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Good (for you) to the last drop!

The table manners practiced in the dining rooms of the Grand Forks Human Nutrition Research Center would curl the hair of etiquette aficionados.

Long-term guests and those who drop in for daily meals always lick their plates, bowls, and utensils, then spritz them with distilled water and drink the residue. But such manners--or lack of manners--are essential to the center's research.

Established by congressional mandate and opened in 1970, the center defines human requirements for minerals--particularly the trace elements--that amount to only thousandths or millionths of a gram each day.

So volunteers need to consume every last bit of their meals, which contain precisely measured amounts of these elements, down to the very last drop. This ensures that findings from dietary studies are based on accurate data.

Center director Forrest H. Nielsen says nearly 75 percent of the human and animal studies aim "to establish our need for various trace elements, the factors that affect that need, and the functions that are impaired if we don't get enough copper, manganese, or boron, for instance."

The other 25 to 30 percent of studies are "specifically designed to establish how much of a trace element we require to reach our genetic potential and maintain optimal health throughout life."

The National Academy of Science's Food and Nutrition Board uses these ARS data when it convenes a committee every 5 years or so to evaluate current Recommended Dietary Allowances (RDA) and Estimated Safe and Adequate Daily Dietary Intakes or to establish new ones.

The trouble is, says Nielsen, "very little research on trace elements is being done with human volunteers outside of ARS nutrition centers. Except for iron, iodine, and zinc, many in the nutrition community don't even think that trace elements are of much nutritional concern."

That explains why, of the 14 or so elements currently thought to be essential for humans, RDA's have been established for only these three, plus selenium. And selenium's addition to the 1989 RDA's was largely due to the efforts of an ARS scientist at the Beltsville (Maryland) Human Nutrition Research Center.

Estimated safe and adequate intake ranges have been set for another five elements--copper, manganese, fluoride, chromium, and molybdenum. But data are still too skimpy for official estimates of our requirements for silicon, vanadium, nickel, boron, and arsenic.

"Unless you identify problems caused by deficiencies," Nielsen asserts, "you'll never know if an element's important."

In the last few years, he and colleagues Curtiss D. Hunt and James E. Penland have put boron "on the map" for essentialness with dozens of animal studies and four human studies to date. Before that, boron was viewed as a traveler just passing through the body with no known metabolic function.

Grand Forks researchers are also conducting animal studies to show the functions and consequences of deficiencies in silicon, vanadium, nickel, and arsenic. That's right, arsenic!

"All trace elements are toxic to one degree or another when taken in excessive doses," says Nielsen. "But it's virtually impossible to get toxic levels of any element through uncontaminated food."

Before the turn of the century, iron and iodine were the only elements recognized as essential for humans. Most of the others, which are sometimes called trace metals, were "discovered" after 1950.

No doubt, new elements will show up with further research. And newly recognized functions for established trace elements continually crop up. So the Grand Forks staff has its research cut out for it well into the next century.

Data for setting the RDA's

"All of the Grand Forks center's human studies contribute useful information for setting RDA's--but some more than others," says Phyllis E. Johnson, who oversaw research on trace element biological availability and absorption there until last fall. "They have also contributed significantly to the new requirements to be published by the World Health Organization."

Now associate director of ARS' Pacific West Area headquartered in Albany, California, Johnson still has a hand in studies she started while at the center.

RDA's are largely based on the amount of an element people need to stay in balance. That's how much we need to consume each day to replace what is lost through the urine, feces, sweat, menstrual flow, and seminal fluid. And it changes throughout our lifetimes.

But because people don't absorb all of the trace elements that are in their foods, researchers also have to determine what percentage is absorbed for the RDA committee to arrive at a recommended intake level. And this absorption rate differs for each element.

Arriving at such figures requires hundreds of precise measurements and a lot of sophisticated number crunching.

In a 2-month study of zinc balance, nutritionist Janet R. Hunt found that men and women lost an average 2 milligrams of zinc a day through urine and feces. But they absorbed only 25 percent, on average, of the zinc present in their diets. This means they would have to consume four times the 2-mg loss, or 8 mg daily, to ensure absorption of enough to replace that loss.

