44 The nutrition handbook for food processors The apparent protection of a diet high in fruit and vegetables is likely to be the result of a multifactorial effect from a number of components in those foods Two recent prospective studies found that subjects entering the studies with higher plasma B-carotene concentrations from dietary intake had a lower risk of lung cancer(McDermott, 2000). This finding perhaps suggests more studies using dietary enrichment with carotenoids rather than pharmacological supplements should be carried out 3.7 Safety of vitamin A and B-carotene 3.7.1 Safety of retinol Symptoms of hypervitaminosis A may occur in the skin, nervous system, mus- culoskeletal, circulatory systems or in internal organs. Toxicity varies with the dose, body mass, age, sex, disease conditions, concurrent drugs being taken and environmental chemical exposure(Blomhoff, 2001). Toxicity is rare from natural diets, the exception is from high intakes of liver (3-5mg/100g)(Northrop- Clewes, 2001b). Fortified foods are used in industrialised countries and can be consumed excessively(e.g. children may consume several bowls of breakfast ereal a day ) Supplements, i.e. multiple micro-nutrients containing vitamin A are readily available in industrialised countries and the usual content 500ug RE non-pregnant, non-lactating women 1000ug RE pregnant/lactating women. 750ug RE for children 5 years However, in general, healthy individuals in industrialised countries should need supplements, as eating a balanced diet should provide all the nutrients required. In contrast, VAD is common among women of reproductive age livin in deprived conditions and may be associated with a substantial increase in mater- nal mortality. The immediate postpartum period represents an opportunity to provide such women with a large dose of vitamin A, which benefits both mother and child. Since 1982 WHO/UNICEF/IVACG have recommended supplement- ing postpartum women and their infants, where VADD are a public health Mothers: 2000001u 6 weeks post partum. Infants: 25000IU at 6. 10. 14 weeks and 100000lu at 9 months. However, theoretical calculations and recent data suggest the dose is too small and so in 2001, new WHO supplement recommendations were proposed Mothers: 200000IU at delivery 2000001u 6-8 weeks after delivery Infants: 50000IU at 6. 10. 14 weeks +1000001U 6-11 months + 200000IU every 4-6 months after 12 months Acute toxicity Acute hypervitaminosis A can be defined as any toxicity manifested following a single very high dose or several very high doses over a few days(Blomhoff
The apparent protection of a diet high in fruit and vegetables is likely to be the result of a multifactorial effect from a number of components in those foods. Two recent prospective studies found that subjects entering the studies with higher plasma b-carotene concentrations from dietary intake had a lower risk of lung cancer (McDermott, 2000). This finding perhaps suggests more studies using dietary enrichment with carotenoids rather than pharmacological supplements should be carried out. 3.7 Safety of vitamin A and b-carotene 3.7.1 Safety of retinol Symptoms of hypervitaminosis A may occur in the skin, nervous system, musculoskeletal, circulatory systems or in internal organs. Toxicity varies with the dose, body mass, age, sex, disease conditions, concurrent drugs being taken and environmental chemical exposure (Blomhoff, 2001). Toxicity is rare from natural diets, the exception is from high intakes of liver (3–5 mg/100 g) (NorthropClewes, 2001b). Fortified foods are used in industrialised countries and can be consumed excessively (e.g. children may consume several bowls of breakfast cereal a day). Supplements, i.e. multiple micro-nutrients containing vitamin A, are readily available in industrialised countries and the usual content is: • 1500mg RE non-pregnant, non-lactating women. • 1000mg RE pregnant/lactating women. • 750mg RE for children < 5 years. However, in general, healthy individuals in industrialised countries should not need supplements, as eating a balanced diet should provide all the nutrients required. In contrast, VAD is common among women of reproductive age living in deprived conditions and may be associated with a substantial increase in maternal mortality. The immediate postpartum period represents an opportunity to provide such women with a large dose of vitamin A, which benefits both mother and child. Since 1982 WHO/UNICEF/IVACG have recommended supplementing postpartum women and their infants, where VADD are a public health problem, with: • Mothers: 200 000 IU < 6 weeks post partum. • Infants: 25 000 IU at 6, 10, 14 weeks and 100 000 IU at 9 months. However, theoretical calculations and recent data suggest the dose is too small and so in 2001, new WHO supplement recommendations were proposed: • Mothers: 200 000 IU at delivery + 200 000 IU < 6–8 weeks after delivery • Infants: 50 000 IU at 6, 10, 14 weeks + 100 000 IU 6–11 months + 200 000 IU every 4–6 months after 12 months. Acute toxicity Acute hypervitaminosis A can be defined as any toxicity manifested following a single very high dose or several very high doses over a few days (Blomhoff, 44 The nutrition handbook for food processors
