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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some chemicals that cause tumours of the urinary tract in rodents. Lyon (FR): International Agency for Research on Cancer; 2019. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 119.)
4.1. Absorption, distribution, metabolism, and excretion
4.1.1. Absorption, distribution, and excretion
(a) Humans
Tetrahydrofuran is extensively absorbed following inhalation (Ong et al., 1991); it rapidly appears in the blood, demonstrating rapid systemic absorption from the lungs of exposed workers. Although dermal uptake does occur, the degree of absorption through the skin was negligible compared with inhalation (Brooke et al., 1998).
The half-life of tetrahydrofuran in humans is estimated to be approximately 30 minutes. Analysis of hepatic blood flow and clearance values suggests that tetrahydrofuran is extensively metabolized in human liver during first-pass metabolism (Fowles et al., 2013).
Several studies of workers exposed to tetrahydrofuran by inhalation were summarized by Droz et al. (1999) and were used to develop a physiologically based pharmacokinetic model for the biomonitoring of exposed workers.
(b) Experimental systems
Chronic exposure of rats to tetrahydrofuran vapour (at 200, 1000, or 2000 ppm) initially resulted in a dose-dependent increase in tetrahydrofuran content in brain and perirenal fat; exposure for up to 18 weeks showed a decrease with time in tetrahydrofuran content in the body, consistent with rapid metabolism and the low potential for bioaccumulation (Elovaara et al., 1984). In a study in which rats and mice were exposed to [14C]-labelled tetrahydrofuran by gavage and monitored for up to 168 hours after dosing (Fowles et al., 2013), rapid absorption and metabolism of tetrahydrofuran, with the majority recovered as carbon dioxide, were observed in rats. Generally similar kinetics were observed for mice; the main difference between observed results for rats and mice was that the maximal plasma concentration in rats of both sexes was achieved at about 4 hours, whereas that in male and female mice was achieved at 0.8 and 1 hour, respectively, consistent with faster overall pharmacokinetics in mice compared with rats.
Tissue distribution of tetrahydrofuran after oral dosing was analysed in male and female Fischer 344 rats or B6C3F1 mice given [14C]-labelled tetrahydrofuran by single gavage at target concentrations of 50 or 500 mg/kg body weight (bw) (DuPont Haskell Laboratory, 1998). The liver exhibited the highest concentrations of radioactivity, followed by fat and adrenal glands. Relatively high amounts of tetrahydrofuran were detected in the spleen, suggesting distribution through the lymphatic circulation. Differences in distribution between the sexes were not evident.
4.1.2. Metabolism
Few data were available on the metabolism of tetrahydrofuran in human or other mammalian systems. The initial step is oxidative metabolism by cytochrome P450 (CYP) enzymes with further hydrolysis by paraoxonase 1 and further action of cytoplasmic dehydrogenases. The specific CYPs have not been clearly identified. One reaction results in hydroxylation of the ring structure, whereas the other results in ring-opening to form a hydroxylated butanal. A major metabolite that is detected is gamma-hydroxybutyrate (GHB; 4-hydroxybutyrate), a neurotoxicant that can arise either from 4-hydroxyl-butanal or from γ-butyrolactone (GBL; 4-butyrolactone) (ECHA, 2010). GHB is oxidized to succinic semialdehyde, which is then converted to succinate and processed through the citric acid cycle to yield carbon dioxide (Fowles et al., 2013).
Both GHB and carbon dioxide have been recovered (Fowles et al., 2013), consistent with the pathway. In a tetrahydrofuran poisoning case (Cartigny et al., 2001; Imbenotte et al., 2003), analysis of urine and serum samples by 1H-nuclear magnetic resonance spectroscopy showed very high concentrations of GHB in urine and serum. Urinary and serum concentrations of tetrahydrofuran were 850 and 813 mg/L (11.8 and 11.3 mM), respectively, and those of GHB were 2977 and 239 mg/L (28.6 and 2.3 mM), respectively.
