Barium selenite

Carcinogenicity

Description of key information

Background

 

A read-across category-approach is used for the assessment of the toxicological properties of selenium and selenium compounds. The following Se-substance are included in the category:

• Se-metal (massive, powder)
• Disodium selenate
• Disodium selenite
• Selenium dioxide / selenious acid
• Zinc selenite
• Barium selenite

A detailed rationale for the read-across hypothesis has been outlined in the read-across report that was generated according to the principles laid out in the Read-Across Assessment Framework (RAAF). In summary, the physico-chemical behavior of elemental selenium (once it has formed an ion-from its metal state), disodium selenite, disodium selenate and selenium dioxide/selenious acid is the same with regard to their metabolic fate. All selenium compounds (organic and inorganic, including elemental selenium), do share the very same metabolic fate in that after their resorption, reduction to the selenide moiety [Se^2-], which is the single common precursor for its further metabolic conversion, takes place.

Therefore, there seems to be good evidence that different selenium moieties will behave very similar also for their ability to form reactive species which may play a decisive role in the generation of cytotoxicity followed likewise by unspecific and secondary clastogenicity and read-across can be made from the available data for disodium selenite. It is concluded that additional testing for each individual member of the proposed Se-category is not necessary and scientifically not meaningful.

In the case of inorganic salts like barium selenite and zinc selenite, uptake is always associated with a dissolution of the substance, i.e. dissociation into the metal cation (Zn²⁺, Ba²⁺) and the selenite anion (SeO₃^2-). It can safely be assumed that the selenium/selenite moiety of barium/zinc selenite is generally of higher toxicological relevance than the zinc/barium cations. Therefore, the subsequent assessment of the toxicity of barium/zinc selenite focuses on the selenium moiety. As no in vivo toxicokinetic data or in vitro bioaccessibility data are available for a comparative assessment of relative bioavailability of various selenite substances, water solubility is adopted as a surrogate for bioavailability. Disodium selenite is readily soluble, with a water solubility of 800-900 g/L at 20°C. Barium selenite and zinc selenite, on the other hand, are poorly soluble salts (water solubility at 20°C of 66.7 mg/L and 16 mg/L, respectively, i.e. a difference of four/five orders of magnitude). Based on that, an intrinsically very conservative read-across from highly soluble forms to the poorly soluble barium/zinc selenite is proposed as the latter are assumed to have a lower solubility. It should also be noted that selenite anions in the tests with disodium selenite are formed under most physiological relevant conditions (i.e. neutral pH), thus facilitating unrestricted read-across between the various substances. In slightly acid conditions (pKa:8.32) the hydrogen selenite ion (HSeO₃^-) is formed whereas in more acidic conditions (pKa:2.62) the formation of selenious acid is observed (H₂SeO₃). Based on such existing equilibrium conditions, read-across between selenites, hydrogen selenites and selenious acid (solubility of 1670 g/L at 20°C) is justified.

 

The results of the evaluation by the expert review by ATSDR (2003) was the starting point for assessing the potential carcinogenic properties of the SE-compounds that are included in the Se-category group for read-across. In summary, 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.

Justification for classification or non-classification

The International Agency for Research on Cancer (IARC, 1975) 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 these findings, and based on the studies that were also used by ATSDR (2003) in their toxicological assessment of selenium compounds, it is concluded that no classification for carcinogenicity is proposed for the following Se-substances: Se-metal (massive, powder)

• Disodium selenate
• Disodium selenite
• Selenium dioxide/selenious acid
• Zinc selenite

There is no evidence to support a causal association between any of these 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.

Additional 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

Additional information

Overview of relevant and reliable data

 

A comprehensive literature search has been conducted by the registrant in factual data bases and secondary literature sources. Studies performed with organic selenium compounds were excluded from evaluation as the bioavailability is much higher than for inorganic selenium compounds. 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.

 

During this search the most comprehensive and recent review document " Toxicological Profile for Selenium”, ATSDR - U.S. Department of Health and Human Services, Public Health Service (2003)" has been identified and is used as the key source of relevant data on selenium and selenium compounds, because it contains an evaluation of the toxicity information performed by a renowned scientific body. Nevertheless all key references identified by ATSDR have been screened for use in the REACH dossiers according to Klimisch and with respect to the requirements for risk assessment.

 

 

 

Literature cited 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.

 

The following statement can be regarded as appropriate for the Se-substances that are considered in the current category : “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 chemo-preventive potential of supplemental selenium is currently under research. "

The mechanism of selenium acting against cancer formation is "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. 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).

ATSDR did point out that 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 have been discussed, and it was concluded that there were several inadequacies in 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 are included in dossier as study-records, but disregarded for the further evaluation of this endpoint.

 

In line with the findings of the ATSDR expert review, it is concluded that the majority of subsequent studies of humans and animals reveal 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). There are, however, some epidemiological and experimental evidence that 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 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).

 

Inhalation exposure

No studies have been identified 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. Until now, there are also no epidemiologic data available that would 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 studies have been identified with regard to potential 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.