1. Exposure Data

1.1. Identification of the agent

1.1.1. Tamoxifen

• Chem. Abstr. Serv. Reg. No.: 10540-29-1
• Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
• IUPAC Systematic Name: 2-[4-[(Z)-1,2-Diphenylbut-1-enyl]phenoxy]-N,N-dimethylethanamine
• Synonyms: 1-p-β-Dimethylaminoethoxyphenyl-trans-1,2-diphenylbut-1-ene; (Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]ethyldimethylamine
• Description: Crystalline solid (O’Neil, 2006)

(a) Structural and molecular formulae, and relative molecular mass

C₂₆H₂₉NO

Relative molecular mass: 371.52

1.1.2. Tamoxifen citrate

• Chem. Abstr. Serv. Reg. No.: 54965-24-1
• Chem. Abstr. Name: (Z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)
• IUPAC Systematic Name: 2-[4-[(Z)-1,2-Diphenylbut-1-enyl]phenoxy]-N,N-dimethylethylamine; 2-hydroxypropane-1,2,3-tricarboxylic acid
• Synonyms: Kessar; Nolvadex; Soltamox; tamoxifen citrate; Z-tamoxifen citrate
• Description: Fine, white, odourless crystalline powder (O’Neil, 2006)

(a) Structural and molecular formulae, and relative molecular mass

C₂₆H₂₉NO.C₆H₈O₇

Relative molecular mass: 563.64

2. Cancer in Humans

3. Cancer in Experimental Animals

Tamoxifen has been tested for carcinogenicity by oral and subcutaneous administration to adult and infant mice and rats, and by transplacental exposure to mice.

3.1. Oral administration

3.1.1. Mouse

In mice treated orally, tamoxifen increased the incidence of benign ovarian and benign testicular tumours in one study (Tucker et al., 1984), but did not increase the tumour incidence in two other studies (Carthew et al., 1996a; Martin et al., 1997).

3.1.2. Rat

Rats dosed orally with tamoxifen had an increased incidence of benign and malignant liver cell tumours in multiple studies (Greaves et al., 1993; Hard et al., 1993; Hirsimäki et al., 1993; Williams et al., 1993, 1997; Ahotupa et al., 1994; Hasmann et al., 1994; Carthew et al., 1995b; Dragan et al., 1995; Kärki et al., 2000; Carthew et al., 2001; Kasahara et al., 2003). When given at a lower dose level, tamoxifen decreased the incidence of benign and malignant mammary gland tumours in female rats, and benign pituitary tumours in both sexes (Maltoni et al., 1997).

See Table 3.1.

Table 3.1

Studies of cancer in experimental animals exposed to tamoxifen (oral exposure).

3.2. Subcutaneous administration

3.2.1. Mouse

In mice treated subcutaneously, tamoxifen decreased the incidence of mammary tumours in multiple studies (Jordan et al., 1990, 1991). One study using a transgenic mouse model susceptible to spontaneous mammary tumours resulted in an increased incidence of malignant mammary tumours (Jones et al., 2005).

3.2.2. Rats

Female rats administered the tamoxifen metabolite 4-hydroxytamoxifen subcutaneously had a decreased incidence of benign and malignant mammary tumours in one study (Sauvez et al., 1999).

See Table 3.2.

Table 3.2

Studies of cancer in experimental animals exposed to tamoxifen (subcutaneous administration).

3.3. Perinatal administration

3.3.1. Mouse

Tamoxifen given orally or subcutaneously to female neonatal mice increased the incidence of uterine tumours in one study (without an obvious dose–response) (Newbold et al., 1997), but had no effect upon urogenital tumours in three other studies (Green et al., 2005; Waalkes et al., 2006a; Razvi et al., 2007). Male mice exposed transplacentally to arsenite and treated neonatally with tamoxifen had a decreased incidence of benign and malignant lung tumours in one study (Waalkes et al., 2006b). One study in which tamoxifen was administered transplacentally to mice was negative (Diwan et al., 1997).

3.3.2. Rat

The administration of tamoxifen to female neonatal rats caused an increase in reproductive tract tumours in one study (Carthew et al., 2000), but no effect in another study of shorter duration with fewer animals (Karlsson, 2006).

See Table 3.3.

Table 3.3

Studies of cancer in experimental animals exposed to tamoxifen (perinatal exposure).

3.4. Administration with known carcinogens

In several studies in both male and female rats, tamoxifen enhanced the hepatocarcinogenicity of previously administered N,N-diethylnitrosamine (IARC, 1996). In one study in rats, tamoxifen enhanced the development of N-nitrosodiethylamine-induced kidney tumours (Dragan et al., 1995). In another study, the administration of tamoxifen to pregnant rats increased mammary gland tumours in offspring subsequently treated with 7,12-dimethylbenz[a]anthracene (Halakivi-Clarke et al., 2000).

