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Benzene-induced micronuclei in erythrocytes: an inhalation concentration-response study in B6C3F1 mice
G M Farris1, V A Wong, B A Wong
1Chemical Industry Institute of Toxicology, Research Iriangle Park, NC 27709-2137, USA.
Abstract:
High concentrations (300-1000 p.p.m.) of benzene have been shown to induce an increase in the frequency of micronucleated erythrocytes in mice. This study investigated the mutagenicity of benzene at lower concentrations, including the current limit for occupational exposure, 1 p.p.m. The frequencies of micronucleated polychromatic erythrocytes (MPCE) in the bone marrow and blood and micronucleated normochromatic erythrocytes (MNCE) in the blood of male B6C3F1 mice were measured following inhalation of benzene at 0, 1, 10, 100 or 200 p.p.m. during an 8 week exposure period. Only 100 and 200 p.p.m. benzene induced a statistically significant increased frequency of micronucleated erythrocytes in the bone marrow and blood. The frequency of MPCE plateaued at week 2 with 43/1000 (100 p.p.m.) and 86/1000 (200 p.p.m.) in the bone marrow as compared with 10/1000 for controls. The frequency of MNCE in the blood progressively increased to 13.4/1000 (100 p.p.m.) and 32.5/1000 (200 p.p.m.) at week 8 as compared with 1.8/1000 for controls. Cytotoxicity of replicating and maturing erythrocytes by 100 and 200 p.p.m. benzene delayed the accumulation of MNCE in the blood. There was not a statistically significant increase in the frequency of micronucleated erythrocytes, as an indicator of mutagenicity, with inhalation of 1 or 10 p.p.m. benzene over an 8 week period. A quadratic curve fit the bone marrow MPCE data of mice exposed to up to 200 p.p.m. benzene with a high correlation (R2 = 0.94) and could not be rejected based on lack of fit.
Insights
Benzene inhalation at 100 and 200 p.p.m. significantly increased micronucleated erythrocytes in mice, indicating mutagenicity. Lower concentrations, including occupational limits, did not show significant mutagenic effects over 8 weeks.
Area of Science:
- Toxicology
- Genetics
- Environmental Health
Background:
- Benzene is a known mutagen at high concentrations.
- Occupational exposure limits for benzene are set at 1 p.p.m.
- Investigating benzene's mutagenicity at lower doses is crucial for risk assessment.
Purpose of the Study:
- To evaluate the mutagenicity of benzene at concentrations relevant to occupational exposure.
- To determine the dose-response relationship of benzene-induced micronucleated erythrocytes.
- To assess the genotoxic potential of benzene following inhalation exposure.
Main Methods:
- Male B6C3F1 mice were exposed to benzene via inhalation (0, 1, 10, 100, 200 p.p.m.) for 8 weeks.
- Frequencies of micronucleated polychromatic erythrocytes (MPCE) in bone marrow and blood were measured.
- Frequencies of micronucleated normochromatic erythrocytes (MNCE) in blood were assessed.
Main Results:
- Benzene at 100 and 200 p.p.m. significantly increased MPCE and MNCE frequencies.
- MPCE levels plateaued by week 2 at higher concentrations.
- MNCE accumulation in blood was delayed by benzene's cytotoxicity to erythrocytes.
- No significant mutagenic effect was observed at 1 or 10 p.p.m. benzene.
Conclusions:
- Benzene is mutagenic at 100 and 200 p.p.m. following inhalation exposure.
- Current occupational exposure limits (1 p.p.m.) and slightly higher concentrations (10 p.p.m.) did not demonstrate significant mutagenicity in this study.
- The findings suggest a threshold for benzene-induced mutagenicity in mice.