The medical journal of australia

Vitamin D and adult bone health in Australia and New Zealand: Working Group of the Australian and New Zealand Bone and Mineral Society, Endocrine Society of Australia and Osteoporosis Australia* significant number of Australians are deficient in vitamin D. Indeed, it is a fallacy that Australians receive adequate A significant number of Australians are deficient in vitamin D
Avitamin D from casual exposure to sunlight. Here, we — it is a fallacy that Australians receive adequate vitamin D outline the causes and outcomes of vitamin D deficiency, the people who are at risk, and recommendations for management ofdeficiency.
People at high risk of vitamin D deficiency include elderly
people (particularly those in residential care), people with skin The Medical Journal of Australia ISSN: 0025- conditions where avoidance of sunlight is advised, those with D 1 March 2005 182
dark skin (particularly if veiled), and those with malabsorption.
Exposure of hands, face and arms to one-third of a minimal
vittamin D3), formed in the skin through the erythemal dose (MED) of sunlight (the amount that produces action of ultraviolet (UV) light on 7-dehydrocholesterol to produce a faint redness of skin) most days is recommended for adequate endogenous vitamin D synthesis. However, Ergocalciferol (vitamin D2), produced by UV irradiation of the
deliberate sun exposure between 10:00 and 14:00 in summer plant steroid ergosterol. Ergosterol is the major form of supple- (11:00–15:00 daylight saving time) is not advised.
mental vitamin D currently available in Australia.
If this sun exposure is not possible, then a vitamin D
supplement of at least 400 IU (10 µg) per day is 1,25-Dihydroxyvitamin D
Vitamin D3 and D2, made in the skin or ingested, are transported In vitamin D deficiency, supplementation with 3000–5000 IU
to the liver and metabolised to 25-hydroxyvitamin D (25-OHD), ergocalciferol per day (Ostelin [Boots]; 3–5 capsules per day) the major circulating form. Further hydroxylation occurs in the kidney to form the highly biologically active 1,25-dihydroxyvita- Larger-dose preparations of ergocalciferol or cholecalciferol
min D (1,25-(OH)2D). This compound promotes: are available in New Zealand, Asia and the United States and absorption of calcium and phosphate from the small intestine; would be useful in Australia to treat moderate to severe extracellular calcium homeostasis, directly and through its vitamin D deficiency states in the elderly and those with poor absorption; one or two annual intramuscular doses of 300 000 IU of cholecalciferol have been shown to reverse vitamin D deficiency states.
University of New South Wales, Sydney, NSW.
Terrence H Diamond, MRCP, FRACP, Associate Professor of Medicine, Sources of vitamin D
Exposure to sunlight: For people living in Australia and New
Garvan Institute of Medical Research, St Vincent’s Hospital and Zealand, the main source of vitamin D is through exposure to University of New South Wales, Sydney, NSW.
sunlight. It has been shown that whole body exposure to 10–15 John A Eisman, PhD, FRACP, Professor and Director, Bone and Mineral minutes of midday sun in summer (about 1 minimal erythemal dose [MED], or the amount of sun exposure which just produces a University of Sydney, NSW.
Rebecca S Mason, MB BS, PhD, Associate Professor, Department of faint redness of skin) is comparable to taking 15 000 IU (375 µg) of Physiology and Institute for Biomedical Research. vitamin D (cholecalciferol) orally.n this basis, exposure of hands, face and arms (around 15% of body surface) to around 1/3 Caryl A Nowson, PhD, DipNutDiet, Associate Professor, School of MED should produce around 1000 IU of vitamin D (cholecalcif- erol). The amount of sun exposure to produce 1/3 MED varies with The University of Melbourne, Geelong, VIC.
latitude, season, time of day and skin type (.
Julie A Pasco, BSc(Hons), PhD, DipEd, Senior Research Fellow, Less vitamin D is synthesised in winter, in those who have dark Department of Clinical and Biomedical Sciences, Barwon Health. skin or are older, and in those who dress with little potential for University of Sydney and Royal North Shore Hospital, NSW.
skin exposure to sunlight for cultural reasons or for sun protection.