Hunt says she began the study because the 1980 RDA's based the zinc requirement on the need to replace a 6-mg daily loss at an absorption rate of 40 percent. But later studies pointed to both a much lower daily loss and a much lower absorption rate.

While Hunt's study was under way, the 1989 RDA's were published. She says, "It based the zinc requirement on a 20-percent absorption rate and a loss of 2.5 mg per day. My data support it."

She adds that absorption rates can vary widely, depending on many factors, so the small difference between her rate and the revised RDA basis is not surprising. And the loss of zinc in sweat, which she did not measure, could account for the slightly higher daily loss used by the RDA committee. "I'm much happier with the revised bases than I was when I started this study," she says.

Hunt says that the changed bases for setting the 1989 zinc RDA didn't alter the recommended amount for men because the absorption rate dropped along with the quantity needed for daily replacement. It remains at 15 mg for men. But the committee did reduce women's RDA to 12 mg because of their smaller body size.

The RDA's are actually higher than the bases call for, Hunt explains, because the data from studies are average values. The RDA's include an added safety factor to protect individuals with the highest requirements.

The committee also considers how much of an element people are already consuming in recommending daily intakes, says Hunt. "The reasoning is, if people are generally healthy, their intakes must be meeting their needs."

Assessing Trace Element Needs

There is no RDA for copper yet. But a study led by Johnson on the effects of age and gender on copper requirements should help move us closer to one. And the findings indicate that women need a little less copper than men--at least up to age 60--because of their smaller size.

Before her study, she says, "there were no data showing whether men and women differ in copper absorption, rate of loss, or basic requirements. And studies on the effect of aging on copper status were limited."

So Johnson measured the copper intakes of 127 men and women from 20 to 83 years old living in the Grand Forks area. She also assessed copper absorption and loss by giving each volunteer a harmless dose of radioactive copper and measuring how long it stayed in the body.

The men consumed about 1.3 mg of copper daily, she says. The women took in 1.1 mg. "My feeling is that these intakes are typical and probably sufficient." The estimated safe and adequate intake is 1.5 to 3 mg per day for both men and women, but most people consume less copper than that.

Johnson notes that the women consumed less copper than the men but compensated by absorbing a higher percentage of their intake. So, pound for pound, both genders absorbed the same amount. "This suggests that women have a lower requirement for dietary copper intake than men," she says, because they generally weigh less.

After age 60, however, the trends seem to reverse. Johnson says that some indicators of copper status slipped in the older women. And the older men absorbed slightly more copper from their diets than the older women. But there were too few older volunteers in the study to draw any statistically sound conclusions, says Johnson, other than that there is a need for a study with more older volunteers.

It's long been known that iron has a profound effect on our energy levels: Blood hemoglobin needs iron to deliver oxygen to body cells. But other trace elements increasingly appear to affect energy metabolism in more subtle ways.

Physiologist Henry C. Lukaski began a series of rat studies to demonstrate the effects of zinc on thyroid function--the primary regulator of energy metabolism. Other investigators, he says, had reported that a low-zinc intake slowed people's basal metabolic rate and reduced blood levels of thyroid hormones.

Since the thyroid doesn't operate in a vacuum, Lukaski explains, he and collaborators looked at the biochemical pathway that stimulates the gland to release its hormone, known as [T.sub.4]. Then he and center colleagues looked at the pathway that regulates the conversion of [T.sub.4] in the blood to its more active form, [T.sub.3].

"There are zinc-dependent enzymes that regulate the synthesis of precursors of TRH (thyrotropin-releasing hormone)," he says, "but no one has looked at the effects of zinc deficiency on TRH production." Synthesized in and around the brain's hypothalamus, TRH stimulates the pituitary gland to release TSH (thyroid-stimulating hormone). TSH, in turn, signals the thyroid gland to release [T.sub.4].

Lukaski collaborated with researchers at the Veterans Administration's Wadsworth Medical Center in Los Angeles on investigating the brain pathway. They found that "the rats fed a no-zinc diet couldn't make the TRH precursors," he says. "And precursor levels were reduced in the animals that got only half the amount of zinc recommended for test rats."

He suspects that inadequate dietary zinc is blunting the activity of the zinc-dependent enzymes that regulate synthesis of these precursors. But that's a question for a future study.

