Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Based on the results of the evaluation by the expert review by ATSDR (2003) and the read-across from the results of other selenites to zinc selenite, “there is no evidence to support a causal association between selenium substances and cancer in humans. In fact, some epidemiological and experimental evidence suggests that selenium exposure under certain conditions may contribute to a reduction in cancer risk. The chemopreventive potential of supplemental selenium is currently under research."

Key value for chemical safety assessment

Additional information

General

An independent, publicly available review of the carcinogenicity of selenium and selenium substances is available from ATSDR (2003). The key conclusions from this ATSDR summary on long-term carcinogen effects are summarised below.

Only the studies which were considered adequate by ATSDR, and which are relevant for the hazard assessment of zinc selenite are described here. Only data from animal studies with inorganic “selenites” (HSeO3-, SeO32-) and SeO2are taken into account (organic selenium substances or selenium sulfide are not considered). Human studies are considered in addition, because many of them were conducted including the determination of systemic selenium levels, e. g. in plasma or blood.

The investigations which were assessed as adequate by expert judgement for the ATSDR review were briefly summarised as endpoint study records, and the main conclusions and a statement concerning the relevance of the carcinogenic effects were included. No studies were identified with zinc selenite as the test substance, but sodium selenite was used as test substance in most of the animal studies. Thus, the read-across concept described below was applied.

Read-across from selenites to zinc selenite

Read-across from sodium selenite and other “selenites” to zinc selenite is considered justified if these substances have a bioavailability similar to that of zinc selenite (or higher) and is these are not associated with any other, substantially more toxic cations. Based on a comparison between toxicity reference values of zinc compounds and selenium compounds, it can safely be assumed that the selenium/selenite moiety of zinc selenite is generally of higher toxicological relevance than the zinc cations (for details see IUCLID section 7.1, endpoint summary "Toxicikinetics, metabolism and distribution"). Therefore, the subsequent assessment of the toxicity of zinc selenite focuses on the selenium moiety

Very little toxicological data exist with the test substance zinc selenite itself. However, for any kind of systemic toxicity, a substance first needs to be taken up systemically. In the case of an inorganic salt like zinc selenite, such an uptake is always associated with a dissolution of the substance, i.e. dissociation into ions. Zinc selenite initially dissociates into zinc cations (Zn2+) and selenite anions (SeO32-). Since toxicological test data are mainly available for sodium selenite (Na2SeO3), the first level of read-across considers extrapolation from this substance to zinc selenite.

Justification:

a) In-vivo toxicokinetic data or in-vitro bioaccessibility data for a comparative assessment of relative bioavailability of various selenite substances are not available. Thus, water solubility is adopted as a surrogate for bioavailability, as follows:

substance

water solubility

sodium selenite

800-900 g/L

zinc selenite

16 mg/L

Sodium selenite is readily soluble, with water solubilities of 800 – 900 g/L at 20 °C, respectively. Zinc selenite is a salt which is only poorly soluble in water at a concentration of 16 mg/L at 20 °C. Based on that, an intrinsically very conservative read-across from the highly soluble selenite to the poorly soluble zinc selenite is proposed , because it may reasonably be assumed that zinc selenite has a lower bioavailability than sodium selenite.

b) Sodium selenite and zinc selenite both liberate the selenite anion upon dissolution. Assuming that (i) sodium selenite and zinc selenite both dissociate in water to SeO32-and the cationic counter-ions, and (ii) the potential effects are caused by SeO32-and not by the cations, the results from the available studies with sodium selenite can be used for read across to zinc selenite. The selenite anions are formed under most physiologically relevant conditions (i.e., neutral pH), thus facilitating unrestricted read-across between these species. In slightly acid condition, the hydrogenselenite ion, HSeO3-, is formed; in more acidic conditions selenous acid, H2SeO3, exists.

H2SeO3<=> H++ HSeO3- (pKa= 2.62)

HSeO3- <=> H++ SeO32-   (pKa= 8.32)

Based on these equilibrium conditions, read-across between the groups of selenites, hydrogenselenites and selenous acid is possible.

Thus, read-across from other “selenites” to zinc selenite seems in principle also possible, if they do not have a bioavailability significantly below zinc selenite or are not associated with any significantly toxic cations.