Vitami 2001). Symptoms of acute toxicity include: increased cerebrospinal fluid pres sure, bulging fontanelle in infants, headache and blurred vision in adolescents and adults, loss of appetite, nausea, vomiting lassitude and abdominal pain. An acceptable dose for mothers is 400000IU vitamin A(120mg retinyl palmitate i. e. 11U=0.3ug retinol) post partum while 500001U is assumed safe for 0-6 month infants. 100000IU for infants >6 months and 200000lu for those >12 months old. however in infants and children 25000-500001U occasion- ally leads to bulging fontanel. In about 6% of infants 3000001U can lead to nausea and vomiting and to diarrhoea in about 16% and although this is transient, it is unacceptable (IoM, 2001) Retinyl esters in plasma are indicators of high or recent vitamin A intake i.e they transiently increase after a vitamin A-rich meal, 1-2 X RNI and particularly with supplementation. Plasma retinoic acid will also go up after eating liver or aking high doses of vitamin A, and in lactating women the retinoic acid may go into the breast milk although this has not been measured. Breast milk retinyl palmitate is a useful indicator to monitor total maternal vitamin A intake, that is milk retinol concentration will be very similar to plasma retinol. There is no evidence of an upper concentration of breast milk vitamin A that is harmful to infants Chronic toxicity from retinol Definitions of upper limits of toxicity (IOM, 2001) No observed adverse effect level (NoAEl) or the highest dose which has no adverse effect Tolerable upper intake level (UL) is the highest level of intake likely to pose no risk for almost all members of the population, where UL NOAEL/uncertainty factor(UF) Chronic hypervitaminosis A can be defined as any symptom resulting from continued ingestion of high doses of vitamin A for months or years(Blomhoff, 2001). In adults, there are many reports of chronic toxicity where the intake of vitamin A exceeds 15 mg/d, characterised by headache, fatigue, anorexia, itch skin, liver damage, desquamation of mucous membranes and of skin The NOAEL for adults is set 15 mg/d and the UL is 3 mg/d, where the UF 5 because of severe irreversible effect and inter-individual variability in sensi- tivity. If the UL was <3 mg, 50%o of adults in the US would exceed the UL, yet few cases of liver toxicity are seen. The mean normal US liver concentration is 100ug/g(range 10-1400ug/g) In infants and young children toxicity produces bulging fontanelle. The NOAEL is 6mg/d and the ul is 0.6mg/d, where the uF= 10 because of uncer- ainty and inter-individual variability in sensitivity In women of child-bearing age, toxicity can lead to teratogenicity, therefore the NOaEl is set at 4.5 mg and the Ul at 3 mg/d(10000IU). The most serious effects of vitamin A toxicity include foetal resorption, birth defects, abortion and permanent learning difficulties in the offspring (IOM, 2001)(see section
2001). Symptoms of acute toxicity include: increased cerebrospinal fluid pressure, bulging fontanelle in infants, headache and blurred vision in adolescents and adults, loss of appetite, nausea, vomiting lassitude and abdominal pain. An acceptable dose for mothers is 400 000 IU vitamin A (120 mg retinyl palmitate i.e. 1 IU = 0.3mg retinol) post partum while 50 000 IU is assumed safe for 0–6 month infants, 100 000 IU for infants > 6 months and 200 000 IU for those > 12 months old. However, in infants and children 25 000–50 000 IU occasionally leads to bulging fontanel. In about 6% of infants 300 000 IU can lead to nausea and vomiting and to diarrhoea in about 16% and although this is transient, it is unacceptable (IOM, 2001). Retinyl esters in plasma are indicators of high or recent vitamin A intake i.e. they transiently increase after a vitamin A-rich meal, 1–2 ¥ RNI and particularly with supplementation. Plasma retinoic acid will also go up after eating liver or taking