Philip N Sambrook, MD, LLB, FRACP, Professor of Rheumatology. Therefore, serum vitamin D levels are lower in winter than in The University of Melbourne and Royal Melbourne Hospital, VIC.
John D Wark, PhD, FRACP, Professor of Medicine. summer Short exposures may be more efficient at producing Reprints will not be available from the authors. Correspondence: Dr vitamin D. Once previtamin D3 (a chemical precursor of vitamin Julie A Pasco, Department of Clinical and Biomedical Sciences, Barwon D3) and vitamin D3 (cholecalciferol) have been formed, continued Health, The University of Melbourne, PO Box 281, Geelong, VIC 3220. exposure to UV results in their degradation to relatively inert over- MJA • Volume 182 Number 6 • 21 March 2005
tively). Radiation in the UVB range is responsible for skin carcino- 1 Recommended sun exposure times (minutes) which
genesis as well as the conversion of 7-dehydrocholesterol into result in 1/3 MED for people with moderately fair skin*
previtamin D3. Glass blocks UVB rays and therefore prevents at different times of day
previtamin D3 synthesis. Concerns were raised that sunscreen usemay cause vitamin D deficiency, especially among older people.
Yet sunscreens are essential to prevent skin damage with longer periods of sun exposure. For incidental sun exposures (< ½ MED), it may be reasonable to omit the sunscreen for the time required.
Groups at risk of vitamin D deficiency
Older people who are institutionalised or housebound are at a particularly high risk of vitamin D deficiency. For example, up to 80% of women and 70% of men living in hostels or nursing homes in Victoria, New South Wales and Western Australia were frankly deficient in vitamin D, and 97% had a 25-OHD level below themedian value of the healthy reference also appears to be a significant prevalence of mild vitamin D deficiency in younger adults, particularly during winter.
Groups for whom low vitamin D levels have been documented older people in low- and high-level residential care;
older people admitted to hospital
patients with hip fracture;
dark-skinned women (particularly if veiled);d
* Exposure times for people with highly pigmented skin would be 3–4 times greater.3 mothers of infants with rickets (particularly if dark-skinned and
† Based on the relationship 1 MED = 200 J/m2 effective or 2 standard erythemal doses for people with type I or II (sensitive) skin. Data for Australian cities were obtained from Gies et al,4 using measured averages of MED/h over the 2 months listed, for a minimum of 5 years in the Vitamin D deficiency and bone
period 1996–2003, except Hobart, which used data from 1 year. Circulating 25-OHD and 1,25-(OH)2D levels decrease with age.
Times for New Zealand were calculated from ultraviolet data averaged over 2 This may be a result of age-related factors, such as reduced years provided by the National Institute of Water and Atmospheric Research.
‡ 11:00 or 15:00 daylight saving time, respectively.
capacity to produce vitamin D, diminished sunlight exposure,reduced intake, decline in renal function, disorders associated withabnormal gut function, or reduced synthesis or enhanced degrada-tion of 25-OHD .
It is therefore prudent to expose hands, face and arms to 1/3 MED of sunlight most daysshows approximate exposure Mild vitamin D deficiency: Defined as serum 25-OHD levels in the
times for various regions, months and skin types. But there is a range 25–50 nmol/L, mild deficiency leads to increased parathy-roid hormone secretion and high bone turnover.
caveat: deliberate exposure to sunlight between 10:00 and 14:00(or 11:00 and 15:00 daylight saving time) in the summer months Moderate vitamin D deficiency: Defined as serum 25-OHD levels
is not advised. If adequate sunlight exposure to generate sufficient of 12.5–25 nmol/L,oderate deficiency has been associated endogenous cholecalciferol is not possible, then a vitamin D with reduced bone density, high bone turnoved increased supplement of at least 400 IU (10 µg) per day is recommended.
risk of hip fracture in older peopleSevere vitamin D deficiency: Serum 25-OHD levels of
Diet: Vitamin D3 is found in small quantities in a few foods, such
< 12.5 nmol/L, resulting in osteomalacia, are rare in Australia and as fatty fish (North Sea salmon, herring and mackerel). Liver, eggs New Zealand. Patients with severe deficiency may present with and fortified foods, such as margarine and some low-fat milks, also bone and muscle pains, weakness and pseudofractures. Bone contain very small amounts of vitamin D.