Data evaluation by ATSDR

The following general statement was made by ATSDR related to the cancer risk of selenium substances: "Studies of laboratory animals and people show that most selenium compounds probably do not cause cancer. In fact, some studies of cancer in humans suggest that lower-than-normal selenium levels in the diet might increase the risk of cancer. Other studies suggest that dietary levels of selenium that are higher than normal might reduce the risk of cancer in humans. However, taking selenium so that your daily amount is greater than that required might just increase your risk of selenium poisoning. Based on studies done until 1987, the International Agency for Research on Cancer (IARC) determined that selenium and selenium compounds could not be classified as to their ability to cause cancer in humans. However, since then, the EPA has determined that one specific form of selenium, called selenium sulfide, is a probable human carcinogen.Selenium sulfide is the only selenium compound shown to cause cancer in animals. "

Selenium sulfide is definitely outside the scope of this hazard assessment, because it is very different from the other inorganic selenium substances, so that the following statement can be regarded as appropriate for zinc selenite: “There is no evidence to support a causal association between selenium compounds and cancer in humans. In fact, some epidemiological and experimental evidence suggests that selenium exposure under certain conditions may contribute to a reduction in cancer risk. The chemopreventive potential of supplemental selenium is currently under research. "

The mechanism of selenium acting against cancer formation is described in ATSDR as follows: "Hypotheses for the protective role of selenium against cancer development include the inhibition of carcinogen-induced covalent DNA adduct formation, retardation of oxidative damage to DNA, lipids, and proteins, and modulation of cellular and molecular events that are critical in cell growth inhibition and in the multi-step carcinogenesis process. ”

It is also worth mentioning that:“The possible inverse relationship between dietary selenium intake and the risk of various types of cancer has been examined in numerous epidemiological studies in the United States and other countries. [... ] In recent years, much of the research in laboratory animals using the oral route of administration of selenium compounds has been directed toward the anticarcinogenic properties of selenium compounds. “

The following is summarised in the ATSDR related to the different routes of exposure and carcinogenicity.

Oral exposure:

“Human dietary studies generally do not identify the selenium form specifically; both organic (from grains and other plant and animal products) and inorganic (from drinking water) forms are ingested. Animal bioassays in which selenium was administered as sodium selenate, sodium selenite, or organic forms of selenium have all shown similar negative results.”

In general it is stated by ATSDR that“The majority of oral studies have provided information on the absence of carcinogenic effects in humans and animals (Beems 1986; Clark et al. 1996a, 1999; Coates et al. 1988; Duffield-Lillico et al. 2002; Harr et al. 1967; Menkes et al. 1986; Thompson and Becci 1979; Virtamo et al. 1987). ”

It is also noted that in„Early studies reporting that selenium was carcinogenic in mammals after being provided as seleniferous corn or wheat in the diet, as sodium selenite or sodium selenate in drinking water, or as sodium selenate in the diet were flawed. “

Two studies(Schroeder and Mitchener 1971a; Vinceti et al. 1998)which showed incidences of melanoma or tumours possibly correlated with administration of selenites were discussed by ATSDR and it was concluded that "There were severalinadequaciesin the early studies that reported carcinogenic effects in animals following oral administration of selenium-containing compounds. ”Since these studies were assessed as unreliable by ATSDR due to expert judgement, they were included as study-records, but disregarded for the further evaluation of this endpoint.

