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A number of studies investigate the mechanism involved in the induction of bladder tumours by terephthalic acid.  A further study assessed the effect of repeated administration of high dietary doses of TPA on oxidative status.  An additional study reports molecular changes in breast cancer cells exposed in vitro to terephthalic acid.

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Mechanism of bladder carcinogenicity

Several studies were completed to investigate possible mechanisms of bladder carcinogenesis for terephthalic acid. Dai et al (2005a) investigated the effects of terephthalic acid on the bladder of male and female Sprague-Dawley rats in a 90-day feeding study using concentrations of 0, 0.04, 0.2, 1 and 5%. Terephthalic acid resulted in a decrease in urinary pH and an increase in urinary Ca2+, Zn2+, Mg2+, K+ and Na+ concentrations . The volume of 24-hour urine was significantly increased in male rats in the 1% and 5% groups. White sediment was found in the urine of both sexes, however males seemed more susceptible than females. Alpha 2µ-globulin (AUG) in serum and urine from male rats was significantly increased in treated groups in a dose-dependent manner. Bladder hyperplasia was seen in 15 rats from the 5% group (14 males and 1 female); all of these rats had white sediment in the urine. The authors conclude that white sediment is the basis of terephthalic acid induced urolith formation, and is associated with terephthalic induced hyperplasia.

The same authors (Dai et al, 2005b) examined the effect of concomitant treatment with sodium bicarbonate or hydrochlorothiazide on terephthalic acid-induced urinary bladder hyperplasia and urolithiasis in weanling male SD rats. Immunohistochemical analyses were also performed. In the terephthalic acid treated group, hyperplasia and urolithiasis were apparent; findings were absent from the control group. PCNA-positive focal hyperplasic lesions involved all epithelial layers. Overexpression of cyclin D1, CDK4, and EGFr were found in the corresponding lesion. p16Ink4a nuclear staining reduced in proliferative bladders especially with a great quantity of stone. In addition, no positive expression was detected on cyclin E. The authors concluded that the present study provided a strong evidence of a link between induction of bladder hyperplasia, deregulation of the p16Ink4a-cyclin D1/CDK4 pathway, and abnormal EGFr mediated signal transduction pathway.

In a further study (Dai et al, 2006a), the authors conclude, based on metabolism and genotoxicity data, that the induction of bladder tumours by terephthalic acid represents a non-genotoxic mode of action.

Cui et al (2006) demonstrated that urinary calculi induced by the administration of 5% TPA in the diet had a strong promoting activity on urinary bladder carcinogenesis when MNU was used as an initiator. Urinary precipitate containing calcium terephthalate formed following the administration of lower dietary concentrations may also have weak promoting activity on urinary bladder carcinogenesis. The same authors (Cui et al, 20007) compared the protein expression pattern of rat bladder transitional cell carcinomas induced by terephthalic acid with that of normal bladder tissues using two-dimensional electrophoresis. Immunohistochemical staining revealed that ANNA1, usually a cytoplasmic protein in normal urothelium, was translocated to the nucleus in rat bladder cancer cells. The authors suggest that overexpression of ANNA1 is involved in bladder carcinogenesis induced by bladder calculi and that translocation of the protein may be partly responsible for the effect.

 

Oxidant status

In a study intended to investigate the effects of terephthalic acid (TPA) on rat lipid metabolism (Dai et al, 2006), five groups of SD rats were administered 0%, 0.04%, 0.2%, 1%, and 5% TPA in the diet for 90 days. The effects of TPA on levels of serum protein, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), total anti-oxidative capability (T-AOC), superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed. Urine samples were collected and analysed for electrolytes. TPA was found to reduce serum total anti-oxidative capability in a dose-dependent manner.  Serum and bladder malondialdehyde levels were significantly increased in the groups administered 1% and 5% TPA. Serum CuZn superoxide dismutase was reduced in groups of 0.2%, 1%, and 5% TPA.  TPA administration had no significant influences on serum total cholesterol, LDL or HDL, but increased serum triglycerides, total protein and albumin after administration of 0.04% and/or 0.2% TPA. Concentrations of urinary Ca2+, Mg2+, Na+, and K+ were elevated in 1% and 5% TPA groups. It was concluded that antioxidant potential decreased in rats after sub-chronic TPA exposure.

