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Stephen Walsh Responds to John Mercer November 11, 2002 1. The paper deceptively omits evidence for beneficial effects of increased circulating IGF-1 levels.My response to each of these claims is given below. While other effects of IGF-1 are beyond the scope of the milk and breast cancer paper, the related issue of optimal protein intake and bone health is discussed in another briefing paper. Protein supplementation of fracture patients is clearly linked to dramatic increases in IGF-1 and faster repair of the fracture. However, studies of protein intake and skeletal health in healthy individuals give mixed and so far inconclusive results. Protein intakes close to the recommended intake of about 0 8 g per kg per day are almost certainly beneficial for bone health compared to lower intakes but a recommendation for intakes above the recommended level is not justified based on current evidence. 2. The paper is incorrect in saying that a direct effect of IGF-1 absorption from milk cannot be entirely ruled out.The estimate of human IGF-1 production by Guler et al. is based on the observation that intravenous infusion of 30,000 micrograms per day of recombinant human IGF-1 (rhIGF-1) triples the body pool of the most stable form of circulating IGF-1, with a half-life of 12 to 15 hours. Under the assumptions that the effect of intravenous rhIGF-1 on IGF-1 reserves is equivalent to other sources, that neither major non-linear effects nor the absence of possible longer term adaptations influenced the results of these experiments, and that IGF-1 disappearing from the main pool is irreversibly removed from the body then the estimate of 10,000 micrograms per day human IGF-1 production would be valid. However, these are big assumptions. An alternative estimate based on typical body stores of 400 micrograms (100 micrograms times 4 litres of blood) and the observed half-life of 12-15 hours (time constant of 17 – 21 hours) suggests a minimum replenishment requirement of 500 micrograms per day. If the IGF-1 removed from the circulating pool is stored in other tissues and re-released into circulation slowly over time then even this lower estimate could be markedly too high. 10 micrograms per day dietary IGF-1 from a litre of milk from a BST treated cow does seem unlikely to have a biologically important effect but is not trivially dismissible as John Mercer suggests. This is borne out by the credence this possibility is given by the leading researchers on IGF-1 and cancer at Harvard Medical School discussed in the briefing paper, who are certainly aware of the paper by Guler et al 3. The paper fails to give due consideration to the possibility that the association between circulating IGF-1 levels and certain cancers is due to IGF-1 levels being boosted by the presence of undiagnosed cancer rather than high IGF-1 levels promoting the development of cancer.The possibility of reverse causation due to the mechanism you describe has been considered in the extensive research on IGF-1 levels and cancer. The main reasons why this possibility is not discussed in the briefing paper, and is not given much credence in the recent literature on IGF-1 and cancer, are the consistency of risk associations between cancer and IGF-1 in prospective studies including or excluding the early years of follow up and the association of genetic defects leading to high IGF-1, such as acromegaly, with increased cancer risk. This evidence makes reverse causation of the form suggested highly unlikely. 4. The increase in IGF-1 levels in milk supplementation experiments is due to increased calorie consumption or weight gain rather than a more specific effect of milk.This is very unlikely as several intervention and observational studies have shown increases of about 10% in IGF-1 levels in response to 2-3 glasses of milk per day. The consistency between the observational and intervention studies and between intervention studies of differing durations makes it clear that the effect is not due to a transient calorie excess. In the observational studies the correlation of IGF-1 with calorie intake is much weaker than the correlation with protein or zinc intake, which as noted in the original briefing paper are plausible and sufficient explanations of the observed association between milk intake and circulating IGF-1.. 5. The magnitude of change in IGF-1 levels in response to realistic dairy consumption (about 10%) is of little biological significance.It is generally accepted that the initial development of cancerous cells is only one part of the process leading to a damaging cancer and that the mechanisms promoting or suppressing cancer cell death are important, particularly when there is no major readily modifiable carcinogen exposure such as smoking or sunburn. The probable role of IGF-1 in altering the balance between cancer cell growth and cell death is a major focus of current cancer research and is not an "anything’s possible" speculation. The magnitude of the association of IGF-1 and cancer risk is such that a 10% difference in average IGF-1 levels may result in a 10-20% difference in risk of premenopausal breast cancer, colorectal cancer, prostate cancer and lung cancer. This is far from trivial at the population level, though as a 10% change corresponds to about half a standard deviation in terms of individual IGF-1 levels, such a change will be no more than a modest modifier of the risk of any particular individual. As emphasised in the briefing paper, any association between milk and breast cancer is unlikely to be a strong one and the evidence is contradictory as to whether any effect is beneficial or adverse, with an adverse effect being somewhat more likely. Based on other available evidence calcium and vitamin D are the main contenders for contributing a beneficial effect and the IGF-1 raising effect is the main contender for contributing an adverse effect. The claims by the UK and US Dairy Councils that milk reduces breast cancer risk by 50% and by Robert Cohen that it increases breast cancer risk by 640% are both indefensible. On the other hand, a strategy of don’t add milk to an already adequate diet seems appropriate and prudent. The briefing paper also highlights other strategies for reducing breast cancer risk based on recent review articles by Walter Willett and Timothy Key, in particular avoiding obesity and excessive alcohol consumption and increasing folate intake. In John’s search for dangerous deceptions, I suggest he is looking in the wrong place. John makes some additional points re animal research which although tangential to his critique of the milk and breast cancer paper deserve a response. Sincerely,
Stephen Walsh, Ph.D.
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