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Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
other: Peer reviewed document
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Type of study / information:
This document is an official opinion of the SCF (Scientific Committee on Food of the European Commission) on derivation of a tolerable upper intake level of calcium.
Endpoint addressed:
repeated dose toxicity: oral
Test guideline
Qualifier:
no guideline followed
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
This scientific opinion includes various forms of calcium.

Method

Ethical approval:
not applicable
Details on study design:
In this document, the different aspects of oral calcium intake are critically reviewed on the basis of different chapters:
- Nutritional background
- Hazard identification
- Dose-response assessment
- Derivation of a tolerable upper intake level
- Characterisation of risk
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE: Only oral supplementation besides the "normal" dietary calcium uptake are considered.

TYPE OF EXPOSURE MEASUREMENT: In the different studies reviewed in this opinion, biomonitoring was mainly conducted by analysis of bone mineral density (BMD) and calcium quantification in blood and urine. .

EXPOSURE LEVELS: Exposure levels taken into consideration for the assessment of adverse effects ranged from 350 mg Ca/day up to 2000 mg Ca/day. These values correspond to calcium carbonate (CaCO3) levels of 875-5000 mg CaCO3/day.

EXPOSURE PERIOD: The exposure period of the different studies ranged from 12 weeks to over 4 years.

Results and discussion

Results:
1). DOSE-RESPONSE ASSESSMENT

Kidney function
A trend for an increase in serum creatinine (by 1.2 μmol/L) with calcium supplements of 1000 and 2000 mg during 3 years in addition to dietary intakes of around 1000 mg/day (total intake 2000 and 3000 mg/day) was seen in a study involving 130 perimenopausal women (Elders et al., 1994). No effects on serum creatinine were reported in 46 women aged between 50 and 70 years who ingested calcium supplements of 1000 mg daily over one year in addition to a dietary calcium intake of 1290 mg/day (Schaafsma et al., 2002).
In conclusion, some perimenopausal women with total calcium intakes between 2 and 3 g/day may show a tendency for compromised glomerular function as indicated by increases in serum creatinine. No such effect was observed in another study with women receiving comparable calcium amounts. This finding should be investigated systematically before it is attributed to calcium.

Milk-alkali syndrome
Manifestation of the milk-alkali syndrome through the combined intake of calcium both from food and especially from supplements and of absorbable alkalinising substances is facilitated by renal insufficiency, alkalosis and dehydration due to vomiting and anorexia and/or the use of thiazide diuretics, which increase renal tubular calcium reabsorption. All reported cases of milk-alkali syndrome in association with the prolonged or acute ingestion of calcium supplements used calcium carbonate as the nutrient source. In these reports the supplemental calcium intakes were reported as between 1.0 and 23 g/day. These patients also differ in their
medical history, use and duration of use of drugs and alkali consumption, and their diets. Their dietary calcium intakes are often not known.
The FNB of the IOM (1997) has taken the approximate median of 4.8 g of reported calcium supplements (the same value derives from our extended list) as the LOAEL for total calcium intake, applied an uncertainty factor of 2 and defined an upper level of 2.5 g calcium/day. From the number of reported cases with milk-alkali syndrome and calcium supplement intakes below or equal to 2.5 g/day (11 of 82) in the list in Annex II, this definition of the LOAEL is not appropriate. Seven of these low-supplement users are reported not to have an additional high dietary calcium intake (>0.9 g/day). Only five of these eleven are reported to have ingested additional sodium bicarbonate or other antacids. Moreover, it is questionable if it is justified to derive a LOAEL for the total dietary calcium intake from data on effects of alkalinising substances plus calcium.
The use of calcium carbonate supplements in doses up to 2000 mg/day, and thereby achieving total daily calcium intakes up to more than 3000 mg/day, for preventive purposes in presumably healthy subjects, has not provoked the development of the milk-alkali syndrome, whereas the administration of large amounts (11.2 g calcium/day) of calcium carbonate in addition to large amounts of milk (1.8 g calcium/day) over 7 days to 20 gastric/duodenal ulcer patients resulted in reversible hypercalcaemia (2.8 mmol/L) in nine patients and renal insufficiency in all. The control group of 20 patients with gastric/duodenal ulcers who received aluminium hydroxide and milk for the same duration did not develop these abnormalities (McMillan and Freeman, 1965).
A patient with a 15-year history of calcium carbonate use (3.3 g/day) had recurrent episodes of severe hypercalcaemia. He was known to have diabetes mellitus, hypothyroidism and renal insufficiency and it is not known if the renal insufficiency was the consequence of recurrent hypercalcaemic episodes or if it was the promoting factor (Smit and Bijvoet, 1986).
Hypercalcaemia occurred in 65 of 297 patients who had undergone major cardiac surgery and who received between 1.3 and 10 g of calcium/day as carbonate (total daily intake 7 to 11 g calcium) for peptic ulcer prevention. It was accompanied by renal failure in 50%, which developed within days of starting the regimen in a few patients, and was completely reversible after stopping calcium carbonate (Kapsner et al., 1986).
Cases of milk-alkali syndrome have been reported with long-standing calcium intakes in the range of 2 to 2.5 g/day with chronic high intakes of antacids (Barragry and Counihan, 1975; Gibbs and Lee, 1992) and of low supplemental calcium intakes (1g/day) in addition to unknown dietary intakes plus sodium bicarbonate (Abreo et al., 1993). These observations seem to indicate that the harmful calcium dose can be lower than 3 g/day if taken together with alkali.
In conclusion, on the basis of the available evidence, a calcium dose which by itself might cause milk-alkali syndrome cannot be identified.

