MuocENic Activity of IGF1

In the JECFA safety review,39 information on the "mitogenic effects of IGF-1 were considered; it is a mitogen for a number of various cell types and has been associated with the growth of tumors, including those of the colon, breast, lung, and osteosar-coma.132-134 The mitogenic effect could also result in proliferative reactions locally in the gut. Thus, orally administered IGF-1 increased the cellularity of the intestinal mucosa of rats in vivo127 and increased the rate of proliferation in cultures of human duodenal epithelial crypt cells.135 Since IGF-1 receptors can be detected throughout the epithelium of the intestine, with a high density in the colon,136 and the incidence of colorectal cancer is increased in acromegalic patients who have pituitary tumors that secrete excessively high concentrations of free IGF-1 in their plasma,137 concern has been expressed that increased concentrations of milkborne IGF-1 may increase the risk of colon cancer."39 After considering all of these factors, and in recognition of the minimal impact of milk IGF-1 on endogenous levels in the body, the JECFA review concluded: "[I]t was extremely unlikely that IGF-1 residues cause any systemic or local mitogenic reaction."39

On the other hand, the mitogenic activity of IGF-1 is also important for normal development, as evidenced in studies with knock-out mice that can no longer produce IGF-1. IGF-1 has been shown to be important to embryonic and postnatal development and knock-out mice (no IGF-1 gene) have impaired maturation of the nervous system, reduced myelination in the brain, and an infantile reproductive system resulting in ste-rility.138-140 Without IGF-1, normal growth and development would not be possible.

Following the JECFA review in 1998,39 a few studies appeared in the literature associating higher circulating levels of IGF-1 with increased risk of development of breast, ovarian, and prostate cancer.141-144 Based on these publications, a Citizen Petition was filed with the FDA suggesting that there was a connection between IGF-1 and cancer, and that bST use could therefore pose a food safety risk to consumers. The FDA responded to the petition, stating, " None of these articles demonstrate a causal relationship between IGF-1 and the appearance of tumors. It must be noted that while large percentage increases in IGF-1 concentrations in human plasma are reported in association with some tumors, the authors of these articles do not reach the conclusion that IGF-1 caused the tumors." The FDA concluded, "...there is no evidence linking rbGH to any increased cancer risks that might be due to increased IGF-1... ."145 There is also no evidence that IGF-1, by itself, can initiate cancer.

Other studies were published that correlated diet intake with circulating IGF-1 levels in men and women and concluded that high energy, protein, and milk intakes were associated with higher levels of IGF-1.146,147 One author concluded that increased circulating IGF-1 was beneficial for bone health,147 whereas the other hypothesized that increased circulating IGF-1 from consumption of certain diets might pose an increased risk for cancer.146 In the Holmes et al. study, intake of fish, cereal, and pasta were more strongly correlated with increased circulating IGF-1 levels than was milk.146 Based on other associations in the Holmes et al. paper, one could conclude from their data that cancer risk can also be reduced by smoking, taking hormone replacement therapy, avoiding exercise, not drinking milk or eating cereals, and eliminating fish as well as vitamins A and D from the diet. It is apparent that the associations developed by these authors made little sense biologically. Curiously, some of the same authors published another study around the same time that reported the opposite associations. After analyzing the data from 88,691 women in the Nurses' Health Study cohort (1980-1996), they found no association between intake of dairy products and breast cancer in postmenopausal women.148 Among premenopausal women, high intake of low-fat dairy foods, especially skim/low-fat milk, was actually associated with reduced risk of breast cancer.148

A subsequent study with healthy, well-nourished men reported that greater dietary intakes of protein, zinc, red meat, fish, and seafood were associated with higher circulating IGF-1 concentrations.149 Other studies in Europe reported that large increases in milk protein (but not meat protein) consumption increased circulating IGF-1 levels in young boys.150,151 Although the results may vary from study to study, it is apparent that, in general, increased intake of energy or protein is associated with increased production of IGF-1 in the body because IGF-1 links nutrition to growth.144 This is why growing children have much higher circulating IGF-1 levels than adults.95,99,100

A putative link between dairy product consumption and increased risk of cancer has not been supported by further studies. A review of 40 case control and 12 cohort studies found no association between consumption of dairy products (including milk) and the risk of breast cancer.152 The review reported that milk contains various components such as fatty acids (butyric, vaccenic, rumenic acid), cysteine-rich whey proteins, calcium, and vitamin D that have the potential to help prevent breast can-cer.152 Additional papers have appeared more recently that also found no association between circulating IGF-1 levels and the risk for developing breast cancer.153-155 The weight of evidence indicates that milk consumption may actually reduce the risk of developing breast cancer and that circulating levels of IGF-1 are not associated with an increased risk of breast cancer.

A new safety issue was recently raised regarding the impact of IGF-1 on twinning in humans. Based on the observation that injection of dairy cows with IGF-1 increases the frequency of multiple ovulations in dairy cows, it was hypothesized that consumption of dairy products from bST-supplemented cows might increase the rate of twinning in humans.156 This hypothesis is not supported by the aforementioned JECFA review,39 which demonstrated that the intake of IGF-1 from bST-supplemented dairy cows is negligible compared to endogenous production in the human body. This is supported by human studies, which showed that consumption of four 8-oz glasses of milk daily for two years produced no changes in circulating IGF-1 levels in the blood of women.157 Thus, the hypothesis that consumption of dairy products from dairy cows supplemented with bST might increase the rate of twinning in humans is not supported by the dietary exposure assessments that have been carried out by various regulatory agencies.158

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