Share This:
https://ntp.niehs.nih.gov/go/817662

Abstract from TR-592 on Dietary Zinc

Toxicology and Carcinogenesis Study of Dietary Zinc[1] (CAS No. 5263-02-5) in Sprague Dawley Rats (Hsd:Sprague Dawley SD) (Feed Study)

CASRN: 5263-02-5
Chemical Formula: C2-H6-O12-Zn5
Molecular Weight: 549.0074
Synonyms/Common Names: Zinc hydroxide carbonate
Report Date: 28-APR-17

Abstract

PLEASE NOTE: The following abstract has been extracted from the DRAFT technical report to be reviewed by the National Toxicology Program Technical Reports Peer Review Panel on July 13, 2017 (see the meeting page). When this report becomes final the entire report will be available in pdf format on the NTP website.

Draft Abstract

Zinc is a naturally occurring element and is ubiquitous in the environment. Zinc itself is stable in dry air, but exposure to moist air results in the formation of zinc oxide or basic carbonate. Due to the reactivity of zinc metal, it is not found as a free element in nature but as a variety of different compounds including zinc chloride, zinc oxide, and zinc sulfate. Zinc and zinc compounds are used across a wide range of industries that include rubber production, animal feed supplementation, as a fertilizer additive, in cosmetics and drugs, as a paint pigment, in dental cements, as a wood preservative, in batteries, in galvanizing and metal work, in textile production, in television screens and watches, and in smoke bombs. Of the zinc compounds, zinc oxide is the most widely used.

Zinc was nominated by the Agency for Toxic Substances and Disease Registry (ATSDR) for carcinogenicity and genotoxicity testing based on the increasing size of the population exposed to zinc through dietary supplements and the lack of studies examining the carcinogenicity of zinc. There was an additional nomination to investigate the tumorigenicity of zinc deficiency by private individuals as a result of data showing that deficiency of some vitamins and minerals in humans can cause DNA damage. Zinc carbonate basic was selected as the source of dietary zinc due to its use as the source of supplemental zinc in rodent diets. Male and female Hsd:Sprague Dawley SD rats were exposed to dietary zinc in feed for 2 years. Genetic toxicology studies were conducted in rat peripheral blood erythrocytes, peripheral blood leukocytes, and colon epithelial cells.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats were fed diets containing varying levels of dietary zinc [3.5, 7, 38 (control), 250, or 500 ppm] for 104 to 106 weeks. The 3.5 and 7 ppm diets were considered to be zinc deficient, the control diet of 38 ppm was considered to be zinc sufficient, and the 250 and 500 ppm dietary zinc concentrations represented diets with excess zinc. Dietary concentrations of 3.5, 7, 38, 250, and 500 ppm resulted in average daily intakes of 0.1, 0.3, 1.4, 8.7, and 17.6 mg dietary zinc/kg body weight to males and 0.1, 0.3, 1.5, 9.9, and 19.9 mg/kg to females. Ten male and 10 female additional special study rats were exposed to the same concentrations for 53 weeks and used for micronuclei evaluations, comet assays, hematology, and trace metal concentration determinations.

There were no chemical-related effects on survival. However, male rats maintained on the 3.5 ppm zinc-deficient diet had an increased survival rate compared to the controls that was likely due to low survival of the control group as a result of nephropathy.

Mean body weights of 3.5, 7, 250, and 500 ppm males and females were within 10% of those of the controls (38 ppm) at the end of the study. Feed consumption by zinc deficient and zinc excess groups of males and females was generally similar to that by the control groups.

The incidences of adenoma of the pancreas were increased in 7 and 3.5 ppm males, and the incidence of multiple adenoma was significantly increased in 3.5 ppm males. Compared to the 38 ppm (control) groups, significantly increased incidences of acinar atrophy occurred in the pancreas of 500 ppm males and females.

In the testis of 3.5 ppm males, the incidence of bilateral germinal epithelium atrophy was significantly increased.

GENETIC TOXICOLOGY

The frequency of micronucleated immature erythrocytes [reticulocytes or polychromatic erythrocytes (PCEs)] was measured in rat peripheral blood samples obtained at five sequential time points (up to 12 months) during the 2-year study. No biologically significant increases in micronucleated red blood cells were observed at any sampling time in either sex. Sporadic alterations in the percentage of PCEs were not considered related to treatment.