For most Australians, adequate vitamin D is unlikely to be achieved through diet alone. Intake is estimated as 2–3 µg/day 2 Recommended adequate intake (AI) for vitamin D from
(< 100 IU). Recommended dietary intakes are currently under the US Food and Nutrition Board6*
review in Australia. Daily reference intakes for vitamin D devisedby the Food and Nutrition Board of the Institute of Medicine of the United States National Academy of Science6 are shown in.
These are similar to the recommendations of the Food and Agriculture Organization of the United Nations (FAO).
* AIs are recommended levels of dietary intake when there are limited data on the relationship between intake and deficiency. AIs cover the needs of adults Broad-spectrum sunscreens protect the skin against UVA and UVB radiation (wavelengths, 320–400 nm and 290–320 nm, respec- MJA • Volume 182 Number 6 • 21 March 2005
histomorphometry shows classic findings of thickened unmineral- 3 Causes of vitamin D deficiency
ised seams, increased osteoclast surfaces, smearing of tetracyclinelabels and prolonged mineralisation lag times. Cortical thinning Reduced intake or synthesis of cholecalciferol occurs because of secondary hyperparathyroidism.
Reduced sunlight exposure: ageing, veiling, illness, immobility
Reduced synthesis from a given ultraviolet exposure: ageing, dark
Vitamin D deficiency, muscle function and falls
Combined with low consumption of foods with high vitamin D
Vitamin D deficiency is an independent predictor of falls in older women in residential care in Australia.t is also linked with falls Disorders associated with abnormal gut function and and fragility fractures in both women and older men Australia, a randomised clinical trial of vitamin D supplementation Small bowel disorders: coeliac disease, sprue, inflammatory bowel
in non-institutionalised people is required to determine whether disorders, infiltrative disorders (eg, lymphoma, granuloma, falls and fracture can be prevented in this group.
Pancreatic insufficiency: chronic pancreatitis, cystic fibrosis
Vitamin D supplementation
Biliary obstruction: primary biliary cirrhosis, external biliary
drainage (eg, treatment for obstructive jaundice or after surgical Some calcium supplements and multivitamin preparations contain vitamin D, but the levels of 32–200 IU per tablet are too Reduced synthesis or enhanced degradation of 25-OHD low to treat vitamin D deficiency.

Chronic hepatic disorders: hepatitis, cirrhosis
Halibut or cod liver oil capsules contain 400 IU of cholecalcif- Drugs: rifampicin, perhaps multiple anticonvulsant drug therapy 3) per capsule. However, although these are cheap (0.08 cents each), they also contain vitamin A (4000 IU), whichmay not be beneficial (epidemiological studies suggest that vitamin available in Australia, and there is concern about inducing hyper- A excess may be associated with an increased fracture risk calcaemia or hypercalciuria if excessive doses are used. Vitamin D3 The single pure vitamin D preparation in Australia is Ostelin appears more effective than D2 in raising serum 25-OHD level.
1000 (Boots), which contains ergocalciferol (vitamin D2) (1000 IU Calcitriol (1,25-(OH)
or 25 µg) and costs about 24 cents per capsule.
patients with deprivational vitamin D deficiency as it has a narrow A larger dose (50 000 IU) of cholecalciferol is available in New therapeutic window, may result in hypercalcaemia or hypercalciu- ria and does not increase serum 25-OHD levels.
Some commercial 25-OHD assays do not measure 25-OHD2 (the vitamin D2 form) as well as they measure 25-OHD3 (thevitamin D3 form) and may not be optimal for monitoring replace- Vitamin D intoxication produces hypercalcaemia (with anorexia,nausea, polyuria, constipation, weakness, weight loss, headache, Dosages required to treat moderate to severe vitamin D depression, vague aches, stiffness, soft tissue calcification, nephro- calcinosis, hypertension and anaemia). In severe cases, hypercal- Vitamin D is stored in fat and muscle and slowly released, caemia may lead to irreversible renal and heart failure or coma particularly during winter.n vitamin D-deficient patients, it is necessary to replete the vitamin D stores. While the daily Vitamin D toxicity can be caused by excess oral intake through
requirement for vitamin D is 400–600 IU, a larger dose is needed supplementatio but not by prolonged exposure of the skin to to treat patients with deficiency. As vitamin D is distributed in the body fat compartment, which is larger than the plasma and No clinical or biochemical evidence of toxicity has been noted
extracellular fluid compartment, large doses are needed before with doses up to 4 000 IU (100 µg) daily.30 Although there is little changes in serum 25-OHD are seen. This may explain the lag evidence for toxicity with high-dose injections (300 000 IU) at time seen with vitamin D supplements before normalisation of intervals of not less than 3–6 monthse safety of such serum 25-OHD levels. Vitamin D status should be assessed 3–4 supraphysiological doses is yet to be established.