Kidney stones
The quantitative relationship between calcium intake, both from the diet and from supplements, and hypercalciuria as a risk factor for nephrolithiasis is far from clear. Also, it is dependent on other dietary factors, especially sodium intake. From epidemiologic studies it appears that dietary calcium intakes in the range of recent recommendations have a favourable effect in the prevention of kidney stone formation and that lower intakes increase the risk (Curhan et al., 1993 and 1997; Sowers et al., 1998).
The influence of a controlled diet for 3 days (1000 mg calcium, 100 mmol sodium, 32.3 mmol potassium/day and 1 g protein/kg body weight/day) and of an oral calcium tolerance test (1000 mg) on urinary calcium excretion was investigated in 124 patients with hypercalciuria (more than 4 mg/kg/day or more than 300 mg/day in men and more than 250 mg/day in women of calcium excreted) identified from 282 patients with calcium oxalate stones. The strongest correlation was found between urinary calcium and sodium. Calcium excretion was less strongly correlated with calcium intake, sodium intake, phosphorus intake, carbohydrate and protein intake. From the regression equation derived from these investigations (Burtis et al., 1994) hypercalciuria in men would be associated with a calcium intake of 2243 mg/day and in women with a calcium intake of 1422 mg/day assuming a moderate sodium excretion of 100 mmol/day. A higher sodium intake (e.g. 150 mmol/day) would result in even lower hypercalciuric calcium intakes, 1685 mg for men and 866 mg/day for women, which are lower than the recommended calcium intake in many countries. The validity of these calculated predictions has never been systematically investigated in hypercalciuric subjects.
From the available data no conclusion is possible on a detrimental calcium dose in individuals with idiopathic hypercalciuria (up to 6% of the population). From the study in patients with kidney stones and idiopathic hypercalciuria it can be deduced that a sodium restricted diet with a normal recommended calcium content of 1200 mg/day does not raise urinary calcium excretion but reduces it (Borghi et al., 2002).
Hypercalciuria which is a risk factor for kidney stone formation has been observed in three of 50 infants receiving 1200 mg of supplemental calcium/day (Dalton et al., 1997) and in postmenopausal women during 4 years of taking calcium supplements of 1600 mg six times as often as in unsupplemented women (Riggs et al., 1996). Different doses have not been systematically tested.
In conclusion, both observational studies on the relationship between total calcium intake and kidney stone incidence and interventional studies with calcium supplements do not allow definition of a calcium intake on a population basis which promotes kidney stone formation. On dietary calcium intakes in the range of the recommended dietary intake the risk of nephrolithiasis is determined by other dietary components and by genetic factors.
In persons with idiopathic hypercalciuria, which is in itself a heterogeneous disorder, the risk of stone formation is not increased with calcium intakes in the range of recommended intakes, when sodium intake is restricted (Borghi et al., 2002). Higher dosages have not been tested.