4.1.3. Modulation of metabolic enzymes
As reviewed by Moody (1991), the effects of tetrahydrofuran on mixed-function oxidation were observed to range from increased, decreased, or no change in activities or processes in studies in vivo. Male Sprague-Dawley rats were exposed to tetrahydrofuran for 16 hours, resulting in the induction of activities dependent upon CYP (CYP2E1). Total CYP content and ethoxycoumarin deethylase (ECOD) activity (marker for CYP1A1) increased in liver microsomes isolated from male Wistar rats exposed by inhalation to tetrahydrofuran for 18 weeks (Moody, 1991). Increased total CYP content and activities of ethoxyresorufin-O-deethylase and pentoxyresorufin-O-depentylase, suggesting induction of CYP1A1 and CYP2B1, respectively, was reported in the liver of female B6C3F1 mice 5 days after exposure by inhalation to tetrahydrofuran at 5400 mg/m3 (1800 ppm) (Gamer et al., 2002). Tetrahydrofuran both stimulates and inhibits other enzyme systems in rats, including inhibition of hepatic alcohol and formaldehyde dehydrogenase activities (Elovaara et al., 1984), and also both stimulates and inhibits rat and rabbit phosphorylase activity (Moody, 1991).
In female B6C3F1 mice, exposure to a high concentration of tetrahydrofuran (15 000 mg/m3) by inhalation markedly induced hepatic microsomal enzymes (van Ravenzwaay et al., 2003). Choi et al. (2017) reported a 1.6-fold increase in total CYP content and a 1.4–1.7-fold increase in mRNA expression of Cyp1a1/1a2 and Cyp2b10 in wildtype [C57BL/6] female mice exposed orally to tetrahydrofuran at 1500 mg/kg bw. The oral exposure of constitutive androstane receptor/pregnane X receptor (Car/Pxr) knockout female mice to tetrahydrofuran at 1500 mg/kg bw had no effect on CYP expression.
In vitro studies, as reviewed by Moody (1991), showed varying degrees of inhibition, primarily in rat but also in pig liver microsomes. In particular, tetrahydrofuran inhibited benzo[a]pyrene metabolism in liver microsomes from phenobarbital-induced rats, and markedly inhibited glutathione S-transferase activity in rat liver cytosol with benzo[a]pyrene, styrene, or 1,2-dichloro-4-nitrobenzene as substrates. Liver microsomes from female rats were notably more sensitive to the inhibition of ECOD by tetrahydrofuran than those from male rats.
4.2. Mechanisms of carcinogenesis
4.2.1. Genetic and related effects
(a) Humans
No data were available to the Working Group.
(b) Experimental systems
(i) Non-human mammals in vivo
No change was seen in micronucleated polychromatic and normochromatic erythrocytes in female B6C3F1 mice and in polychromatic erythrocytes in male mice exposed to tetrahydrofuran by inhalation at up to 5000 ppm for 14 weeks. However, an increase in the frequency of micronucleated normochromatic erythrocytes was observed in male mice at the end of the 14-week exposure period: a significant increase (P = 0.004) was observed in male mice exposed at 1800 ppm relative to the control group, but the trend test was not significant (P = 0.074) (NTP, 1998).
Although induction of sister-chromatid exchange (SCE) was seen in the bone marrow of male B6C3F1 mice 23 hours (but not 42 hours) after exposure to tetrahydrofuran by intraperitoneal injection at 2000 mg/kg bw, this was not reproduced in a second trial at doses up to 2500 mg/kg bw (lethal dose) (NTP, 1998). No increase in chromosomal aberrations was induced in the bone marrow of male B6C3F1 mice by exposure to tetrahydrofuran by intraperitoneal injection in phosphate-buffered saline or corn oil [the Working Group noted that the vehicle was not clearly reported] at up to 2000 mg/kg bw (NTP, 1998).
(ii) Non-human mammalian cells in vitro
[The Working Group noted that, due to its volatility, the concentration of tetrahydrofuran in the cell culture medium may decline rapidly in the absence of specific controls for volatility. Tetrahydrofuran concentrations in the cell culture medium at different time points from the beginning of the incubations were not assessed in the in vitro studies cited below.]