months after commencing treatment. Recommendations for The contraindication for administration of vitamin D is hyper-
management of vitamin D deficiency states are summarised in Cod liver oil also contains vitamin A, which can be toxic at high
High dosages of Ostelin (3000–5000 IU daily for 6–12 weeks)
can be used to replete body stores. Indeed, oral doses of 10 000 IUper day have been given without adverse effects for at least 90 daysin postmenopausal women. Oral dosing can be effective in individuals with malabsorption, unless it is very severe, but higher The greatest benefits of vitamin D supplementation are seen in high-risk vitamin D-deficient individuals with demonstrated Higher single doses of 50 000–500 000 IU orally or 300 000–
decreases in bone density. Increases in bone density from 0–4% in 600 000 IU vitamin D3 intramuscularly can effectively treat vita- vitamin D-insufficient patients and from 10%–40% in vitamin D- min D deficiency One or two annual intramuscular doses of deficient patients with osteomalacia have been reported after 300 000 IU of cholecalciferol have been shown to reverse vitamin optimal treatment with vitamin D. It is unlikely that vitamin D D deficiency states.Intramuscular preparations are preferable for supplementation has any role in vitamin D-replete individuals.
malabsorption. However, these formulations are not currently However, the optimal level of serum 25-OHD is unknown; MJA • Volume 182 Number 6 • 21 March 2005
4 Recommendations for management of vitamin D
We thank the many members of the Australian and New Zealand Bone and deficiency states
Mineral Society (ANZBMS), Osteoporosis Australia (OA), the Endocrine Society of Australia (ESA) and the Cancer Councils of Australia for theirsuggestions and critical comments; the Australian Radiation Protection and Elderly people, particularly in residential care
Nuclear Safety Agency for calculating the data and providing information on People with skin cancers or skin-related conditions where
sun exposure times; and Dr Richard McKenzie (National Institute of Water and Atmospheric Research) for providing the New Zealand data. We also Dark-skinned people, particularly veiled women
thank Professor BEC Nordin for critical appraisal of the final draft of theposition statement and Professor GC Nicholson (Chair, Medical and Scien- Patients with malabsorption syndromes
tific Affairs Committee, ANZBMS) for commissioning the project on behalf of ANZBMS.
Consensus process: This position statement was developed by a working 25-hydroxyvitamin D (25-OHD) (note that not all commercially-
group commissioned by the ANZBMS and OA. The first draft was developed available assays detect 25-OHD2 [vitamin D2 form] optimally) by the seven members of the working group with expertise in bone health and osteoporosis. Drafts were circulated to other experts in the area and also Fatty fish, such as mackerel and herring
to the Cancer Council of Victoria for advice on sun exposure recommenda-tions. The subsequent draft was posted on the ANZBMS website for Liver
widespread comment and feedback. Suggested revisions were incorporated Foods fortified with vitamin D (margarine and some milks)
with consensus from each member of the working party. Further adviceabout sun exposure was provided by the Australian Radiation Protection and Minimum sun exposure to prevent deficiency Nuclear Safety Agency. The final manuscript was reviewed by Councils of the For most people, exposure of hands, face and arms to 1/3 minimal
ANZBMS, ESA and OA scientific affairs committees.