Interaction with minerals
The studies of acute effects of single calcium supplements at various doses and from various sources on iron and zinc absorption (Spencer et al., 1984; Hallberg et al., 1991) cannot be converted into general statements on a dose dependent negative effect of total daily dietary calcium intake, because the timing of the supplement and other interfering factors of the diet have to be taken into account.
Observational epidemiological studies on the influence of dietary calcium intake in different populations and age groups on parameters of iron status do not allow the identification of threshold values of calcium intake that lead to reductions in these parameters (Lynch, 2000). Intervention studies with calcium supplements up to 1200 mg/day in addition to dietary intakes between 280 and 1100 mg/day did not show adverse effects on iron status (Lynch, 2000). Negative interactions of calcium intakes in excess of 2000 mg/day that have been reported for iron, phosphorus, magnesium and zinc would be a problem only when these are ingested in inadequate amounts (Whiting and Wood, 1997).
In conclusion, single-dose experiments demonstrate interference of both dietary and supplemental calcium with the absorption of other minerals. This effect is not demonstrable in long-term observational and interventional studies at dietary calcium intakes in the range of recommended intakes and at supplemental calcium of up to 2000 mg/day in adults and up to 1200 mg/day in one study with infants (Dalton et al., 1997).
The decrease of serum zinc levels in 10 healthy adults after two weeks of a total calcium intake of 3000 mg/day (Raschke and Jahreis, 2002) is of insufficient power to consider it as a systematic effect. The cross-sectional study in seven countries which shows a dose dependent effect of calcium intake from dairy products on serum ferritin levels in young women did not define a threshold dose of calcium intake (van de Vijver et al., 1999).

Cytogenetic effects
The data are insufficient to allow conclusions to be drawn from the available studies.

2). DERIVATION OF A TOLERABLE UPPER INTAKE LEVEL (UL)

Adults
The Committee decided to base the derivation of an UL for calcium on the evidence of different interventional studies of long duration in adults, some of which were placebo controlled and in which total daily calcium intakes of 2500 mg from both diet and supplements were tolerated without adverse effects. Because of the abundance of data the application of an uncertainty factor was considered unnecessary. An UL of 2500 mg of calcium per day for calcium intake from all sources is proposed.

Pregnancy and lactation
Large placebo controlled intervention studies for preventive purposes with supplemental calcium carbonate of up to 2000 mg calcium in addition to the calcium intake from the diet (>400 mg/day) have been conducted in more than 3000 pregnant women and no adverse effects have been reported. There are no data to suggest an increased susceptibility for lactating women. Therefore, the UL of 2500 mg calcium per day applies also to pregnant and lactating women.

Children and adolescents
Six percent of 50 infants who received a calcium-enriched formula after the third month of life (1700 to 1560 mg calcium per day after 4 and 9 months, respectively), developed hypercalciuria (Dalton et al., 1997). These data are insufficient to define an UL for infants.
No adverse effects of calcium citrate-malate supplements (500 to 1000 mg calcium over 1.5 to 3 years) and of extra dairy foods or foods fortified with milk extracts (700 to 820 mg calcium extra over one year) were reported in 217 children between 6 and 14 and 6.6 and 11 years, respectively in comparison to unsupplemented controls.
These data are considered insufficient to derive an UL for children and adolescents. The Committee decided that it was inappropriate to base the UL for calcium for this age group on the tolerable upper level for adults of 2500 mg calcium/day, with correction for differences in basal metabolic rate using scaling according to body surface area (body weight0.75). For calcium deposition in bone during the growth period proportionality to lean body mass cannot be assumed. Therefore, the Committee cannot propose age-dependent ULs for children and adolescents.