high doses of vitamin A, and in lactating women the retinoic acid may go into the breast milk although this has not been measured. Breast milk retinyl palmitate is a useful indicator to monitor total maternal vitamin A intake, that is, milk retinol concentration will be very similar to plasma retinol. There is no evidence of an upper concentration of breast milk vitamin A that is harmful to infants. Chronic toxicity from retinol Definitions of upper limits of toxicity (IOM, 2001) No observed adverse effect level (NOAEL) or the highest dose which has no adverse effect. Tolerable upper intake level (UL) is the highest level of intake that is likely to pose no risk for almost all members of the population, where UL = NOAEL/uncertainty factor (UF). Chronic hypervitaminosis A can be defined as any symptom resulting from continued ingestion of high doses of vitamin A for months or years (Blomhoff, 2001). In adults, there are many reports of chronic toxicity where the intake of vitamin A exceeds 15 mg/d, characterised by headache, fatigue, anorexia, itchy skin, liver damage, desquamation of mucous membranes and of skin. The NOAEL for adults is set 15 mg/d and the UL is 3 mg/d, where the UF = 5 because of severe irreversible effect and inter-individual variability in sensitivity. If the UL was <3 mg, 50% of adults in the US would exceed the UL, yet few cases of liver toxicity are seen. The mean normal US liver concentration is 100mg/g (range 10–1400mg/g). In infants and young children toxicity produces bulging fontanelle. The NOAEL is 6 mg/d and the UL is 0.6 mg/d, where the UF = 10 because of uncertainty and inter-individual variability in sensitivity. In women of child-bearing age, toxicity can lead to teratogenicity, therefore the NOAEL is set at 4.5 mg and the UL at 3 mg/d (10 000 IU). The most serious effects of vitamin A toxicity include foetal resorption, birth defects, abortion and permanent learning difficulties in the offspring (IOM, 2001) (see section 3.3.3). Vitamins 45
46 The nutrition handbook for food processors 3.7.2 Safety of B-carotene Experimental studies with animals have shown that p-carotene is not mutagenic or teratogenic. In addition, doses of 180 mg/day have been used over many years to treat patients with erythropoietic protoporphyria, with no evidence of vitamin A toxicity(Blomhoff, 2001). B-Carotene is considered not to be toxic because bsorption becomes inefficient at high intakes, possibly because conversion of p- carotene and other provitamin A carotenoids is regulated by the vitamin A status of the individual. In two studies in which very different large intakes of B-carotene were given(15 and 40 mg), the mean absorption of B-carotene was <2mg sug- gesting the human intestine possess only a limited capacity to absorb B-carote (van Vliet et al, 1995; O'Neill and Thurnham, 1998) 3. 8 Vitamin Recognition of the antirichitic effect of meat fat in the 1920s, as well as the pre tective effects of sunlight led to the discovery of vitamin D. Vitamin D is the name given to a group of fat-soluble compounds essential for maintaining the mineral balance of the body. Vitamin d is also known as calciferol and the anti- rachitic vitamin and its principal function is to regulate calcium and phosphate metabolism. It has two main forms: ergocalciferol, vitamin D2(plant origin)and cholecalciferol, vitamin D,(animal origin) Vitamin D is produced from endogenous sources, synthesised in the skin from 7-dehydrocholesterol (7DHC)in a reaction catalysed by the ultra-violet (UV) light, and exogenous sources from the diet. There are only a few natural food sources, egg yolk, oily fish, butter and milk (Table 3.2). Margarines and spreads are fortified with vitamin d. vitamin d. either natural or added. is stable in foods cooking do not affect its activity. The normal human diet is, however, a trivial source of vitamin D, since the biggest source results from exposure to sunlight. However, vitamin D production by the skin is strongly related to latitude and season, because short UV wavelengths of light are neces- sary for photoconversion. This means that in the UK and other countries in the northern latitudes, sunlight during the winter months is ineffective for the pro- duction of vitamin d because the sun is so low in the sky, the absorption by ozone too great and Uv-B radiation too scattered(Maxwell, 2001). There are at least 37 metabolites of vitamin D(Norman, 1990) but only three 25 hydroxyvitamin D(25-OHD), 1, 25 dihydroxvitamin D3(1, 25-OHD) and 24, 25 dihydroxyvitamin D(24, 25-OHD) have any important biological activity Plasma 25-OHD is an index of availability of vitamin D and the normal range is 20-150nmol/L(8-60ng/ml). Values below 25 nmol/L (10ng/ml) indicate risk of deficiency and toxicity occurs at levels above 150nmol/L(60ng/mI). The average intake within the UK ranges from 0.5 to &ug/day, dependent on season, with a mean around 3ug/day. Table 3. 1 shows no DRV for those aged between 4 and 65 years as usual daily activity of able-bodied persons should provide sufficient exposure to UV light. The elderly and those confined indoors are recommended