Zinc-poor diets also have an effect at the other end of the thyroid hormone pathway. Rats fed either a no-zinc diet or a reduced-zinc diet had significantly lower blood levels of [T.sub.4] and [T.sub.3] as well as TSH. The more deficient the diet, Lukaski notes, the greater the reduction in these hormones.

And a big dip in these hormones can have a chilling effect. When the rats that got a no-zinc diet were put in a cold room several degrees above freezing, they couldn't maintain their core body temperature.

They produced more norepinephrine, or adrenaline, in an attempt to stoke their metabolic furnaces. But their thyroid hormone levels were just too low to maintain body heat.

Boron is another trace element that increasingly appears to be involved in energy metabolism. But its effects are obvious only when test animals are under stress, says Grand Forks anatomist Curtiss D. Hunt, who has been studying these effects for nearly a decade.

For instance, vitamin D deficiency causes several metabolic abnormalities in chickens, including elevated levels of blood glucose and triglycerides as well as pyruvate--a primary product of glucose metabolism. Adding boron to the chicks' diets markedly decreased those elevated levels.

Boron also reduced blood pyruvate levels in vitamin D-deprived rats, Hunt notes. This could mean that boron increases the rate at which the rats recycle energy metabolites. Or it could mean that the rats had less glucose to metabolize, which seemed to be the case. Their glucose levels tended to be lower than those in the control animals, he says, but not significantly.

Now, Hunt is finding in a new series of studies that he can alter a biochemical indicator of muscle function in exercising rats simply by changing the level of boron in their diets.

"I'm convinced that the amounts of boron found in a healthful diet affect energy metabolism," he says. "It appears to increase the rate at which animals bum fuel and perhaps the efficiency by which it is burned. But we don't yet know the mechanism." He and Nielsen are also convinced that boron affects the way we use minerals--particularly, some minerals important to healthy bones: calcium, magnesium, and copper. Human studies led by Nielsen indicate that boron helps stem the loss or improves the absorption or use of these minerals. And animal studies done by Hunt show that boron helps overcome bone abnormalities and altered gait that result from raising chicks on vitamin D-deficient diets.

Hunt says the reason boron's effects have gone unnoticed is that most commercial feeds for test animals are quite high in the element. A typical rat chow contains about 12 parts per million, whereas he sees positive effects beginning at only 1.4 ppm. And commercial chick starter contains alfalfa, which is naturally high in boron.

Plant-based foods are much higher in boron than animal foods, says Hunt. He has analyzed dozens of foods common in the human diet and found the richest boron sources to be apples, pears, grapes, and the juices of these fruits.

Too Little Copper-Hard on the Heart?

Copper is one trace element that may have giant implications for public health. More than 20 years ago, Grand Forks physician and research leader Leslie M. Klevay raised rats' plasma cholesterol by feeding them a low-copper diet.

He hypothesized that long-term, inadequate dietary intake of copper is a major factor in the prevalence of heart disease--the number one cause of death in the United States.

Klevay has amassed a veritable library of epidemiological studies on heart disease and animal studies on the effects of copper deficiency. So far, he says he has identified "more than 60 similarities between animals deficient in copper and people with heart disease." These include such major risk factors as elevated blood pressure, blood glucose, and cholesterol levels; abnormal heart rhythms; and differences between male and female responses to low copper.

One similarity was recently discovered in Klevay's lab by postdoctoral fellow Sean M. Lynch, who is now at the Harvard School of Public Health. Lynch found that copper-deficient mice took 2.5 times longer to dissolve blood clots than mice that got adequate copper in their feed.

Heart disease patients also take longer to dissolve clots when assessed by the same test done on the mice--the euglobulin clot lysis test (ECLT), says Klevay.

Tiny blood clots are part of the plaque-forming debris that accumulates in arteries, gradually narrowing the vessels and reducing blood flow. If the ability to dissolve a clot is impaired, the clot thickens--and so does the plaque.

Klevay points out that copper is a component of enzymes the body uses to make all three types of connective tissue found in arteries. It is also a component of at least three enzymes that protect body tissues, including arteries, from damage by oxygen free radicals, says Jack T. Saari, a physiologist.