Tetrahydrofuran (at up to 5000 μg/mL) was negative in the assays for SCE and chromosomal aberrations in Chinese hamster ovary cells (Galloway et al., 1987; NTP, 1998). No increase in micronuclei was seen in metabolically active Syrian hamster embryo cells exposed to tetrahydrofuran (at 3000, 3500, and 4000 µg/mL) for 24 hours (Gibson et al., 1997).
(iii) Non-mammalian systems
Assays for the mutagenicity of tetrahydrofuran (oral exposure at 125 000 ppm in feed or exposure by injections at 40 000 ppm) were negative in Drosophila melanogaster (Valencia et al., 1985; NTP, 1998) and in different strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) (Mortelmans et al., 1986; NTP, 1998).
Tetrahydrofuran is a solvent prone to oxidation to peroxides, butyric acid, butyraldehyde, and related compounds, mainly on ageing and in the presence of light, heat, and moisture (Coetzee & Chang, 1985). Tetrahydrofuran containing 2-hydroxy-tetrahydrofuran as a result of its natural oxidation reacted with DNA bases, giving four adducts as products of the reaction of 4-hydroxy-butanal with the DNA bases (Hermida et al., 2006). The adducts were also detected in calf thymus DNA samples after in vitro reactions with oxidized tetrahydrofuran. Rat liver microsomes oxidized tetrahydrofuran to the reactive 4-hydroxy-butanal, assessed by the formation of the dGuo-THF 1 adduct (Hermida et al., 2006).
4.2.2. Altered cell proliferation or death
(a) Humans
No data in exposed humans were available to the Working Group.
In one study using human embryonic lung fibroblasts, tetrahydrofuran (at 0.2% for 24 hours, used to dissolve β-carotene) reduced the percentage of cells in S-phase (Stivala et al., 1996).
(b) Experimental systems
Marginal increased incidences of hyperplasia of the bone marrow in male B6C3F1 mice during the 2-year inhalation study of tetrahydrofuran were reported by NTP (1998).
In the NTP 13-week study (Chhabra et al., 1990; NTP, 1998), inhalation exposure to tetrahydrofuran increased liver weight in male (at 600, 1800, and 5000 ppm) and female (at 1800 and 5000 ppm) B6C3F1 mice, and in female F344 rats (at 5000 ppm). Minimal to mild hepatic centrilobular hypertrophy occurred in male and female mice (at 5000 ppm).
Absolute and relative liver weights increased in female mice exposed to tetrahydrofuran at 1800 ppm (5400 mg/m3) for 20 days (Gamer et al., 2002). Cell proliferation, assessed by the number of cells in S-phase, increased mainly in the subcapsular region of the renal cortex in male rats exposed to tetrahydrofuran at 1800 ppm for 5 days and at 600 and 1800 ppm for 20 days. The number of apoptotic cells increased in the renal cortex of male rats exposed to 1800 ppm for 20 days and also for 5 days (the latter evaluated 21 recovery days later).
Cell proliferation in liver was increased in female B6C3F1 mice exposed to tetrahydrofuran by inhalation at 5000 ppm for 6 hours per day, for 5 days (van Ravenzwaay et al., 2003).
In B6C3F1 and C57BL/6 female mice given tetrahydrofuran by oral gavage at 300, 1000, or 1500 mg/kg bw per day for 7 days, hepatocellular proliferation was observed, assessed by 5-bromo-2′-deoxyuridine staining. The same effect was not observed in constitutive androstane receptor/pregnane X receptor (Car/Pxr) double-knockout C57BL/6 mice that received tetrahydrofuran by oral gavage at 1500 mg/kg bw per day, for 7 days (Choi et al., 2017).
In a study in vitro, tetrahydrofuran at 30–100 μL per 5 mL culture medium inhibited metabolic cooperation, an indication of gap-junctional intercellular communication inhibition, in Chinese hamster V79 lung fibroblast cells (Chen et al., 1984).
