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Phenolphthalein: induction of micronucleated erythrocytes in mice
1Oak Ridge Institute for Science and Education, TN 37831-0117.
Abstract:
Phenolphthalein was tested for the induction of micronucleated erythrocytes in mice. Results of an initial investigation revealed significant, dose-related increases in micronucleated polychromatic erythrocytes (MN-PCE) and normochromatic erythrocytes (MN-NCE) in peripheral blood samples of male and female mice exposed to 0.6% to 5% phenolphthalein (approximately 1100 to 10,000 mg/kg/day) in feed for 90 days (Dietz et al., 1992). Results from a second long-term feed study with Swiss CD-1 mice confirmed this effect. However, administration of comparable doses of phenolphthalein by corn oil gavage on two consecutive days gave negative results in a mouse bone marrow micronucleus test. Subsequent tests were performed to clarify the conflicting results seen in the chronic exposure, dosed-feed, peripheral blood studies and the acute, corn oil gavage, bone marrow studies. Phenolphthalein was administered to male B6C3F1 mice in feed (3%) for 14 days. Peripheral blood samples taken at 4, 7, and 14 days all showed significant increases in micronucleated PCE; bone marrow samples taken on days 7 and 14 also were clearly positive for micronucleus induction. Therefore, comparable results were obtainable from both bone marrow and peripheral blood analyses. Because of the negative results in the two-exposure gavage test, additional tests were then designed to investigate the effects of bolus vs continuous dosing, feeding vs gavage administration, and corn oil vs feed as a carrier for phenolphthalein. Results of these tests indicated that the rate of exposure to phenolphthalein affects the frequency of induced MN-PCE and that micronucleated erythrocytes can be induced by phenolphthalein either by feeding or by corn oil gavage administration. In all the acute exposure studies, relatively high doses of phenolphthalein (2000-6000 mg/kg/day for at least 2 days) were required to induce micronuclei. The positive results obtained with phenolphthalein in vivo were consistent with the results of an in vitro chromosomal aberration test in Chinese hamster ovary cells, where dose-related increases in aberrations were noted only in cells treated in the presence of induced rat liver S9.
Insights
Phenolphthalein exposure in mice caused dose-related increases in micronucleated erythrocytes, indicating genotoxicity. The rate and method of administration influenced the frequency of these effects, with continuous feeding showing clearer results than acute gavage.
Area of Science:
- Toxicology
- Genetics
- Mammalian studies
Background:
- Phenolphthalein is a compound previously used as a laxative and pH indicator.
- Previous studies have shown conflicting results regarding phenolphthalein's genotoxic potential in vivo.
- Understanding the genotoxicity of phenolphthalein is crucial for risk assessment.
Purpose of the Study:
- To investigate the genotoxic effects of phenolphthalein in mice.
- To clarify conflicting results from previous studies on phenolphthalein-induced micronuclei formation.
- To determine the influence of administration route and rate on phenolphthalein's genotoxicity.
Main Methods:
- Mice were exposed to phenolphthalein via feed and corn oil gavage at various doses and durations.
- Micronucleated polychromatic erythrocytes (MN-PCE) and normochromatic erythrocytes (MN-NCE) were analyzed in peripheral blood and bone marrow.
- In vitro chromosomal aberration tests were conducted in Chinese hamster ovary cells.
Main Results:
- Long-term feeding studies showed significant, dose-related increases in MN-PCE and MN-NCE.
- Acute gavage administration yielded negative results, suggesting a difference based on exposure rate.
- Subsequent studies confirmed micronucleus induction by both feeding and gavage, but higher doses were needed for acute gavage.
- In vitro tests showed dose-related chromosomal aberrations in the presence of induced rat liver S9.
Conclusions:
- Phenolphthalein induces micronucleated erythrocytes in mice, confirming its genotoxic potential.
- The rate of exposure significantly impacts the frequency of induced micronuclei.
- Both feeding and gavage administration can induce genotoxicity, but continuous exposure appears more effective or sensitive.
- Results suggest phenolphthalein's genotoxicity is mediated by metabolic activation, consistent with in vitro findings.