In earlier collaboration with researchers at the Veterans Administration's Medical Center in Tucson and at the University of North Dakota Medical School in Grand Forks, Saari found that copper-deficient rats are more susceptible to oxidative damage. And they were protected by adding antioxidants to their feed. [For more about oxygen free radicals, see "Vitamin E Is for Exercise," Agricultural Research, September 1992, p. 14.]

Now he is finding that copper deficiency causes changes in heart and arterial cells that further point to its role in heart disease.

Over the last dozen years, Saari explains, scientists have learned that the cells lining all blood vessels are not passive. When stimulated by certain bloodborne chemicals, these endothelial cells release substances that cause the adjacent smooth muscle cells to either relax or contract.

When the muscle cells are signaled to relax, blood pressure goes down. But copper deficiency decreases release of endothelial-derived relaxing factor (EDRF) in test rats' aortas--the largest artery in both humans and animals, says Saari.

Another study with researchers at the University of Louisville produced the same results for smaller blood vessels, known as arterioles.

Saari says: "We think this is the mechanism by which copper deficiency raises blood pressure in adult rats."

Although people consume more copper than the animal diets contained, a large majority of Americans don't get the estimated safe and adequate daily intake of 1.5 to 3 mg.

According to USDA's 1987-88 food consumption survey data to be published soon, U.S. men average 1.2 to 1.3 mg of copper daily from their diets; women average 0.9 to 1.0 mg. Over many years, these marginal intakes may fail to maintain the integrity of arteries and protect them from damaging oxygen free radicals.

What's more, too much of the sugar fructose can magnify the effects of a marginal copper intake, according to studies at the ARS Beltsville center and now at Grand Forks.

Nielsen and chemist David Milne looked for signs of oxidative stress in a carefully controlled 7-month study of six men during which their copper intake was reduced to 0.6 mg per day and fructose supplied 20 percent of their calories.

Americans typically derive 10 to 14 percent of their calories from fructose, which constitutes half of table sugar (sucrose) and close to half of high-fructose corn sweeteners, explains Milne. People who consume a lot of nondiet soft drinks can easily get more than 15 percent.

While extra fructose did not reduce copper absorption, it significantly decreased levels of two copper-containing enzymes that function as antioxidants when the men got only 0.6 mg of copper per day.

Also, the low-copper intake by itself caused the men to produce more of an antioxidant that does not contain copper to take up the slack. Glutathione levels went up during the low-copper periods, regardless of whether the diets contained fructose or the control carbohydrate, a starch, says Milne.

He concludes that "fructose may increase the potential for tissue damage by oxygen free radicals during short-term copper deprivation."

He notes, however, that there was so much variability among the six men that factors other than dietary copper--for example, genetic makeup, previous body levels of copper, and exposure to oxidant stress--must have influenced their response to short-term deprivation.

"We're getting all kinds of evidence that copper deficiency has pathological consequences," says Nielsen. "I think low copper intakes typical in the United States and in other industrialized countries can lead to problems, particularly in older people."

Possibly, just one extra milligram of copper each day could put a big dent in the incidence of heart disease. But the burden of proof falls on the Grand Forks center, where many of the human copper studies are being done.

Future studies may also show the potential of zinc, magnesium, boron, or other obscure trace elements to keep us healthier well into old age. The work at Grand Forks and other ARS centers is demystifying their functions and proving their importance. This new knowledge should inspire others in the nutrition community to help define human requirements for all trace elements.--By Judy McBride, ARS.

All researchers are at the USDA-ARS Grand Forks Human Nutrition Research Center, P.O. Box 7166, University Station, Grand Forks, ND 58202-7166. Phone (701) 795-8353, fax number (701) 795-8395.

Copper: Used in the body to aid iron absorption, in hemoglobin, and for cardiovascular health. It is most plentiful in liver, oysters, lobster, nuts, seeds, olives (green), soy flour, wheat bran, wheat germ, dark chocolate, and dried peas.

Boron: Used to maintain healthy bone structure. It is found in noncitrus fruits such as apples, pears, peaches, grapes, and cherries; nuts, dried peas, beans, lentils, and other legumes.
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Title Annotation:includes related article on the psychological effects of trace elements; Grand Forks Human Nutrition Research Center research on trace elements
Author:McBride, Judy
Publication:Agricultural Research
Date:Oct 1, 1992
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