3). CHARACTERISATION OF RISK
Data from European populations indicate that the intakes of calcium from all sources in adolescents and adults can be close to the UL in a small percentage of the population, especially in those taking supplements. In the United Kingdom the 97.5 percentile of calcium intake in men 16 to 49 year old is 1600 mg/day (EGVM, 2001). In the Netherlands with a traditionally high consumption of milk products the 95 percentile of calcium intake without supplements is 2100 mg per day in young men between 16 to 22 years old (Hulshof and Kruizinga, 1999). In Germany the mean calcium intake of male subjects between 15 and 24 years old is 2100 mg/day (Heseker et al., 1994), but some 10% of adolescents consume more than 2100 mg per day (Alexy and Kersting, 1999).
In Dutch children the 95 percentile of calcium intake in boys and girls between one and 4 years of age is around 1300 mg/day, it is between 1400 and 1700 mg/day in boys and girls 4 to 13 years of age (Hulshof and Kruizinga, 1999). Somewhat lower 97.5 percentile intakes of 1200 to 1500 mg/day have been observed in British children between 1.5 and 14 years of age. The 90 percentile of calcium intake of 750 German children participating in a longitudinal observational study was 800 to 1000 mg/day between age one and 2 years, 700 to 900 mg/day between age 4 to 6 years and 1000 to 1600 mg/day between age 7 to 14 years (Alexy and Kersting, 1999).
These calcium intakes are quite similar to the calcium intakes of 1100 to 1900 mg/day supplied in intervention trials with children between 6 and 14 years of age which studied the effect on bone mineral mass and bone density (Johnston et al., 1992; Lloyd et al., 1993; Chan et al., 1995; Bonjour et al., 1997).
In British infants the 97.5th percentile of calcium intake was 1400 mg/day (EGVM, 2001). In German non-breast-fed infants the 90th percentile of calcium intake was 700 to 900 mg/day (Alexy and Kersting, 1999).
Although there are no data to set a numerical UL for children and adolescents no appreciable risk has been identified even with current extreme levels of calcium intake in this age group.

REFERENCES


Abreo K, Adlakha A, Kilpatrick S, Flanagan R, Webb R, Shakamuri S (1993). The milkalkali syndrome: a reversible form of acute renal failure. Arch Int Med 153: 1005-1010.

Alexy U and Kersting M (1999). Was Kinder essen - und was sie essen sollten. Hans Marseille Verlag, München.

Barragry JM and Counihan TB (1975). Milk-alkali syndrome associated with calcium carbonate consumption. J Irish Med Ass 68: 221-224.

Bonjour JP, Carrie AL, Ferrari S, Clavien H, Slosman D, Theintz G, Rizzoli R (1997). Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, doubleblind, placebo-controlled trial. J Clin Invest 99: 1287-1294.

Borghi L, Schianchi T, Meschi T, Guerra A, Allegri F, Maggiore U, Novarini A (2002). Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 346: 77-84.

Burtis WJ, Gay L, Insogna KL, Allison A, Broadus AE (1994). Dietary hypercalciuria in patients with calcium oxalate kidney stones. Am J Clin Nutr 60: 424-429.

Chan GM, Hoffman K, McMurray M (1995). Effects of dairy products on bone and body composition in pubertal girls. J Pediatr 126: 551-556.

Curhan GC, Willett WC, Rimm EB, Stampfer MJ (1993). A prospective study of dietarycalcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 328:833-838.

Dalton MA, Sargent JD, O'Connor GT, Olmstead EM, Klein RZ (1997). Calcium and phosphorus supplementation of iron-fortified infant formula: no effect on iron status of healthy full-term infants. Am J Clin Nutr 65: 921-926.

EGVM (Expert Group on Vitamins and Minerals) (2001). Review of calcium, EVM/01/12. May 2001. London.

Elders PJM, Lips P, Netelenbos JC, van Ginkel FC, Khoe E, van der Vijgh WJF, van der Stelt PF (1994). Long-term effect of calcium supplementation on bone loss in perimenopausal women. J Bone Miner Res 9: 963-970.

FNB (Food and Nutrition Board) (1997). Dietary Refernce Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Institute of Medicine, National Academic Press, Washington, D.C.

Gibbs CJ and Lee HA (1992). Milk-alkali syndrome due to Caved-S. J Roy Soc Med 85: 498-499.

