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- An exposure-response curve for copper excess and deficiency
Since there's no risk in increasing the consumption to their proposed range and it ended up being pretty reasonable, it's preferable to err on the assumption that current recommendations are not enough.
Whenever someone logs a diet in nutrition apps, the person can get a different sense of their situation depending on how these (adjustable) limits are set, judging adequate a diet that's not. Experiments to define them are also based on wealthy people, so the particular need might be higher than what's required to cover most of the population.
Bill could've written:
"The purpose of the current paper [was] to provide a brief review of current dietary reference values for copper; define the acceptable range of oral intake as described by the World Health Organization; present the results of the literature review update; and utilize the updated database to construct an exposure-response model for copper deficiency and excess."
"For adult men and women, the recommended dietary intake (RDI) is currently set at 0.9 mg Cu/day (Food and Nutrition Board, 2001). The RDI is defined as being equal to the estimated average requirement (EAR) plus twice the coefficient of variation (set at 15%) to cover the needs of 98% percent of individuals (the RDI is thus 130% of the EAR)."
"In North America the EAR is the intake level for a nutrient at which the needs of 50% of the population will be met (Cockell et al., 2008). Data from three studies were used to set the EAR at 0.7 mg Cu/day (Turnlund et al., 1990; Milne et al., 1996; Turnlund et al., 1997). No single indicator was judged to be adequate for deriving the EAR for adults. A combination of indicators from these studies were used, including plasma copper, ceruloplasmin, erythrocyte superoxide dismutase activity (SOD), and platelet copper concentrations (Food and Nutrition Board, 2001)."
"The Food and Nutrition Board (FNB) comments on the fact that these indicators do not always reflect dietary intake and that they may be inadequate for the detection of marginal copper status (Food and Nutrition Board, 2001). For example, during pregnancy, two commonly used indicators, serum copper and ceruloplasmin, increase independent of diet. Similarly, as ceruloplasmin is an acute phase protein, both serum copper and ceruloplasmin often rise with numerous disease conditions (Food and Nutrition Board, 2001)."
"Biologically based dose-response models are of particular interest in the risk assessment of essential metallic elements, since different mechanisms may lead to adverse health outcomes from both states of excess and deficiency. In general there is a lack of understanding of the dynamic and kinetic properties of copper in animal and human tissues, which limits the application of biologically based exposure-response models. The review by Stern et al (2007) identified categorical regression as a potentially useful approach for modeling the exposure-response relationship of copper. Categorical regression involves the organization of qualitatively heterogeneous response data in the form of ordered categories of severity and the application of regression analysis to predict the probability that a particular severity category occurs as a function of one or more independent variables (i.e., concentration and duration of exposure). This modeling strategy can incorporate data for multiple endpoints from multiple studies of copper excess and deficiency (Stern et al., 2007)."
"The purpose of defining a model with animal studies is to fill information gaps that exist among studies on humans. It is readily appreciated that experimental toxicity data is gathered more easily in animals than humans in part because of the unique ethical considerations associated with conduct of controlled human studies. As a result, it is not surprising that in the current copper database the studies with rats greatly outnumbered the studies with humans. To look at the impact of combining data from multiple animal species, three further models were defined. One model used only the human data, the second model used only the rat data and the last model used only the data on mice. The ERC10-T100 estimates produced from these three separate analyses were compared to the original analysis that incorporated all animal species."
"Based on the various results from sensitivity analyses, the final copper deficiency and excess models utilized exposure duration expressed in days and all of the available data on humans, rats and mice in a combined analysis. The cumulative odds models defined by these specifications produced an ERC10-T100 estimate at 2.2 mg/day (90% CI ) for severity level 2 or greater for copper deficiency and 3.3 mg/day (90% CI ) for severity level 2 or greater for copper excess. Figure 6a-d, presents the plots of the probability curves for severity levels 1 to 3 for both copper deficiency and copper excess. Equation 1 was used to create a summative U-shaped exposure-response curve (represented by the dotted curves in Figures 6b-d). The resulting trough in the U-shaped curve or the AROI is quite narrow. At the lowest level in the U-shaped curve for severity level 2 or greater (p=0.1080), the corresponding dose is equal to 2.6 mg/day. [f.lux is on, hopefully this is green] Therefore, the optimal intake level to protect the population from severity level 2 or greater responses associated with both copper deficiency and excess is approximately 2.6 mg/day. The optimal intake level to protect the population from severity level 3 or greater responses associated with both copper deficiency and excess is approximately 2.2 mg/day. It is important to note because group data, and not individual subject data, were used in this analysis, it complicates the interpretation of the final risk estimates."
"Figure 6a presents probability curves for copper deficiency and copper excess for severity levels 1 to 3.
Figures 6b‐d present probability curves for copper deficiency and excess for severity levels 1 to 3, respectively.
Each figure (6b‐d) also presents the summative probability curves defined by Equation 1. This curve is represented by: - - -"
You can tell that's even higher than 2.6 mg/d if you rely on the lowest point of the dip in 6b for severity 1.
"For adult men and women, the recommended dietary intake (RDI) is currently set at 0.9 mg Cu/day (Food and Nutrition Board, 2001). The RDI is defined as being equal to the estimated average requirement (EAR) plus twice the coefficient of variation (set at 15%) to cover the needs of 98% percent of individuals (the RDI is thus 130% of the EAR)."
