Comparison of single and multiple treatment regimens in the mouse bone marrow micronucleus assay for hydroquinone (HQ) and cyclophosphamide (CP)

Adler, I.‐D.; Kliesch, U.

doi:10.1016/0165-1161(90)90002-6

Cited by 46 publications

(21 citation statements)

References 30 publications

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“…dosing regimens, largely positive results have been obtained with HQ in the mouse bone marrow micronucleus assay. 125,145,[157][158][159][160][161][162][163][164][165][166][167][168][169][170] Transplacental induction of MN in blood cells from fetal mouse liver following exposure of pregnant dams to HQ has been reported. 171 The lowest positive dose of HQ in these experiments was approximately 40 to 50 mg/kg, and i.p.…”

Section: Genotoxicitymentioning

confidence: 97%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

174

128

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Hydroquinone (HQ) is a high-volume commodity chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It is also used in over-the-counter (OTC) drugs as an ingredient in skin lighteners and is a natural ingredient in many plant-derived products, including vegetables, fruits, grains, coffee, tea, beer, and wine. While there are few reports of adverse health effects associated with the production and use of HQ, a great deal of research has been conducted with HQ because it is a metabolite of benzene. Physicochemical differences between HQ and benzene play a significant role in altering the pharmacokinetics of directly administered when compared with benzene-derived HQ. HQ is only weakly positive in in vivo chromosomal assays when expected human exposure routes are used. Chromosomal effects are increased significantly when parenteral or in vitro assays are used. In cancer bioassays, HQ has reproducibly produced renal adenomas in male F344 rats. The mechanism of tumorigenesis is unclear but probably involves a species-, strain-, and sex-specific interaction between renal tubule toxicity and an interaction with the chronic progressive nephropathy that is characteristic of aged male rats. Mouse liver tumors (adenomas) and mononuclear cell leukemia (female F344 rat) have also been reported following HQ exposure, but their significance is uncertain. Various tumor initiation/promotion assays with HQ have shown generally negative results. Epidemiological studies with HQ have demonstrated lower death rates and reduced cancer rates in production workers when compared with both general and employed referent populations. Parenteral administration of HQ is associated with changes in several hematopoietic and immunologic endpoints. This toxicity is more severe when combined with parenteral administration of phenol. It is likely that oxidation of HQ within the bone marrow compartment to the semiquinone or p-benzoquinone (BQ), followed by covalent macromolecular binding, is critical to these effects. Bone marrow and hematologic effects are generally not characteristic of HQ exposures in animal studies employing routes of exposure other than parenteral. Myelotoxicity is also not associated with human exposure to HQ. These differences are likely due to significant route-dependent toxicokinetic factors. Fetotoxicity (growth retardation) accompanies repeated administration of HQ at maternally toxic dose levels in animal studies. HQ exposure has not been associated with other reproductive and developmental effects using current USEPA test guidelines. The skin pigment lightening properties of HQ appear to be due to inhibition of melanocyte tyrosinase. Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. The most serious human health effect related to HQ is p...

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Section: Genotoxicitymentioning

confidence: 97%

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

DeCaprio¹

1999

Critical Reviews in Toxicology

174

128

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“…MMC is well known to induce micronuclei in polychromatic erythrocytes in various mouse strains [4,[11][12][13]. CP is a mutagen in the chromosome aberration test, in the sister chromatid exchange and micronucleus test in vivo and in vitro [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Micronucleus formation induced by the combination of low doses of X-rays and antineoplastic drugs in bone marrow of male mice

Dobrzyńska¹

2000

Teratog. Carcinog. Mutagen.

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People are widely exposed during their lifetime to many biological, chemical, and physical agents in the environment and at work. In this paper the effects of combined exposures of nonmutagenic doses of X-rays and anticancer agents (cyclophosphamide, mitomycin C, and vinblastine) have been investigated on the induction of micronuclei in the bone marrow of laboratory mice. The combination of X-rays and anticancer drugs enhanced the frequency of micronuclei in some cases. The strongest effects were found after the combination of X-rays and cyclophosphamide at 24 h and 72 h. The combined treatment of X-rays and mitomycin C enhanced the mutagenic effect at 72 h. The combination of X-rays + vinblastine slightly potentiated the mutagenic effect at 24 h and 48 h.