Investigation of endocrine disruptor activity

A number of studies have investigated the potential of TPA and the read-across substance DHET/DOTP to cause endocrine disruption.

Luciani-Torres et al (2015) investigated the effects of terephthalic acid in human breast cancer cells. TPA is reported to increase the ERα: ERβ ratio in multiple human high-risk donor breast epithelial cell (HRBEC) samples, suggesting an oestrogenic effect. TPA also promoted resistance to tamoxifen-induced apoptosis and arrested cell proliferation. DNA-PK, ATM and members of the MRN complex, known to be involved in DNA damage sensor and effector proteins, were elevated, indicating the induction of DNA strand-breaks. Early DNA damage checkpoint response, mediated through p53/p21, led to G1 arrest in TPA-exposed cells. Removal of TPA from the growth medium resulted in the rapid induction of BCL2, increasing the ratio of anti-:pro-apoptotic proteins, together with overexpression of Cyclin A/CDK2 proteins. Consequently, despite elevated p53pSer15 and H2AXpSer139, indicating sustained DNA damage, TPA exposed cells resumed robust growth rates seen prior to TPA exposure. The authors therefore conclude that exposure to TPA has the potential to perpetuate DNA aberrations that activate DNA damage pathways in cultured non-malignant breast cells. The significance of this non-standard study is unclear. It is notable that there is no indication of oestrogenic effects or increased incidences of mammary tumours in studies performed with TPA.

Expert assessment of the findings of this study (RSA, 2015) in the context of the wider dataset concludes that in vivo data provide no evidence that TPA interacts with estrogen or androgen hormonal systems. The in vitro data of Luciani-Torres et al. indicate that TPA increases ER-alpha levels in human breast cells, but this does not seem to be related to estrogenic (or antiestrogenic effects). It seems more likely to be related to effects on cell cycle machinery. Other cited references also provide no evidence that TPA is estrogenic whilst the paper of Osimitz et al. (2012) indicates that TPA has been tested in in vitro tests and found to be negative. In vivo reproductive and endocrine studies on TPA also indicate that these chemicals do not interact with the estrogen or androgen hormonal systems. The conclusion for mutagenicity and carcinogenicity mentions the low potential exposure of consumers to TPA and this combined with the lack of endocrine activity indicates very low risk.

Osimitz et al (2012) report an absence of androgenic and oestrogenic effects for TPA, based on assessment in a number of QSAR models and in vitro in receptor binding and activation assays. A similar lack of androgenic and oestrogenic effects is reported by the same authors (Osimitz et al., 2015) for TPA based on QSAR modelling, molecular docking studies and in vitro receptor binding and activation assays. The results of these batteries of in silico and in vitro assays therefore indicate that terephthalic acid has no activity at the androgen or oestrogen receptor. Jang & Ji (2015) report an absence of effects of TPA in a steroidogenesis assay performed in cultured H295R cells at concentrations of up to 6024 nM.

A number of studies are also available for the read-across substances DEHT/DOTP (which is hydrolysed to TPA in the gastrointestinal tract) and DMT (which is metabolised to TPA). Liu et al (2005) report an absence of effects of DEHT on gene expression in male rats exposed in utero; the negative findings for DEHT were in contrast to those reported for other phthalate esters known to be developmentally toxic. A uterotrophic assay with DHET/DOTP also reports a negatiave result. Osimitz et al (2012) reports a lack of activity for DMT in Hershberger and uterotrophic assays, therefore indicating a lack of oestrogenic, androgenic and anti-androgenic activity in vivo for DMT (and similarly for its primary metabolite, TPA).

The weight of evidence from studies in silico, in vitro and in vivo therefore indicates a lack of endocrine disruption potential for terephthalic acid.