"In North America the EAR is the intake level for a nutrient at which the needs of 50% of the population will be met (Cockell et al., 2008). Data from three studies were used to set the EAR at 0.7 mg Cu/day (Turnlund et al., 1990; Milne et al., 1996; Turnlund et al., 1997). No single indicator was judged to be adequate for deriving the EAR for adults. A combination of indicators from these studies were used, including plasma copper, ceruloplasmin, erythrocyte superoxide dismutase activity (SOD), and platelet copper concentrations (Food and Nutrition Board, 2001)."
"One study found that 0.4 mg Cu/day was not adequate to maintain levels of serum copper, ceruloplasmin and SOD activity in 8 of 11 young men (Turnlund et al., 1997). In the second study, 0.8 mg Cu/day did not result in a significant decline in serum copper, caeruloplasmin, or SOD activity (Turnlund et al., 1990). It was therefore decided that the copper intake needed to maintain copper status in half of the individuals in a group was more than 0.4 mg/day but less than 0.8 mg/day. The data from these two studies were then used to construct a linear model, which suggested that half of the male subjects would not maintain their copper status with a copper intake of 0.6 mg/day. The third study found that platelet copper concentration declined in 8 of 10 women given 0.6 mg/day, but increased with copper supplementation (Milne et al., 1996). As this study suggested that 0.6 mg/day may be a marginal intake level in over half the female population, an increment of 0.1 mg/day was added to cover the female population, resulting in an EAR of 0.7 mg Cu/day."
"The Food and Nutrition Board (FNB) comments on the fact that these indicators do not always reflect dietary intake and that they may be inadequate for the detection of marginal copper status (Food and Nutrition Board, 2001). For example, during pregnancy, two commonly used indicators, serum copper and ceruloplasmin, increase independent of diet. Similarly, as ceruloplasmin is an acute phase protein, both serum copper and ceruloplasmin often rise with numerous disease conditions (Food and Nutrition Board, 2001)."
"Biologically based dose-response models are of particular interest in the risk assessment of essential metallic elements, since different mechanisms may lead to adverse health outcomes from both states of excess and deficiency. In general there is a lack of understanding of the dynamic and kinetic properties of copper in animal and human tissues, which limits the application of biologically based exposure-response models. The review by Stern et al (2007) identified categorical regression as a potentially useful approach for modeling the exposure-response relationship of copper. Categorical regression involves the organization of qualitatively heterogeneous response data in the form of ordered categories of severity and the application of regression analysis to predict the probability that a particular severity category occurs as a function of one or more independent variables (i.e., concentration and duration of exposure). This modeling strategy can incorporate data for multiple endpoints from multiple studies of copper excess and deficiency (Stern et al., 2007)."
"The purpose of defining a model with animal studies is to fill information gaps that exist among studies on humans. It is readily appreciated that experimental toxicity data is gathered more easily in animals than humans in part because of the unique ethical considerations associated with conduct of controlled human studies. As a result, it is not surprising that in the current copper database the studies with rats greatly outnumbered the studies with humans. To look at the impact of combining data from multiple animal species, three further models were defined. One model used only the human data, the second model used only the rat data and the last model used only the data on mice. The ERC10-T100 estimates produced from these three separate analyses were compared to the original analysis that incorporated all animal species."
"Based on the various results from sensitivity analyses, the final copper deficiency and excess models utilized exposure duration expressed in days and all of the available data on humans, rats and mice in a combined analysis. The cumulative odds models defined by these specifications produced an ERC10-T100 estimate at 2.2 mg/day (90% CI ) for severity level 2 or greater for copper deficiency and 3.3 mg/day (90% CI ) for severity level 2 or greater for copper excess. Figure 6a-d, presents the plots of the probability curves for severity levels 1 to 3 for both copper deficiency and copper excess. Equation 1 was used to create a summative U-shaped exposure-response curve (represented by the dotted curves in Figures 6b-d). The resulting trough in the U-shaped curve or the AROI is quite narrow. At the lowest level in the U-shaped curve for severity level 2 or greater (p=0.1080), the corresponding dose is equal to 2.6 mg/day. [f.lux is on, hopefully this is green] Therefore, the optimal intake level to protect the population from severity level 2 or greater responses associated with both copper deficiency and excess is approximately 2.6 mg/day. The optimal intake level to protect the population from severity level 3 or greater responses associated with both copper deficiency and excess is approximately 2.2 mg/day. It is important to note because group data, and not individual subject data, were used in this analysis, it complicates the interpretation of the final risk estimates."
"Figure 6a presents probability curves for copper deficiency and copper excess for severity levels 1 to 3.
Figures 6b‐d present probability curves for copper deficiency and excess for severity levels 1 to 3, respectively.
Each figure (6b‐d) also presents the summative probability curves defined by Equation 1. This curve is represented by: - - -"
You can tell that's even higher than 2.6 mg/d if you rely on the lowest point of the dip in 6b for severity 1.
Since there's no risk in increasing the consumption to their proposed range and it ended up being pretty reasonable, it's preferable to err on the assumption that current recommendations are not enough.
Whenever someone logs a diet in nutrition apps, the person can get a different sense of their situation depending on how these (adjustable) limits are set, judging adequate a diet that's not. Experiments to define them are also based on wealthy people, so the particular need might be higher than what's required to cover most of the population.
Bill could've written:
"What will be proved is now only imagin'd."
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