Overall, it was concluded by the ATSDR expert review that "The majority of subsequent studies of humans and animals have revealed no association between selenium intake and the incidence of cancer(e. g. Azin et al. 1998; Beems 1986; Coates et al. 1988; Harr et al. 1967; Ma et al. 1995; Menkes et al. 1986; Ratnasinghe et al. 2000; Thompson and Becci 1979; Vinceti et al. 1995; Virtamo et al. 1987)or a clear chemopreventive association(Birt et al. 1982; Clark et al. 1996a, 1999; Finley et al. 2000; Ip 1981, 1983; Ip and Lisk 1995; Ip et al. 1996, 1997, 1998, 2000a, 2000b; Jiang et al. 1999; Ma et al. 1995; Medina and Shepherd 1981; Overvad et al. 1985; Schrauzer et al. 1976, 1977; Shamberger et al. 1976; Soullier et al. 1981; Thompson and Becci 1980; Woutersen et al. 1999; Yoshizawa et al. 1998).Some epidemiological and experimental evidence suggests that selenium exposure, under certain conditions, may contribute to a reduction in cancer risk(Clark et al. 1996a, 1999; El-Bayoumy 2001; Ganther 1999; Moyad 2002; Spallholz 2001; Yoshizawa et al. 1998) ", and that“... selenium supplementation has generally been shown to significantly inhibit tumours induced by chemicals, viruses, or ultraviolet light(e. g. Birt et al. 1982; Finley et al. 2000; Ip 1981, 1983; Jabobs 1983; Jacobs et al. 1977a, 1977b, 1979, 1981; Jiang et al. 1999; Medina and Shepherd 1981; Overvad et al. 1985; Schrauzer et al. 1976; Soullier et al. 1981; Thompson and Becci 1980; Woutersen et al. 1999).Results following administration of selenium as sodium selenate, sodium selenite, and organic forms of selenium are similar.”

Inhalation exposure

According to ATSDR,"no studies were located regarding carcinogenic effects in laboratory animals after inhalation exposure to selenium or selenium compounds. No further investigation is needed since humans have not been shown to have an increased risk of malignancy from selenium exposure [...] There are no epidemiologic data that support a causal association between the inhalation of elemental selenium dusts or selenium compounds and the induction of cancer in humans (Gerhardsson et al. 1986; Wester et al. 1981). In one study, postmortem samples were collected from copper smelter workers who were exposed to several different airborne compounds, including selenium compounds. Samples from lung cancer cases had lower concentrations of selenium in lung tissue than samples from controls or from workers who had died from other causes (Gerhardsson et al. 1986). In another autopsy study of smelter workers,Wester et al. (1981)found that the selenium concentrations in kidney tissues from workers who had died of malignancies were lower than the selenium concentrations in kidney tissues from workers who died of other causes."

Dermal exposure

No study reports on dermal exposure are described in ATSDR (2003) concerning zinc selenite or any other “selenite” compound”.According to ATSDR,"no studies were located regarding carcinogenic effects in humans after dermal exposure to selenium or selenium compounds. The results of most animal studies have not indicated that elemental selenium or selenium compounds are carcinogenic when topically applied to the skin of experimental animals... ”

Justification for classification or non-classification

"In 1975, the International Agency for Research on Cancer (IARC) evaluated the literature relating selenium to carcinogenesis in both humans and animals. The Agency stated that the available data provided no suggestion that selenium is carcinogenic in humans(IARC 1975a), and IARC subsequently assigned selenium to Group 3: not classifiable as to its carcinogenicity to humans (IARC 1987). The forms of selenium considered included sodium selenate, sodium selenite, and the organic forms of selenium contained in plant materials. "IARC proposed the same classification in IARC, 2001.

Additionally, according to EPA“selenium is not classifiable as to its carcinogenicity in humans and is rated as Group D (IRIS 2003). ”

Based on the results of the evaluation by ATSDR (2003), the IARC evaluation and the possibility of read-across from the results of other selenites to zinc selenite, no classification for carcinogenicity is proposed for zinc selenite since “there is no evidence to support a causal association between selenium compounds and cancer in humans. In fact, some epidemiological and experimental evidence suggests that selenium exposure under certain conditions may contribute to a reduction in cancer risk. The chemopreventive potential of supplemental selenium is currently under research. "

References:

IARC 1975a:IARC monographs on the evaluation of carcinogenic risk of chemicals to man: Some aziridines, N-, S-, & O-mustards and selenium. Vol. 9. Lyon, France: World Health Organization, International Agency for Research on Cancer

IARC 1987: IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans: Summary table. Lyon, France: World Health Organization, International Agency for Research on Cancer Supp 7:71

IARC, 2001: Selenium and selenium compounds: Summary of data reported and evaluation. Lyon, France: World Health Organization, International Agency for Research on Cancer

IRIS 2003: Integrated Risk Information System. Washington, DC: U. S. Environmental Protection Agency