See Table 3.4.

Table 3.4

Studies of cancer in experimental animals exposed to tamoxifen and known carcinogens.

4. Other Relevant Data

In the previous IARC Monograph (IARC, 1996), tamoxifen was found to increase liver tumour incidence in rats. The available evidence indicated that tamoxifen is both a genotoxic carcinogen and a tumour promoter in rat liver, and that humans are likely to be less susceptible to the genotoxicity of the drug. It was suggested that tissue-specific effects of tamoxifen binding to the estrogen receptor on gene expression might be involved in the ability of tamoxifen to increase or decrease tumour risk. The pertinent mechanistic data that appeared since this review are summarized below.

4.2. Genetic and related effects

4.2.1. Direct genotoxicity

(a) DNA adducts

(i) Humans

Tamoxifen–DNA adducts have not been detected in human liver in vivo (IARC, 1996), and the low level of DNA covalent-binding by α-hydroxytamoxifen in cultured human hepatocytes (Phillips et al., 1996a) probably reflects the intrinsic chemical reactivity of α-hydroxytamoxifen rather than enzymatic activation, as this metabolite is a poor substrate for human sulfotransferases (Glatt et al., 1998a; Shibutani et al., 1998a). Moreover, the glucuronidation pathway predominates in incubations of α-hydroxytamoxifen with human liver microsomes (Boocock et al., 2000), which presumably leads to detoxification.

There are conflicting results on the formation of tamoxifen–DNA adducts in humans. The evidence for (Hemminki et al., 1996; Shibutani et al., 1999, 2000a; Martin et al., 2003) and against (Carmichael et al., 1996, 1999; Beland et al., 2004a) such adducts in the human endometrium in vivo has been reported by several groups. This is also the case in studies on the formation of tamoxifen–DNA adducts from incubation of tamoxifen with human endometrium explants, with positive (Sharma et al., 2003) and negative (Beland et al., 2004b) findings being reported in samples from the same origin. Some studies reported the presence of such adducts in white blood cells from tamoxifen-treated patients (Hemminki et al., 1997; Umemoto et al., 2004), while others reported negative results (Phillips et al., 1996b; Bartsch et al., 2000). With the exception of the study by Martin et al. (2003), who used accelerator mass spectrometry, most studies used ³²P-postlabelling for adduct detection. Beland et al. (2004a, b) used HPLC coupled with tandem mass spectrometry, which can provide unequivocal structural characterization.

A recent study has reported the presence of (E)-α-(deoxyguanosin-N²-yl)tamoxifen (dG-Tam) at levels of 1–7 adducts/10⁹ nucleotides in enzymatically hydrolysed colorectal DNA from 3/10 women administered a single dose of 20 mg ¹⁴C-labelled tamoxifen approximately 18 hours before colon resection surgery. The detection methodology involved HPLC coupled with accelerator mass spectrometry, and the identification was based upon comparison with an authentic adduct standard. All colon samples had detectable levels of CYP3A4 (Brown et al., 2007).

(ii) Experimental systems

DNA adducts have been detected at dose-dependent levels in rat liver following administration of tamoxifen (IARC, 1996), and some of its metabolites, such as N-desmethyltamoxifen, α-hydroxytamoxifen, and α-hydroxy-N-desmethyltamoxifen (Brown et al., 1998, 1999; Martin et al., 1998; Phillips et al., 1999, 2005; Gamboa da Costa et al., 2000, 2001; White et al., 2001). A quantitatively minor phase I pathway that leads to the metabolic activation of tamoxifen to DNA-binding electrophiles in rat liver is catalysed by CYP3A enzymes. This involves hydroxylation at the allylic (α) carbon of tamoxifen (Kim et al., 2003) and N-desmethyltamoxifen, which is then followed by phase II conjugation. Although acetyltransferases have been proposed as mediators in the activation of α-hydroxylated tamoxifen metabolites, the most convincing evidence indicates that activation occurs through sulfotransferase-mediated sulfation, specifically by the STA2 isoform of hydroxysteroid sulfotransferase (Davis et al., 1998, 2000; Glatt et al., 1998a, b; Shibutani et al., 1998a, b; Kim et al., 2005; Phillips et al., 2005). In addition, a parallel adduct formation pathway involving N-demethylation, as well as α-hydroxylation and O-sulfonation occurs (Fig. 4.1). The N-demethylation of tamoxifen is also mediated by the CYP3A subfamily (IARC, 1996). In-vitro reactions conducted with either the synthetic model esters, α-acetoxytamoxifen and α-acetoxy-N-desmethyltamoxifen (Osborne et al., 1996; Dasaradhi & Shibutani, 1997; Kitagawa et al., 2000) or the corresponding synthetic sulfates (Dasaradhi & Shibutani, 1997; Gamboa da Costa et al., 2000) have led to the identification of the major DNA adducts as (E)-α-(deoxyguanosin-N²-yl)tamoxifen (dG-Tam) and (E)-α-(deoxyguanosin-N²-yl)-N-desmethyltamoxifen (dG-desMe-Tam), which exist as mixtures of epimers at the allylic carbon. Minor adducts from these reactions include the Z diastereomers from dG-Tam and dG-desMe-Tam (Dasaradhi & Shibutani, 1997; Osborne et al., 1997; Kitagawa et al., 2000), and a deoxyadenosine-tamoxifen adduct, linked through the amino group of adenine (Osborne et al., 1997). Comparison with characterized synthetic standards has confirmed that dG-Tam and dG-desMeTam are the major adducts formed in rat liver following treatment with tamoxifen regardless of the rat strain, the route of administration, or the length of exposure (Osborne et al., 1996; Rajaniemi et al., 1998, 1999; Brown et al., 1999; Phillips et al., 1999; Firozi et al., 2000; Gamboa da Costa et al., 2000). Interestingly, the R enantiomers of α-hydroxytamoxifen (Osborne et al., 2001) and α-hydroxy-N-desmethyltamoxifen (Osborne et al., 2004) have much higher binding affinity in rat hepatocytes than the corresponding S isomers, presumably as a result of better affinity of the R enantiomers for the sulfotransferases.