3.7.2 Safety of b-carotene Experimental studies with animals have shown that b-carotene is not mutagenic or teratogenic. In addition, doses of 180 mg/day have been used over many years to treat patients with erythropoietic protoporphyria, with no evidence of vitamin A toxicity (Blomhoff, 2001). b-Carotene is considered not to be toxic because absorption becomes inefficient at high intakes, possibly because conversion of bcarotene and other provitamin A carotenoids is regulated by the vitamin A status of the individual. In two studies in which very different large intakes of b-carotene were given (15 and 40 mg), the mean absorption of b-carotene was <2 mg suggesting the human intestine possess only a limited capacity to absorb b-carotene (van Vliet et al, 1995; O’Neill and Thurnham, 1998). 3.8 Vitamin D Recognition of the antirichitic effect of meat fat in the 1920s, as well as the protective effects of sunlight led to the discovery of vitamin D. Vitamin D is the name given to a group of fat-soluble compounds essential for maintaining the mineral balance of the body. Vitamin D is also known as calciferol and the antirachitic vitamin and its principal function is to regulate calcium and phosphate metabolism. It has two main forms: ergocalciferol, vitamin D2 (plant origin) and cholecalciferol, vitamin D3 (animal origin). Vitamin D is produced from endogenous sources, synthesised in the skin from 7-dehydrocholesterol (7DHC) in a reaction catalysed by the ultra-violet (UV) light, and exogenous sources from the diet. There are only a few natural food sources, egg yolk, oily fish, butter and milk (Table 3.2). Margarines and spreads are fortified with vitamin D. Vitamin D, either natural or added, is stable in foods, and storage, processing and cooking do not affect its activity. The normal human diet is, however, a trivial source of vitamin D, since the biggest source results from exposure to sunlight. However, vitamin D production by the skin is strongly related to latitude and season, because short UV wavelengths of light are necessary for photoconversion. This means that in the UK and other countries in the northern latitudes, sunlight during the winter months is ineffective for the production of vitamin D because the sun is so low in the sky, the absorption by ozone too great and UV-B radiation too scattered (Maxwell, 2001). There are at least 37 metabolites of vitamin D (Norman, 1990) but only three: 25 hydroxyvitamin D (25-OHD), 1,25 dihydroxvitamin D3 (1,25-OHD) and 24, 25 dihydroxyvitamin D (24,25-OHD) have any important biological activity. Plasma 25-OHD is an index of availability of vitamin D and the normal range is 20–150 nmol/L (8–60 ng/ml). Values below 25 nmol/L (10 ng/ml) indicate risk of deficiency and toxicity occurs at levels above 150 nmol/L (60 ng/ml). The average intake within the UK ranges from 0.5 to 8mg/day, dependent on season, with a mean around 3mg/day. Table 3.1 shows no DRV for those aged between 4 and 65 years as usual daily activity of able-bodied persons should provide sufficient exposure to UV light. The elderly and those confined indoors are recommended 46 The nutrition handbook for food processors
Vita Table 3.3 Main causes of rickets and osteomalacia Cause Clinical features Lack of sunlight vitamin D deficiency e.g. in Asian immigrants and the elderly Malabsorption coeliac disease intestinal bypass surgery Renal disease: tubular inherited hypophosphataemia Fanconi syndrome Renal disease. Osteodystrophy glomerular Dialysis bone disease to take 10ug/day. Vitamin D is stored in various fat depots throughout the body and, because of its lipid nature, it is carried by a specific transport protein, o globulin, within the circulation. 