Hydroquinone (HQ) is a nonvolatile chemical used in the photographic, rubber, chemical, and cosmetic industries. HQ is also known to occur in nature as the beta-D-glucopyranoside conjugate (arbutin), and free HQ is a known component of cigarette smoke. Low concentrations of HQ have been detected in the urine and plasma of humans with no occupational or other known exposure to HQ. The studies reported here investigate dietary and other potential sources of HQ and their contribution to HQ concentrations in the plasma and urine of human volunteers. Analysis of possible food sources of HQ by GC indicated significant amounts of arbutin in wheat products (1-10 ppm), pears (4-15 ppm), and coffee and tea (0.1 ppm). Free HQ was found in coffee (0.2 ppm), red wine (0.5 ppm), wheat cereals (0.2-0.4 ppm), and broccoli (0.1 ppm). After consuming a meal including arbutin- and HQ-containing foods, volunteers showed significant increases in plasma and urinary levels of HQ and its conjugated metabolites (total HQ). Mean plasma concentrations of total HQ peaked at 5 times background levels at 2 h after the completion of the meal, and mean urinary excretion rates of total HQ peaked at 12 times background at 2-3 h after the meal. Immediately after smoking four cigarettes in approximately 30 min, mean plasma concentrations of total HQ were maximally 1.5 times background levels; mean urinary excretion rates of total HQ peaked at 2.5 times background at 1-3 h after smoking. These data indicate that considerable human exposure to HQ can result from plant-derived dietary sources and, to a lesser extent, from cigarette smoke.

Hydroquinone exposure has been reported by the National Toxicology Program (NTP) to produce renal tubule adenomas and to exacerbate spontaneous chronic progressive nephropathy (CPN) in male F344 rats. A mechanism for hydroquinone-related tumorigenesis has not been established, but CPN is known to involve, and hydroquinone produces, enhanced renal tubule cell proliferation. Through an independent review of the renal histopathology from the NTP study, the grade of CPN and the presence of atypical tubule hyperplasia and adenomas was evaluated. Hydroquinone exposure in males at 50 mg/kg, produced a statistically significant increase in the grade of CPN. At 0, 25, and 50 mg/kg, 0/44, 4/49, and 15/51 male rats had either atypical tubule hyperplasias or adenomas; all were within areas of severe or end-stage CPN and were statistically significantly associated with CPN grade. Additionally, there was a dose-related increase in profiles believed to represent new tubule proliferation within areas of advanced CPN, as well as an apparent expansion of these into unusual complex tubule profiles in end-stage kidneys of the high-dose male group. In summary, this histopathological review suggest a mechanism for hydroquinone-related adenoma formation that includes enhancement of the severity of CPN coupled with stimulation of tubule proliferation.

1,2-Cyclohexanedicarboxylic acid, 1,2-diisononylester (DINCH), a polyvinyl chloride plasticizer, has food, beverage, and medical device applications that may result in general population exposure. Although no apparent toxicity information in humans was identified, there is a substantial data set in lab animals to serve as the basis of hazard identification for DINCH. Target tissues associated with repeated dietary DINCH exposure in lab animals included liver, kidney, and thyroid and mammary glands. In contrast to some phthalate ester plasticizers, DINCH did not show evidence of hepatic peroxisomal proliferation, testicular toxicity, or liver tumors in rats. Liver and thyroid effects associated with DINCH exposure were attributed to compensatory thyroid stimulation secondary to prolonged metabolic enzyme induction. The toxicological significance of mammary fibroadenomas in female rats is unclear, given that this common benign and spontaneously occurring tumor type is unique to rats. The weight of evidence suggests DINCH is not genotoxic and the proposed mode of action (MOA) for thyroid gland lesions was considered to have a threshold. No adverse reproductive effects were seen in a two-generation study. An oral reference dose (RfD) of 0.7 mg/kg-d was derived from a human equivalent BMDL₁₀ of 21 mg/kg-d for thyroid hypertrophy/hyperplasia seen in adult F₁ rats also exposed in utero. The total uncertainty factor of 30x was comprised of intraspecies (10×) and database (3×) factors. An interspecies extrapolation factor was not applied since rodents are more sensitive than humans with respect to the proposed indirect MOA for thyroid gland lesions.

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