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“…Positive micronucleus test results for Hydroquinone were obtained by Gad-El Karim et al (1986), Ciranni et al (1988a,b), Shimada et al (1988), Glatt et al (1989), Adler and Kliesch (1990), Robertson et al (IWO), Yager et al (1990), Adler et al (1991), Marrazzini et al (1991), Pacchierotti et al (19!21), and Marrazzini et al (1992). In the study by Robertson et al (l!BO), coadministration of equimolar concentrations of Hydroquinone and catechol produced a significant synergistic effect on micronucleated cells as compared with Hydroquinone alone.…”

mentioning

confidence: 91%

“…Hydroquinone was clastogenic for male mouse germ cells (Ciranni and Adler, 1991) and for mouse bone marrow cells. Chromosomal aberrations were induced in mouse bone marrow cells (Xu and Adler, 1990;Pacchierotti et al, 1991;Marrazzini et al, 1991;Marrazzini et al, 1992;Sbrana et al, 1992) and c-mitotic effects were observed in mouse bone marrow cells (Miller and Adler, 1989) and in human lymphocyte cultures (Sbrana et al, 1992). Hydroquinone induced chromosome loss in yeast strain 0 6 without metabolic activation (Parry et al, 1990), but did not induce chromosomal malsegregations using Saccharomyces cerevisiae D61.M (Albertini, 1990).…”

mentioning

confidence: 99%

Addendum to the Final Report on the Safety Assessment of Hydroquinone

1994

Journal of the American College of Toxicology

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An assessment of the safety of Hydroquinone was first published in 1986 (J Am Coll Toxic01 5: 123-65). The ingredient was found to be safe for use at limited concentrations for certain formulations. This addendum reviews new data and presents a revised conclusion regarding safety. Hydroquinone is an aromatic compound used principally in hair dyes and colors, but it is also in lipsticks, skin fresheners, and other skin care preparations. Hydroquinone in an aqueous solution was shown to be absorbed through human skin at a rate of 0.55 k 0.13 p,g/crn*/h. Hydroquinone is rapidly absorbed and excreted in urine in rats following oral administration. Absorption from an alcohol vehicle is greater than from an aqueous solution. Hydroquinone was found to be cytotoxic to rat hepatoma cells in culture, and nephrotoxic in male rats dosed orally by gavage. Oral administration of Hydroquinone to rats resulted in dosedependent mortality, lethargy, tremors, and increased liver and kidney weights. Oral administration did not produce embryotoxic, fetotoxic, or teratogenic effects in rats. In rats, dermal application produced slight to severe irritation. In a guinea pig maximization test, induction with 2% Hydroquinone injected intradermally, followed by challenge with 0.5% Hydroquinone, showed extreme sensitization. In 80 patients known to be sensitive to aromatic compounds, 0.5% Hydroquinone elicited no reactions. Hydroquinone can cause depigmentation of skin. Various genotoxicity assays show that Hydroquinone can induce sister chromatid exchanges, chromosomal aberrations and loss, and increased frequency of mitotic crossovers. It also induced DNA strand breaks and inhibited DNA and RNA synthesis in rabbit bone marrow mitochondria. Forward mutation assays with or without metabolic activation were positive, but the results with the Ames test, a mouse test for somatic mutations, and other tests were negative. Hydroquinone, given to rats orally by gavage five times per week for up to 103 weeks at doses of 25 or 50 mg/kg, resulted in a significant increase of renal adenomas in males given 50 mg/kg and of mononuclear cell leukemia in females with both doses. At doses of 50 or 100 m a g on the same schedule, there was a significant increase in hepatocellular adenomas in both male and female mice. Other studies of Hydroquinone showed no significant difference in tumors between control and exposed groups, and marginal to no activity as a tumor promoter. It is concluded that Hydroquinone is safe at concentrations of al% for aqueous cosmetic formulations designed for discontinuous, brief use followed by rinsing from the skin and hair. Hydroquinone should not be used in leave-on, nondrug cosmetic products. Key Words: Safety assessment-Hydroquinone.The Cosmetic Ingredient Review (CIR) Expert Panel has previously concluded that Hydroquinone (CAS No. 123-31-9) is safe for cosmetic use at ~1 % in formulations designed for discontinuous, brief use followed by rinsing from the skin and hair (Elder, 1986). The carcinogenicity data used to reach the...

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Comparison of single and multiple treatment regimens in the mouse bone marrow micronucleus assay for hydroquinone (HQ) and cyclophosphamide (CP)

Cited by 46 publications

References 30 publications

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

Micronucleus formation induced by the combination of low doses of X-rays and antineoplastic drugs in bone marrow of male mice

Addendum to the Final Report on the Safety Assessment of Hydroquinone

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