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Center for Studies of Sensory Impairment
Aging and Metabolism (CESSIAM)
Guatemala City
Guatemala
Institute for Physiology of Nutrition
Technical University Munich
Herzogstrasse 31
D-80803 Munich
Germany
E-mail: k.schuemann{at}lrz.uni-muenchen.de
Dear Sir:
In his letter, Dr Kapil has done a service to the readership of the Journal in providing us an update on the final evaluation and legal evolution of the unfortunate situation that arose in the state of Assam in northeastern India in 2001, one that we previously commented on in our "collateral damage" commentary in these pages (1). We lament any suffering or loss of life resulting from iatrogenic factors. As trained physicians, Dr Kapil and we are linked in being imbued with the Hippocratic premise that actively doing harm to one's patientseven by accidentis a major moral proscription.
We need, however, to focus in on the aspects of negligence in the findings. In deference to cultural and religious sensitivities, instead of the animal-derived gelatin habitually used to compound the high-dose vitamin A capsules, India uses a titrated liquid syrup containing 100,000 IU vitamin A/mL. The field-campaign process in Assam in 2001 theoretically allowed for the delivery of up to 500 000 IU or 151 500 retinol activity equivalents (275 mg retinyl palmitate) of vitamin A in a single dose, if the 5-mL medicine cup had been filled. Placed into perspective, this would constitute a single dose of vitamin A that is unprecedented in the annals of human health-care exposures. The conventionally recommended vitamin A exposure for periodic dosing is 100 000 IU for infants 611 mo old and 200 000 IU for children 1259 mo old, administered every 6 mo. The original safety trials for vitamin A supplements for young children, conducted in India, showed general security for a 300 000-IU dose in preschool children (2). Only recently, a 400 000-IU one-time dose of vitamin A has been advocated for immediate postpartum delivery to lactating mothers (3)that is, adult women. Prorated over the 180 d in 6 mo, a dose of 275 mg retinyl palmitate would represent an average daily exposure of 842 retinol activity equivalents; the tolerable upper level of vitamin A for children aged 13 y has been set at 600 µg/d (4).
It is stated that, in the final years of the campaign to eradicate smallpox, many more people were dying of vaccine-related disseminated vaccinia than from native variola. Similarly, in the current, final throes of the efforts to eradicate polio, more cases of paralysis can be attributed to variant mutant strains in oral polio vaccine than to sporadic cases of the wild-type infection transmitted in the population (5). Although the equation for vitamin A is far from having shifted in these directions, some of the findings presented by Kapil provide food for thought as the vitamin A programs go forward. The Assam High Court judges found that children were exposed to "stronger doses of the VA [vitamin A] ... that many of the sick children could not tolerate." Were the most malnourished and sickly children indeed those most vulnerable to harm from excessive vitamin A exposure? Kapil notes that, in the specific district setting of the child deaths in question, the background vitamin A status has improved and that vitamin A deficiency "was not a public health problem." Could it be, therefore, that an exposure to excessive high-dose vitamin A on top of a vitamin Areplete status would be the more problematic scenario? Supporting such a speculation, a presentation at Experimental Biology 2003 parsed the data on therapeutic trials of high-dose vitamin A in children hospitalized for acute infectious diseases; it was concluded that those with low vitamin A status on admission tended to benefit, but that no gainsand even adverse effectsbefell those with adequate preadmission vitamin A status who were exposed to additional vitamin A in the hospital (J Griffith, unpublished data, 2003).
A poor-quality diet and recurrent infections are the permanent factors that keep the children of India at intrinsic risk of hypovitaminosis A. However, only several systematic semi-annual vitamin A supplementation rounds are needed to produce a stabilized and satisfactory vitamin A status (6), a situation apparently approached in parts of Assam, according to Kapil. Within the legal judgment, it seems that the postulate of Parcelsusthat everything can be toxic; it is just a matter of dosagewas found to have played out its unfortunate course among deprived populations in northeastern India. Harm may have been the concomitant result of intentions to do positive social and public health good.
Beyond establishing absolute safeguards against unintended overdosing of concentrated vitamin A to children, thought should be given to the efficacy-safety equation with respect to the perpetual maintenance of campaign-style vitamin A delivery, because these programs achieve their intended effect of raising the vitamin A status across the preschool population of deprived groups.
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