3.9 Specific nutritional deficiencies 3.9.1 Asian communities in the uK Osteomalacia in adults and rickets in children occur as a result of vitamin d defi ency or from a disturbance in its metabolism(see Table 3.3). The frequency of occurrence depends on the distribution of the populations affected. In the nine teenth century nutritional rickets were endemic in industrial cities of Britain due to the poor diet and environmental conditions of children. As a result of effec tive public health measures privational rickets virtually disappeared from the UK by 1940(Maxwell, 2001). However, in the 1960s low vitamin D status was found to be common among immigrant Asian children adolescents and women living in the uk due to a combination of factors including the type of vegetarian diet which was high in phytate from unleavened breads(see section 3. 11), low calcium intake and limited exposure to sunlight. A striking reduction in Asian rickets occurred in Glasgow when free vitamin D supplements were introduced for children up to 18 years old(Smith, 2000) 3.9.2 Elderly The elderly, especially those over 75 years, may have 25-OHD levels less than 12 nmol/L during the winter months because they expose insufficient skin to the sun during the summer months. Fifteen elderly people, living at 37 latitude whe formerly went outside infrequently, were studied over a 4 week period while spending 0, 15 and 30 minutes on a veranda exposing the face and legs to sunlight. At the end of the study period, plasma 25-OHD levels increased by
to take 10mg/day. Vitamin D is stored in various fat depots throughout the body and, because of its lipid nature, it is carried by a specific transport protein, a2- globulin, within the circulation. 3.9 Specific nutritional deficiencies 3.9.1 Asian communities in the UK Osteomalacia in adults and rickets in children occur as a result of vitamin D defi- ciency or from a disturbance in its metabolism (see Table 3.3). The frequency of occurrence depends on the distribution of the populations affected. In the nineteenth century nutritional rickets were endemic in industrial cities of Britain due to the poor diet and environmental conditions of children. As a result of effective public health measures privational rickets virtually disappeared from the UK by 1940 (Maxwell, 2001). However, in the 1960s low vitamin D status was found to be common among immigrant Asian children, adolescents and women living in the UK due to a combination of factors including the type of vegetarian diet, which was high in phytate from unleavened breads (see section 3.11), low calcium intake and limited exposure to sunlight. A striking reduction in Asian rickets occurred in Glasgow when free vitamin D supplements were introduced for children up to 18 years old (Smith, 2000). 3.9.2 Elderly The elderly, especially those over 75 years, may have 25-OHD levels less than 12 nmol/L during the winter months because they expose insufficient skin to the sun during the summer months. Fifteen elderly people, living at 37° latitude who formerly went outside infrequently, were studied over a 4 week period while spending 0, 15 and 30 minutes on a veranda exposing the face and legs to sunlight. At the end of the study period, plasma 25-OHD levels increased by Vitamins 47 Table 3.3 Main causes of rickets and osteomalacia Cause Clinical features Lack of sunlight vitamin D deficiency e.g. in Asian immigrants and the elderly Malabsorption coeliac disease postgastrectomy intestinal bypass surgery Renal disease: tubular inherited hypophosphataemia Fanconi syndrome Renal disease: Osteodystrophy glomerular Dialysis bone disease
48 The nutrition handbook for food processors 18.5 nmol/L (7.4ug/ml) in the group spending 30 minutes/day and there was a small but insignificant rise in those who spent 15 minutes outside(Reid et al, 1986). Reid and his co-workers thought this a safe inexpensive method for the prevention of osteomalacia in frail elderly subjects. Histologically proven osteo- malacia occurs in 2-5% of the elderly in hospitals( Campbell et al, 1994)and low plasma 25-OHD in up to 40% of elderly living in homes and hospitals. Dietary or supplementary vitamin D may be the only effective way of maintaining or improving status in this group when it is not possible to expose them to sunlight 3.9.3 Other diseases linked to vitamin d deficiency After nutritional vitamin D deficiency, coeliac and renal diseases are the most important causes of osteomalacia and rickets In coeliac disease there is a patchy enteropat hy of the gut which can potentially lead to fat malabsorption. The effi- cient absorption of fat is essential for the absorption of fat-soluble vitamins, thus in patients with inadequate sunlight exposure, vitamin D deficiency can occur. Patients with kidney diseases are also susceptible to vitamin d deficiency as the enzyme