Hallberg L, Brune M, Erlandsson M, Sandberg AS, Rossander-Hulten L (1991). Calcium: effect on different amounts on nonheme- and heme-iron absorption in humans. Am J Clin Nutr 53: 112-119.

Heseker H, Adolph T, Eberhardt W, Hartmann S, Herwig A, Kübler W, Matiaske B, Moch KJ, Mitsche A, Schneider R, Zipp A (1994). Lebensmittel- und Nährstoffaufnahme Erwachsener in der Bundesrepublik Deutschland. Band III. VERA-Schriftenreihe. Wiss. Fachverlag Dr. Fleck, Niederkleen.

Hulshof KFAM and Kruizinga AG (1999). Third Dutch National Food Consumption Survey (DNFCS-3) 1997-1998. TNO Zeist, The Netherlands.

Johnston CC, Miller JZ, Slemenda CW, Reister TK, Hui S, Christian JC, Peacock M (1992). Calcium supplementation and increases in bone mineral density in children. N Engl J Med 327: 82-87.

Kapsner P, Langsdorf L, Marcus R, Kraemer FB, Hoffmann AR (1986). Milk-alkali syndrome in patients treated with calcium carbonate after cardiac transplantation. Arch Int Med 146: 1965-1968.

Lloyd T, Andon MB, Rollings N, Martel JK, Landis R, Demers LM, Eggli DF, Kieselhorst K, Kulin HE (1993). Calcium supplementation and bone mineral density in adolescent girls. J Am Med Ass 270: 841-844.

Lynch SR (2000). The effect of calcium on iron absorption. Nutr Res Rev 13: 141-158.

McMillan DE and Freeman RB (1965). The milk alkali syndrome: a study of the acute disorder with comments on the development of the chronic condition. Medicine 44: 485-501.

Raschke M and Jahreis G (2002). Der Einfluss von Calciumsupplementen auf den Stoffwechsel von Calcium und weiteren Mineralstoffen. Ernährung im Fokus 2/05: 110-113.

Riggs BL, O’Fallon WM, Muse J, O'Conner MK, Melton LJ (1996). Long-term effects of calcium supplementation on serum PTH, bone turnover, and bone loss in elderly women (Abstr). J Bone Miner Res 11: S118.

Schaafsma A, van Doormaal JJ, Muskiet FAJ, Hofstede GJH, Pakan I, van der Veer E (2002). Positive effects of a chicken eggshell powder-enriched vitamin-mineral supplement on femoral neck bone mineral density in healthy late post-menopausal Dutch women. Brit J of Nutr 87: 267-275.

Smit MJM and Bijvoet (1986). Het melk-alkalisyndroom. Ned Tijdschr Geneeskd 130: 665-667.

Sowers MFR, Jannausch M, Wood C, Pope SK, Lachance LL, Peterson B (1998). Prevalence of renal stones in a population-based study with dietary calcium, oxalate, and medication exposures. Am J Epidemiol 147: 914-920.

Spencer H, Kramer L, Norris C, Osis D (1984). Effect of calcium and phosphorus on zinc metabolism in man. Am J Clin Nutr 40: 1213-1218.

van de Vijver LPL, Kardinaal AFM, Charzewska J, Rotily M, Charles P, Maggiolini M, Ando S, Vaananen K, Wajszczyk B, Heikkinen J, Deloraine A, Schaafsma G (1999). Calcium intake is weakly but consistently negatively associated with iron status in girls and women in six European countries. J Nutr 129: 963-968.

Whiting SJ and Wood RJ (1997). Adverse effects of high-calcium diets in humans. Nutr Rev 55: 1-9.

Applicant's summary and conclusion

Conclusions:
The Committee decided to base the derivation of an UL for calcium for adults on the evidence of different interventional studies of long duration in adults, some of which were placebo controlled and in which total daily calcium intakes of 2500 mg from both diet and supplements were tolerated without adverse effects. Because of the abundance of data the application of an uncertainty factor was considered unnecessary. An UL of 2500 mg of calcium per day for calcium intake from all sources is proposed.
The UL of 2500 mg calcium per day applies also to pregnant and lactating women.
The available data are considered insufficient to derive an UL for children and adolescents.