Older people require more frequent exposure
Competing interests
Dietary vitamin D required to prevent deficiency At least 200 IU (5 µg) (age < 50 years) or 600 IU (15 µg) (age > 70
Those with substantial sun avoidance may require higher doses
Vitamin D supplementation required to reduce fracture risk in the 1 DeLuca HF, Zierold C. Mechanisms and functions of vitamin D. Nutr Rev 2 Holick MF. McCollum Award Lecture, 1994: vitamin D — new horizons for About 1000 IU (25 µg) per day
the 21st century. Am J Clin Nutr 1994; 60: 619-630.
Vitamin D required to treat moderate to severe deficiency 3 Pathak MA, Nghiem P, Fitzpatrick TB. Acute and chronic effects of the sun.
In: Freedberg I, Eisen A, Wolff K, et al, editors. Fitzpatrick’s dermatology in 3000–5000 IU (75–125 µg) per day for at least 6–12 weeks; this will
general medicine. 5th ed. Vol 1. New York: McGraw-Hill, 1999: 1598-1607.
usually return serum 25-hydroxyvitamin D levels to the reference 4 Gies P, Roy C, Javorniczky J, et al. Global Solar UV Index: Australian range, and allow ongoing treatment with a lower dose (eg, 1000 IU measurements, forecasts and comparison with the UK. Photochem Photo- For example, Ostelin (1000 IU ergocalciferol; Boots), 3–5 capsules
5 Pasco JA, Henry MJ, Nicholson GC, et al. Vitamin D status of women in the per day for 6–12 weeks, followed by 1 capsule per day.
Geelong Osteoporosis Study: association with diet and casual exposure tosunlight. Med J Aust 2001; 175: 401-405.
An alternative is Calciferol Strong (50 000 IU cholecalciferol; PSM
6 Food and Nutrition Board: Institute of Medicine. Dietary reference intakes Healthcare), 1 tablet once per month for 3–6 months (available in for calcium, phosphorous, magnesium, vitamin D, and fluoride. Washing- ton, DC: National Academy Press, 1997.
7 Human vitamin and mineral requirements. Report of a joint FAO/WHO Most patients will need ongoing treatment with a lower dose (eg,
expert consultation. Bangkok, Thailand. Rome: World Health Organiza- tion, Food and Agriculture Organization of the United Nations, 2002.
8 Flicker L, Mead K, MacInnis RJ, et al. Serum vitamin D and falls in older women in residential care in Australia. J Am Geriatr Soc 2003; 51: 1533-1538.
threshold values ranging from 50 nmol/L to as high as 110 nmol/L 9 Sambrook PN, Cameron ID, Cumming RG, et al. Vitamin D deficiency is have been suggested.ome of the benefit of vitamin D common in frail institutionalised older people in northern Sydney [letter].
supplementation may relate to improved muscle function and 10 Stein M, Scherer S, Walton S, et al. Risk factors for secondary hyperparath- yroidism in a nursing home population. Clin Endocrinol 1996; 44: 375-383.
In randomised controlled trials, vitamin D plus calcium
11 Inderjeeth CA, Nicklason F, Al-Lahham Y, et al. Vitamin D deficiency and reduced the risk of hip and other non-vertebral fractures in older secondary hyperparathyroidism: clinical and biochemical associations in people living in institutions or at home.
older non-institutionalised Southern Tasmanians. Aust N Z J Med 2000; 30: A comprehensive meta-analysis suggests that vitamin D reduces 12 Morris HA, Morrison GW, Burr M, et al. Vitamin D and femoral neck the risk of vertebral fractures by 37% with no significant reduction fractures in elderly South Australian women. Med J Aust 1984; 140: 519-521.
13 Diamond T, Smerdely P, Kormas N, et al. Hip fracture in elderly men: the importance of subclinical vitamin D deficiency and hypogonadism. Med J A recent double-blind randomised placebo-controlled trial of oral cholecalciferol (100 000 IU 4-monthly over 5 years) showed 14 Grover SR, Morley R. Vitamin D deficiency in veiled or dark-skinned that it reduced the risk of first hip, wrist, forearm or vertebral pregnant women. Med J Aust 2001; 175: 251-252. 15 Diamond TH, Levy S, Smith A, Day P. High bone turnover in Muslim women fracture by 33% in people over the age of 65 years living in the with vitamin D deficiency. Med J Aust 2002; 177: 139-141. 16 Skull SA, Ngeow JY, Biggs BA, et al. Vitamin D deficiency is common and Adequate dietary calcium is likely to be required together with
unrecognized among recently arrived adult immigrants from The Horn ofAfrica. Intern Med J 2003; 33: 47-51.