Figure 4.1

Proposed pathways of activation of tamoxifen in rat liver.

Although a significant level of the didesmethylated analogue of dG-Tam and dG-desMeTam was detected in rat liver following administration of the putative metabolite, α-hydroxy-N,N-didesmethyltamoxifen, the low extent of binding obtained upon dosage with N,N-didesmethyltamoxifen indicates that metabolic activation to α-hydroxy-N,N-didesmethyltamoxifen is a minor pathway in the rat (Gamboa da Costa et al., 2003). Likewise, metabolism via 4-hydroxytamoxifen does not seem to be a significant pathway to DNA-adduct formation in the rat (Beland et al., 1999; Osborne et al., 1999; Kim et al., 2006a), despite the fact that the metabolite can be activated enzymatically to products covalently bound to DNA in cell-free or subcellular systems (Pathak et al., 1995, 1996), and both its oxidation products, 4-hydroxytamoxifen quinone methide (Marques & Beland, 1997) and α-4-dihydroxytamoxifen (Hardcastle et al., 1998) give DNA adducts upon reaction with DNA in vitro. An additional minor pathway to DNA adduct formation in rat liver has been reported to proceed via α-hydroxytamoxifen N-oxide, again involving binding at the α carbon through the exocyclic nitrogen of deoxyguanosine (Umemoto et al., 1999, 2001).

While tamoxifen–DNA adducts are consistently detected in rat liver, most studies have not detected DNA adducts in the uterus and other extrahepatic tissues from rats administered tamoxifen or tamoxifen metabolites (Li et al., 1997; Brown et al., 1998; Beland et al., 1999; Carthew et al., 2000; Gamboa da Costa et al., 2001; Phillips et al., 2005). However, one study, which involved the use of accelerator mass spectrometry, reported that [¹⁴C]tamoxifen binds to DNA in the liver, intestine, reproductive tract, spleen, lung, and kidney of rats dosed orally (White et al., 1997). However, this methodology does not provide any structural information. [The Working Group noted that it was not clear whether the measured radioactivity corresponded exclusively to tamoxifen covalently bound to DNA.]

Tamoxifen also forms DNA adducts in mouse liver, though the levels are typically lower than in the rat (IARC, 1996). In addition, chronic exposure does not lead to accumulation of DNA adducts, which, combined with the absence of tamoxifen-induced cell proliferation, may account for the lack of hepatic carcinogenicity in the mouse, as opposed to the rat (Martin et al., 1997). Similarly to what is found in the rat, the major DNA adducts in mouse liver are dG-Tam and dG-desMeTam; although still minor, the adduct diastereomers derived from α-hydroxytamoxifen N-oxide make up a higher proportion in the mouse than in the rat (Umemoto et al., 2000, 2001). The presence of DNA adducts in mouse extrahepatic tissues, including the uterus, has not been investigated.

Low levels of combined dG-Tam and dG-desMeTam were detected by different methods in the liver, brain cortex, kidney, ovary, and uterus of a group of three female cynomolgus monkeys dosed with a daily regimen of 2 mg tamoxifen/kg body weight for 30 days (Schild et al., 2003; Shibutani et al., 2003). These studies have shown that tamoxifen DNA adducts can be formed in extrahepatic tissues of non-human primates.