necessary to convert 25-OHD to the metabolically active vitamin D metabolite, 1, 25-OHD, is located in the kidney 3.9.4 Vitamin D and type l diabetes A follow-up study in Finland of 10821 people born in Oulu and Lapland in 1966 showed that those who received recommended supplements of vitamin D during their first year of life were 80%less likely to develop type 1 diabetes over the next 30 years. Type 1 diabetes is thought to be an autoimmune disease caused when immune system cells attack insulin-producing cells in the pancreas. Vitamin D is known to be an immune system suppressant and the authors believe that vitamin D might somehow inhibit this autoimmune reaction(Hypponen et al, 2001). Finnish children are less exposed to sunlight than those in more southerly ountries, hence most receive vitamin D supplements. It is also suggested that mothers'worries over UV exposure and skin cancer may also be contributing to world-wide increases in type I diabetes. There is evidence that parents are restrict- ing childrens exposure to sunlight by using more sun-screen than previously and this might have played a part. Early infections with enterovirus and childhood obesity were also associated with increased risks of type 1 diabetes(Hypponer et al, 2001). Nevertheless, none of the above explains the molecular role in the pathogenesis of type I diabetes and more work is needed in the area 3.10 Synthesis and actions of 1, 25-OHD The most biologically active form of calciferol is 1, 25-OHD and its synthesis is tightly controlled (Loveridge, 2000). The kidney produces both dihydroxylated forms of vitamin D(1, 25 and 24, 25-OHD); the dominant form is determined by
18.5 nmol/L (7.4mg/ml) in the group spending 30 minutes/day and there was a small but insignificant rise in those who spent 15 minutes outside (Reid et al, 1986). Reid and his co-workers thought this a safe inexpensive method for the prevention of osteomalacia in frail elderly subjects. Histologically proven osteomalacia occurs in 2–5% of the elderly in hospitals (Campbell et al, 1994) and low plasma 25-OHD in up to 40% of elderly living in homes and hospitals. Dietary or supplementary vitamin D may be the only effective way of maintaining or improving status in this group when it is not possible to expose them to sunlight. 3.9.3 Other diseases linked to vitamin D deficiency After nutritional vitamin D deficiency, coeliac and renal diseases are the most important causes of osteomalacia and rickets. In coeliac disease there is a patchy enteropathy of the gut which can potentially lead to fat malabsorption. The effi- cient absorption of fat is essential for the absorption of fat-soluble vitamins, thus in patients with inadequate sunlight exposure, vitamin D deficiency can occur. Patients with kidney diseases are also susceptible to vitamin D deficiency as the enzyme necessary to convert 25-OHD to the metabolically active vitamin D metabolite, 1,25-OHD, is located in the kidney. 3.9.4 Vitamin D and type 1 diabetes A follow-up study in Finland of 10 821 people born in Oulu and Lapland in 1966 showed that those who received recommended supplements of vitamin D during their first year of life were 80% less likely to develop type 1 diabetes over the next 30 years. Type 1 diabetes is thought to be an autoimmune disease caused when immune system cells attack insulin-producing cells in the pancreas. Vitamin D is known to be an immune system suppressant and the authors believe that vitamin D might somehow inhibit this autoimmune reaction (Hyppönen et al, 2001). Finnish children are less exposed to sunlight than those in more southerly countries, hence most receive vitamin D supplements. It is also suggested that mothers’ worries over UV exposure and skin cancer may also be contributing to world-wide increases in type I diabetes. There is evidence that parents are restricting children’s exposure to sunlight by using more sun-screen than previously and this might have played a part. Early infections with enterovirus and childhood obesity were also associated with increased risks of type 1 diabetes (Hyppönen et al, 2001). Nevertheless, none of the above explains the molecular role in the pathogenesis of type 1 diabetes and more work is needed in the area. 3.10 Synthesis and actions of 1,25-OHD The most biologically active form of calciferol is 1,25-OHD and its synthesis is tightly controlled (Loveridge, 2000). The kidney produces both dihydroxylated forms of vitamin D (1,25 and 24,25-OHD); the dominant form is determined by 48 The nutrition handbook for food processors