4.2.3. Other mechanisms
Tetrahydrofuran was negative when tested for induction of cell transformation in cultured Syrian hamster embryo cells (Kerckaert et al., 1996) and mouse fibroblast BALB/c-3T3 cells (Matthews et al., 1993).
4.3. Data relevant to comparisons across agents and end-points
For the results of high-throughput screening assays of the Toxicity Testing in the 21st Century (Tox21) and Toxicity Forecaster (ToxCast) research programmes of the government of the USA (Kavlock et al., 2012; Tice et al., 2013; EPA, 2016a, b; Filer et al., 2016), see Section 4.3 of the Monograph on 1-tert-butoxypropan-2-ol in the present volume.
4.4. Susceptibility to cancer
No data were available to the Working Group.
4.5. Other adverse effects
4.5.1. Humans
The only available data came from case reports of occupational exposure to a glue containing tetrahydrofuran (8 hours per day, for 3 days) during plastic pipe repair in a confined space and without the use of any protective device; reported effects were consistent with liver toxicity (Garnier et al., 1989).
4.5.2. Experimental systems
In the NTP 2-year inhalation study (NTP, 1998), effects observed in male B6C3F1 mice exposed to tetrahydrofuran at 1800 ppm were hyperplasia of the bone marrow and iliac lymph nodes, haematopoietic cell proliferation of the spleen, and thymic atrophy, considered to be consequences of the inflammation of the urinary and urogenital tracts. Liver necrosis was increased in female mice exposed to tetrahydrofuran at 1800 ppm (NTP, 1998). In the NTP 13-week study (Chhabra et al., 1990; NTP, 1998), serum bile acids in female F344 rats were increased. Mild degeneration of the X-zone of the innermost cortex of the adrenal glands and uterine atrophy were observed in the female B6C3F1 mice exposed to tetrahydrofuran at 5000 ppm. Tetrahydrofuran also induced narcosis in mice and ataxia in rats.
A concentration-dependent accumulation of α2u-globulin, assessed by immunohistochemistry, was observed in the renal cortex of male F344 rats exposed to tetrahydrofuran for 5 and 20 days, with no regression in the animals that were killed 21 recovery days after 5 days of exposure. However, renal cortex α2u-globulin accumulation in the animals that were killed 21 recovery days after 5 days of exposure (concentrations were close to or higher than those observed after 20 days of exposure to tetrahydrofuran) was not accompanied by increased cell proliferation (Gamer et al., 2002).
IARC established seven criteria for the induction of kidney tumours to have occurred by an α2u-globulin-associated response (IARC, 1999). The criterion that was met was the identification of the accumulating protein as α2u-globulin (by immunohistochemical staining, in the short-term studies of Gamer et al., 2002). However, six criteria were not met, specifically: (i) lack of genotoxic activity of the agent and/or metabolite (tetrahydrofuran containing 2-hydroxy-tetrahydrofuran was reactive towards DNA bases in vitro, giving different DNA adducts; see Section 4.2.1); (ii) reversible binding of the chemical or metabolite to α2u-globulin (no data are available); (iii) induction of sustained increases in cell proliferation in the renal cortex (no demonstration of sustained cell proliferation); (iv) induction of the characteristic sequence of histopathological changes associated with α2u-globulin accumulation (the histopathological changes were not detected); (v) male rat specificity for nephropathy and renal tumorigenicity (there was no increase in the incidence or severity of nephropathy in exposed male rats; NTP, 1998); and (vi) similarities in dose–response relationships of the tumour outcome with histopathological end-points associated with α2u-globulin nephropathy (no evidence of histopathological end-points associated with α2u-globulin nephropathy in chronic and subchronic studies; NTP, 1998).
- Mechanistic and Other Relevant Data - Some chemicals that cause tumours of the u...Mechanistic and Other Relevant Data - Some chemicals that cause tumours of the urinary tract in rodents
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