Zinc selenite

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference

Reference Type:

publication

Title:

Studies of Human Maximal and Minimal Safe Intake and Requirement of Selenium

Author:

Yang G et al

Year:

1989

Bibliographic source:

Selenium in biology and Medicine, A Wendel, Springer Verlag, 1989

Materials and methods

Study type:

cohort study (prospective)

Endpoint addressed:

repeated dose toxicity: oral

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Se in a mainly natural food form

IUPAC Name:

Se in a mainly natural food form

Details on test material:

The chemical form of Se ingested was mainly in a natural food form.

Method

Type of population:

general

Ethical approval:

not applicable

Details on study design:

Three sites with low, medium and high Se levels in theseleniferous region in Enshi county were chosen for this study.
Two hundred to 300 subjects of different ages and sexes were included from each site.
The chemical form of Se ingested was mainly in a natural food form.
The subjects arc life-long residents and cases of selenosis appeared in the high Se site.
Field studies conducted in April and September 1986 followed the pilot study of November 1985.

Details on exposure:

Foods consumed during the 3-day survey were collected for Se analysis.
Blood, 24-h urine, breast milk and tissue samples were collected for Sc. Hg, Cd, Zn, Cu or As determination.
In order to determine the expected level of Se-intake, individual Se intakes or tissue Se levels were correlated with either biochemical parameters
or clinical signs. If the tissue-Se level was known, it could be transferred to the respective Se intakes through regression equations.

The average daily Se intakes in medium and high Se sites were around 3- to 20-fold that of the low Se site.
No significant differences were found between male and female adults.
Se intake and tissue or body fluid Se concentration were found to be significantly correlated, and similar relationships were also found between Se
concentrations of tissue.
Of the metals analyzed, only Cd and As were considered high either in the blood and hair or hair respectively of high Se site residents,
but their effects on Se metabolism remain to be studied.

Results and discussion

Results:

Results show that clinical signs may occur at a marginal blood-Se level of approximately ≥ 1 µg/mL or a corresponding marginal
daily Se-intake of 850 µg/day, while biochemical alterations suggested a marginal blood-Se level of around ≤ 1.0 µg/mL or an approximate, marginal,daily safe Se intake of 750 µg/day. As a safety factor of 1.3 is used, a maximal daily safe Se intake of 550 µg/day is suggested for inhabitants in
seleuiferous area.

Any other information on results incl. tables

Percentage of Se Excretion from Se Intake:

The percentage varied within 40-45 of a wide range of Se intakes until approximately 2000 µg/ day (10- 2000 µg) was attained. However, such a homeostatic regulation weakened and the excretion percentage began to plateau as Se intake increased to near 800 µg/day (blood-Se level 0.95 µg/mL). As the Se intake further increased to over 1000 µg, the percentage excretion increases nearly to a constant. This seems to indicate that as Se intake increases to around 800 µg/day the kidney would begin failing to regulate the excretion of Se in the urine. No notable change of the (CH)₃Se⁺ content in urine was observed.

Plasma Prothrombin Time:

Excessive ingestion of Se may damage the parenchymal cells of the liverand impair the hepatic synthesis of clotting factor(s). Blood samples of inhabitants from different sites were collected for measurement of plasmaprothrombin time. It was found that as blood-Se increased to a level above 1µg/mL (850 µg Se intake), cases with a prolonged prothrombin time increased abruptly.

Other Biochemical Parameters:

As Se intake increased to a high level, changes of other biochemical parameters were observed:

(I) decrease of the plasma-Se to erythrocyte-Se ratio may indicate an increased burden of Se to the body.

(2) Decrease of whole blood GSH concentration may indicate the shifting of blood GSH metabolism towards a higher oxidation stale. (3) No indication of anemia was observed from hemoglobin, hematocrit or erythrocyte-free proporphyrin content determination.

(4) Severe liver damage was again not detected either from analyses of biochemical indicators such as serum GPT, ZnTT, TTT, icteric index and alkaline phosphatase activity or through supersonic B morphologic examination.

(5) White cell count increased stepwise from the low to high Se site; its significance is not clear.