In the comet assay, no effects on percent tail DNA in blood leukocytes of male or female rats were observed at 19 days (male rats only), 3 months, or 6 months or in males at 9 months. At 12 months, increases in percent tail DNA were seen in blood leukocytes of male rats in both the excess dietary zinc and zinc-deficient diet groups. In female rats, increases in percent tail DNA were observed in blood leukocytes in the zinc-deficient diet group at 9 and 12 months.

In the colon epithelial cell samples obtained at 12 months, increased levels of DNA damage were observed in male and female rats fed a diet containing excess zinc. In addition, a significant decrease in DNA migration (percent tail DNA) was observed in females maintained for 12 months on the zinc-deficient diets. This decrease is suggestive of DNA cross-linking, a type of DNA damage.

CONCLUSIONS

Under the conditions of this 2-year dietary study, there was equivocal evidence of carcinogenic activity of diets deficient in zinc in male Hsd:Sprague Dawley SD rats based on higher incidences of adenoma of the pancreas and increased incidences of animals with multiple pancreatic adenomas. There was no evidence of carcinogenic activity of diets deficient in zinc (3.5 or 7 ppm) in female Hsd:Sprague Dawley SD rats. There was no evidence of carcinogenic activity of diets containing excess zinc (250 or 500 ppm) in male or female Hsd:Sprague Dawley SD rats.

Exposure to diets containing excess zinc resulted in increased incidences of nonneoplastic lesions of the pancreas in male and female rats. Exposure to diets deficient in zinc resulted in increased incidences of nonneoplastic lesions of the testes in male rats.

Synonym: Zinc hydroxide carbonate


[1] Zinc carbonate basic (CAS No. 5263-02-5) was used as the dietary zinc source, and the formula and molecular weight shown are for zinc carbonate basic.


Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Dietary Zinc
  Male
Hsd: Sprague Dawley SD Rats
Female
Hsd: Sprague Dawley SD Rats
Concentrations in feed 3.5, 7, 38 (control), 250, or 500 ppm 3.5, 7, 38 (control), 250, or 500 ppm
Survival rates 31/50, 28/50, 20/50, 21/50, 21/50 32/50, 34/50, 25/50, 27/50, 31/50
Body weights Exposed groups within 10% of the control group at the end of the study Exposed groups within 10% of the control group at the end of the study
Nonneoplastic effects Pancreas: acinus, atrophy (3/50, 4/48, 3/49, 3/48, 13/48)
Testis: bilateral, germinal epithelium, atrophy (7/50, 1/50, 0/50, 0/50, 1/50); germinal epithelium, atrophy (3/50, 0/50, 5/50, 3/50, 4/50); germinal epithelium, atrophy, includes bilateral (7/50, 1/50, 0/50, 0/50, 1/50)
Pancreas: acinus, atrophy (4/48, 2/49, 2/50, 5/49, 10/49)
Neoplastic effects None None
Equivocal findings Pancreas: adenoma (21/50, 19/48, 11/49, 13/48, 10/48) None
Level of evidence of carcinogenic activity Equivocal evidence with a diet deficient in zinc (3.5 and 7 ppm)
No evidence with excess zinc in the diet (250 and 500 ppm)
No evidence with a diet deficient in zinc (3.5 and 7 ppm)
No evidence with excess zinc in the diet (250 and 500 ppm)
Genetic toxicology
Micronucleated erythrocytesin rat peripheral blood in vivo: Negative in males and females
DNA damage (comet assay) in rats

Blood in rats fed zinc deficient diets:


Blood in rats fed excess zinc diets:

Colon in rats fed zinc deficient diets:

Colon in rats fed excess zinc diets:


Positive in males at 12 months and females at 9 and 12 months. Negative in males at 19 days and 3, 6, and 9 months and females at 3 and 6 months.

Positive in males at 12 months. Negative in males at 19 days and 3, 6, and 9 months and females at all time points.

Negative in males and positive in females.

Positive in males and females.

 

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies