effectively screens for reproductive and developmental toxicity in chemicals. This short-term study identifies potent toxicants, aiding chemical prioritization and dose range determination for further research.
Area of Science:
- Toxicology
- Reproductive Toxicology
- Developmental Toxicology
- Chemical Safety Assessment
Background:
- Short-term tests are crucial for preliminary toxicity data on chemicals with limited existing information.
- An ideal short-term test should comprehensively assess reproduction and identify target toxic processes efficiently.
- Evaluating novel testing designs is essential for advancing chemical safety evaluations.
Purpose of the Study:
- To evaluate a novel, short-term (21-day) testing design for reproductive and developmental toxicity.
- To assess the utility of this design in identifying and differentiating toxicant potency among chemicals.
- To determine if this design can aid in prioritizing chemicals for further toxicological investigation.
Main Methods:
- A 21-day protocol involving Swiss mice, with timed mating for gestational exposure and separate groups for continuous exposure.
- Gestational exposure (Gestation Days 8-14) with endpoints including pup viability and body weight through Postnatal Day 4.
- Continuous exposure for females and males, followed by evaluation of fertility, fetal development, and male reproductive organ assessment (sperm count, motility, histology).
Main Results:
- The short-term test successfully identified three out of four known reproductive and developmental toxicants (boric acid, ethylene glycol, ethylene glycol monomethyl ether, theophylline).
- The design effectively distinguished between potent and less potent toxicants among the tested chemicals.
- The protocol provided preliminary data that could guide dose selection for more extensive toxicity studies.
Conclusions:
- The evaluated 21-day testing strategy is a viable approach for preliminary screening of chemical reproductive and developmental toxicity.
- This method can efficiently prioritize chemicals requiring further, more in-depth toxicological assessment.
- The design aids in understanding relative toxicities and establishing appropriate dose ranges for subsequent studies.