Applicant's summary and conclusion

Conclusions:

The main findings of the study are summarized below:
• A significant correlation was found between Se-intake and tissue/body fluid Se concentrations.
• Se-levels in blood from individuals that were diagnose with selenosis (long, persisting distinct clinical signs) ranged between 1.05-1.85 µg/mL, and the value of 1.05 µg/mL corresponds to an approximate intake of 909 µg Se/day.
• Excretion percentage began to plateau as Se-intake increased to near 800 µg/day, indicating towards a weakening of the homeostatic regulation. Further increase to over 1000 µg Se/day resulted in a constant Se-concentration that was excreted (failure of the kidneys to further regulate Se-excretion).
• From Se-levels of 1 µg/mL blood onwards the hepatic synthesis of clotting factors in parenchymal liver cells was impaired, resulting in an (adrupt) prolongation of the plasma prothrombin time.

A summary of all assessed endpoints and the related Se-intake (derived from regression equations) is given hereunder. The value that is associated with long persistence of clinical signs ( 900 µg/day) is put forward as relevant dose descriptor for DNEL-derivation purposes.

Executive summary:

Yang et al (1989) assessed the impact of dietary Se-intake in three large sub-populations (n=200-300) that were living in areas with different natural Se-levels (low, medium, high). Each group included individuals that represented different sexes and ages. Subjects were life-long residents of the different areas, and cases of selenosis have been observed in the group of subjects that were living at the site with high natural levels. Diagnosis of selenosis was based mainly upon morphological alterations of the fingernails. This method is considered to be relevant as selenium concentration in (toe)nails have been related to chronic/long-term selenium intake and to selenium status (Rajpathak et al., 2005; Geybels et al., 2013).

The intake of Se was determined via a 3-day survey and analysis of the food that was consumed by the subjects of each group. No significant differences were noted between adult males and females with regard to average daily Se-intake levels:

* Average Se-intake at the site with low Se-status: 66.3 µg/day (n=102)

* Average Se-intake at the site with medium Se-status: 196.4 µg/day (n=158)

* Average Se-intake at the site with high Se-status: 1338.4 µg/day (n=119)

The average intake of Se at the medium/high Se-status sites was a factor of 3 and 20 higher than the low Se-status site, respectively.

 

Blood, 24h-urine, breast milk and tissue samples were collected and analysed for Se, Hg, Cd, Zn, Co and As. In order to determine the expected level of Se-intake, individual Se intakes or tissue-Se levels were correlated with either biochemical parameters or clinical signs.  

 

The main findings of the study are summarized below:

1) A significant correlation was found between Se-intake and tissue/body fluid Se concentrations.

2) Se-levels in blood from individuals that were diagnose with selenosis (long, persisting distinct clinical signs) ranged between 1.05-1.85 µg/mL, and the value of 1.05 µg/mL corresponds to an approximate intake of 909 µg Se/day. 

3) Excretion percentage began to plateau as Se-intake increased to near 800 µg/day, indicating towards a weakening of the homeostatic regulation. Further increase to over 1000 µg Se/day resulted in a constant Se-concentration that was excreted (failure of the kidneys to further regulate Se-excretion).

4) From Se-levels of 1 µg/mL blood onwards the hepatic synthesis of clotting factors in parenchymal liver cells was impaired, resulting in an (adrupt) prolongation of the plasma prothrombin time.

 

A summary of all assessed endpoints and the related Se-intake (derived from regression equations) is given hereunder. The value that is associated with long persistence of clinical signs (±900 µg/day) is put forward as relevant dose descriptor for DNEL-derivation purposes.

 

Evidence	Se-intake (µg/day) based on regression equation	Blood Se-level (µg/mL)
Manifestation of clinical signs	£875	£1.02
Long persistence of clinical signs	£909	£1.05
Delay of prothrombin time	£853	£1.00
Reduction of whole blood GSH content	»853	»1.0
Plateau of percentage of Se-excretion to Se-intake	£800	£0.95
Remarkable reduction of plasma-Se to erythrocyte-Se ratio	»743	»0.9

 

 

 

Plasma selenium concentrations from 70 to 100 μg/L (have been proposed by different authors to reflect ― seleniumadequacy(Combs, 2001). Studies in European adult populations, reviewed by Carmona-Fonseca (2010), report average plasma selenium concentrations ranging from 48 to 124 μg/L, with most mean values in the range 75– 110 μg/L. In European populations aged below 19 years, average plasma selenium concentrations ranged from 47 to 145 μg/L, with most mean values in the range 60–90 μg/L. Significant differences were observed by sex and age and by country, region and measurement technique.

EFSA (2014) concluded that plasma response to selenium intake depends on the chemical nature of ingested selenium and exhibits large individual variation in response to a given intake, and therefore it is not possible to translate these adequate Se-levels to a daily intake levels without information on the chemical characteristics of the ingested Se.