(b) Additional genotoxic effects

Tamoxifen induces micronuclei in metabolically proficient human cells and causes aneuploidy and chromosomal aberrations in rat liver (IARC, 1996; Styles et al., 1997). Moreover, both tamoxifen and α-hydroxytamoxifen cause mutations in the lacI reporter gene and the cII gene in the livers of Big Blue transgenic rats (Davies et al., 1996, 1997, 1999; Styles et al., 2001; Chen et al., 2002; Gamboa da Costa et al., 2002) although α-hydroxytamoxifen causes significantly higher mutant frequencies than does tamoxifen, the mutational spectra induced by the two compounds are very similar in both genes, with the predominant mutations being G→T transversions. Mutations are not observed in extrahepatic tissues, including the uterus, which is in agreement with the general lack of detection of DNA adducts in rat tissues other than the liver. Consistent with the mutation profile in rat liver, when single-stranded shuttle vectors containing each of the four dG-Tam diastereomers were transfected into simian kidney (COS7) cells, the prevalent mutations were, in all instances, G→T transversions (Terashima et al., 1999). Likewise, when α-hydroxytamoxifen was tested in V79-rHSTa cells, a mammalian cell line with stable expression of rat hydroxysteroid sulfotransferase A (STA2), mutations at the Hprt gene were mainly GC→TA transversions, although single G:C base-pair deletions and partial/complete exon skippings were also observed, almost exclusively at guanines on the non-transcribed strand (Yadollahi-Farsani et al., 2002). Additionally, both 4-hydroxytamoxifen quinone methide and the model ester, α-acetoxytamoxifen, are promutagenic using adducted pSP189 plasmid DNA containing the supF gene transfected into cultured human fibroblasts and kidney cells (McLuckie et al., 2002, 2005). Experiments involving the use of site-specific modified oligonucleotides as templates in primer extension reactions with several mammalian DNA polymerases indicate that all four dG-Tam diastereomers have high miscoding potential (G→T mutation) (Shibutani & Dasaradhi, 1997; Yasui et al., 2006). These adducts undergo nucleotide excision repair in vitro (Shibutani et al., 2000b). A comparative study in excision-repair-deficient (XPC knockout) and wild-type mice indicated that they have similar removal rates in both strains, which indicates that hepatic tamoxifen DNA-adducts are not efficiently repaired by this pathway (Kim et al., 2006b).

A study of the DNA-damaging potential of tamoxifen in normal human peripheral blood lymphocytes and MCF-7 breast cancer cells using the comet assay reported evidence for the presence of free radicals, which might account, in part, for the genotoxicity of tamoxifen under the experimental conditions presumably due to incomplete repair of double-strand breaks (Wozniak et al., 2007).

Both tamoxifen and its β-chlorinated analogue toremifene, which has a much lower potential for DNA-adduct formation (Gamboa da Costa et al., 2007), are associated with endometrial K-ras codon 12 mutations (Wallén et al., 2005), although a different study concluded that toremifene has a much lower potential than tamoxifen for K-ras mutation induction in the human endometrium (Hachisuga et al., 2005). [The Working Group noted that mutations in TP53 and K-RAS are low-frequency lesions in the common form of endometrial cancer and even those mutations appear late in the course of tumour development (Sherman, 2000).]

4.2.2. Estrogen-receptor-mediated mechanism

Experimental evidence increasingly supports the importance of estrogen-receptor-mediated gene regulation as the mechanism responsible for the differential action of tamoxifen in distinct tissues (Wu et al., 2005). Selective estrogen-receptor modulators such as tamoxifen have tissue-specific estrogenic activity. Tamoxifen is an estrogen-receptor antagonist in the breast but an estrogen-receptor agonist in the bone and uterus. The two main forms of the estrogen receptor, estrogen receptor-α and estrogen receptor-β, have different tissue expression profiles. The uterus predominantly expresses estrogen receptor-α but the observation of increased cell proliferation and excessive response to estrogen in estrogen-receptor-β-knockout mice has suggested that estrogen receptor-β could modulate estrogen receptor-α in the uterus, and have an antiproliferative role (Lecce et al., 2001). Tamoxifen stimulates proliferation of the human endometrial epithelium (Mourits et al., 2002). Tamoxifen-liganded estrogen receptors associate with multiple co-activator proteins, which together determine tamoxifen binding and transactivation activity (Shang, 2006). Tamoxifen regulates gene transcription in epithelial cells from type I endometrial carcinomas (Wu et al., 2005), and transcriptional responses have been identified in epithelial cells but not in stromal cells (Pole et al., 2004). There is also evidence that the genes targeted by tamoxifen differ from those targeted by estrogen (Pole et al., 2005).

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of tamoxifen. Tamoxifen causes cancer of the endometrium.

For cancer of the female breast, there is evidence suggesting lack of carcinogenicity. An inverse relationship has been established between exposure to tamoxifen and cancer of the female breast.

There is sufficient evidence in experimental animals for the carcinogenicity of tamoxifen.

Tamoxifen is carcinogenic to humans (Group 1).

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