adequate vitamin D to reduce fracture rates, as most studies have 17 Nozza JM, Rodda CP. Vitamin D deficiency in mothers of infants with used a combination of vitamin D and calcium supplementation.
rickets. Med J Aust 2001; 175: 253-255. MJA • Volume 182 Number 6 • 21 March 2005
18 Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the 30 Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake elderly: consequences for bone loss and fractures and therapeutic implica- exceeding the lowest observed adverse level. Am J Clin Nutr 2001; 73: tions. Endocr Rev 2001; 22: 477-501.
19 Dawson-Hughes B, Dallal GE, Krall EA, et al. Effect of vitamin D supple- 31 Parfitt AM. Osteomalacia and related disorders. In: Avioli LV, Krane SM, mentation on wintertime and overall bone loss in healthy postmenopausal editors. Metabolic bone disease and related disorders. Philadelphia: WB women. Ann Intern Med 1991; 115: 505-512.
20 Kipen E, Helme RD, Wark JD, Flicker L. Bone density, vitamin D nutrition, 32 Mithal A, Sen I, Naik V, Ravishakar U. Spectacular recovery of bone mineral and parathyroid hormone levels in women with dementia. J Am Geriatr density following treatment of osteomalacia [abstract]. J Bone Miner Res 21 Weatherall M. A meta-analysis of 25 hydroxyvitamin D in older people with 33 Freaney R, McBrinn Y, McKenna MJ. Secondary hyperparathyroidism in fracture of the proximal femur. N Z Med J 2000; 113: 137-140.
elderly people: combined effect of renal insufficiency and vitamin D 22 Pfeifer M, Begerow B, Minne HW, et al. Effects of short-term vitamin D and deficiency. Am J Clin Nutr 1993; 58: 187-191.
calcium supplementation on body sway and secondary hyperparathy- 34 Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, season, and roidism in elderly women. J Bone Miner Res 2000; 15: 1113-1118.
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supplementation on falls: a randomised controlled trial. J Bone Miner Res 35 Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992; 327: 1637-1642.
24 Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip 36 Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and fractures among postmenopausal women. JAMA 2002; 287: 47-54.
vitamin D supplementation on bone density in men and women 65 years 25 Mawer EB, Backhouse J, Holman CA, et al. The distribution and storage of of age or older. N Engl J Med 1997; 337: 670-676.
vitamin D and its metabolites in human tissues. Clin Sci 1972; 43: 413-431.
37 Papadimitropoulos E, Wells G, Shea B, et al. Meta analyses of therapies for 26 Mastaglia S, Oliveri B, Parisi MS, et al. 10,000 IU of oral vitamin D per day postmenopausal osteoporosis. VIII Meta analysis of the efficacy of vitamin are required to rapidly (3 months) reach adequate 25OHD in osteoporotic D treatment in preventing osteoporosis in postmenopausal women.
women. J Bone Miner Res 2003; 18 (Suppl 2): S55.
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27 Tjellesen L, Hummer L, Christiansen C, Rodbro P. Serum concentration of 38 Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 vitamin D metabolites during treatment with vitamin D2 and D3 in normal (cholecalciferol) supplementation on fractures and mortality in men and premenopausal women. Bone Miner 1986; 1: 407-413.
women living in the community: randomised double blind controlled trial.
28 Swain R, Kaplan B. Vitamins as therapy in the 1990’s. J Am Board Fam Pract 29 Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an over-the-counter supplement. N Engl J Med 2001; 345: 66-67.
(Received 26 Nov 2004, accepted 24 Dec 2004) MJA • Volume 182 Number 6 • 21 March 2005


Multnomah County and AMR Clackamas County, Oregon Emergency Medical Services Patient Treatment Protocols Effective: February 1, 2008 CONTENTS Table of Contents Preface Section 00.000 Advance Directives and Do Not Attempt Resuscitation Orders .00.020Medical Control for Drugs and Procedures .00.040 Treatment . Section 10.000 Anaphylaxis and Allergic Reaction .10.

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