title: The toxicology of hydroquinone--relevance to occupational and environmental exposure.
abstract: 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 pigmentation of the eye and, in a small number of cases, permanent corneal damage. This effect has been observed in HQ production workers, but the relative contributions of HQ and BQ to this process have not been delineated. Corneal pigmentation and damage has not been reported at current exposure levels of <2 mg/m3. Current work with HQ is being focused on tissue-specific HQ-glutathione metabolites. These metabolites appear to play a critical role in the renal effects observed in F344 rats following HQ exposure and may also be responsible for bone marrow toxicity seen after parenteral exposure to HQ or benzene-derived HQ.
authors.affiliation: ChemRisk Division, McLaren/Hart, Inc., Albany, NY 12203, USA. apd04@health.state.ny.us
authors.forename: A P
authors.initials: AP
authors.lastname: DeCaprio
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D004781:Environmental Exposure; D006801:Humans; D006873:Hydroquinones / Q000633:toxicity*; D016273:Occupational Exposure
chemical_list: D000975:Antioxidants; D006873:Hydroquinones; C031927:hydroquinone