Biomed Res Trace Elements 16(3) : 169 176 2005 169

Review Articles

Recent progress in exploring the essentiality of the ultratrace element to the nutrition of animals and man

Manfred Anke, Winfried Arnhold, Ulrich Schafer, Ralf Mtiller*)

Institute of Nutrition and Environment, Faculty of Biology and Pharmacy, Friedrich Schiller University Jena, D-07743 Jena, Germany ; *) Society of Ecology and Environmental Chemistry Ltd., Zittauer Str. 27, D-99091 Erfurt, Germany

Abstract A Iithium content below 1.7 mg/kg diet dry matter (DM) had a particular effect on the growth, reproduction performance, wellness and mortality of goats. The significant shift of the sex ratio of kids toward females, reduced monoaminooxidase activity in the liver, and increased creatine kinase activity (a stress indicator) are also interesting results. The normative lithium requirement of animals (goats, pigs) amounts to < 2.5 mg/kg diet DM, while that of adult humans might amount to < 200 /lg/day.

Ke ywords lithium, essentiality for animals, geological influences, intake by man, foodstuffs

Introduction life, since the natural offer meets the requirements or, During the long passage of inorganic components of in part, exceeds them considerably [3, 4, 5, 6, 7]. foodstuffs, water and air through the fauna (and man), With the help of semisynthetic feeds poor in lithium, which has lasted for several hundreds millions of rubidium, , aluminum, , arsenic, years, the majority of these substances have most or , the essentiality of these likely become parts or activators of proteins, ultratrace elements was examined, their offer deter- enzymes, hormones or other essential components of mined in dependence of the geological origin of the the body. Consequently, both a deficiency and a toxic soil, and the intake of these ultratrace elements by excess in supply must be considered for most elements adult humans with mixed and ovolacto-vegetarian [1] (Figure 1). diets was ascertained. The normative requirement for ultratrace elements, being partly extremely low, is reliably met. Apart Material and methods from genetic defects which prevent the utilization of The "essentiality" of the ultratrace elements lith- these substances [2], deficiency symptoms do not ium, rubidium, cadmium, aluminum, vanadium, arse- occur. Hints as to the biological essentiality of these nic, fluorine and bromine was exarnined in goats elements were only obtained in experiments with (Figure 2). Besides the use of synthetic feeds and semi-synthetic feeds extremely poor in the element intrauterine depletion over generations, the animal under test and after intrauterine depletion of this species selected for the study is important. The use of element. These conditions can to performance ruminant species (goats) has allowed researchers to drops, deficiency diseases and reduced life expec- substitute chemically pure urea for a significant pro- tancy. These symptoms were not registered in real portion of trace element-containing proteins. Further- more, an intrauterine depletion over three and more Address correspondence to : generations of an animal species has been shown to be Manfred Anke, Am Steiger 12, highly effective in discovering the essentiality of sev- D-07743 Jena, Germany eral elements [8]. E-mail : [email protected] An essential element is one that is required to TEL : + +49 3641 448536 support adequate growth, reproduction and health FAX : + +3641 448536 throughout the life cycle if all other nutrients are 170 Bromed Res Trace Elements 16(3) : 169-176, 2005

optimal. Besides the deficiency group, every determined for wheat (Triticum sativum), rye (Secale deficiency experiment needs a control group with cereale) and red clover (Trifolium pratense sativurn) identical conditions, feed, and the element tested. In of the field and meadow varieties (Trifolium pratense addition, the animals of both groups should live to spontaneum). The green plants were harvested when their natural death. the rye was in blossom, the wheat shooting, the field The synthetic feed, when tested for the essentiality red clover in bud, and the meadow red clover in of one element, must be supplemented with all ele- blossom [9]. ments contained in the normal feed of the animals. The ultratrace element intake was determined by The synthetic feed of the ruminants (goats), in addi- the duplicate portions technique over seven consecu- tion to cellulose in the form of purified paper (which tive days in a test comprising seven women and seven was used as litter and nutrient), contained all essential men aged between 20 and 69 years in 15 test popula- nutrients and all mineral elements present in the tions in Germany and two in Mexico. The ovolacto- normal feed, with the exception of Ra, Fr, Ac, Po, At, vegetarians were all Germans [10, 1l]. Re and the rare earth metals Pr, Nd, Pm, Sm, Eu, Gd, The analysis of the five metals and three nonmetals Tb, Dys, Ho, Er, Tm, Yb, and Cp which were delivered was made by atomic absorption spectroscopy (AAS) as impurities of the lanthanides [4] (Table 1). With (Li, Rb) [12, 13] , flameless AAS (Cd), graphite furnace the help of synthetic feeds it was possible to obtain AAS and a nitrate matrix modifier (A1) extensive data concerning the essentiality of several L14, 15], inductively coupled plasma optical emission metals (Cr, W, Cd, Pb, V, Li, Rb, A1, Ti) and also spectroscopy (ICP-OES) (V) [16], AAS hydride tech- nonmetals (F, Br, Si, As, B) [8]. nique (As) and neutron activation analysis (F and Br) The influence of the geological origin of the soil on L17]. IAEA H-9 reference material (mixed human the ultratrace element contents of the vegetation was diet) was used for checking the method.

ept{(ne{ ee~~e f ~e~s~

,OO et.

Ceoeef#rut~) eF ~t~eke ct r~tien$ Figure 1 The dependence of performance on ultratrace element supply

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Figure 2 Goat house Figure 3 Skin lesions of a lithium-deficient she-goat Recent progress in exploring the essentiality of the ultratrace element lithium to the nutrition of animals and man 171

Table 1 Components of semi-synthetic feed for ruminants

Essentiality of lithium for animals significant. The increased abortion rate of lithium- Whether lithium is essential for the fauna has been deficient goats is also important. Miscarriages occur- investigated systematically since 1976 in goats [18, 19, red at a rate of 14% between the third and fifth 20, 21, 22, 23, 24], sheep [25], and rats [26, 27] in months of ~ravidity. The effect of lithium deficiency Germany, Hungary, the USA, and Japan. The influ- on the sex ratio was most surprising. As a rule, ence of a lithium-poor feed on the pre- and postnatal hornless goats give birth to more male than female growth of goats was tested with 14 repetitions over 15 kids. Lithium-deficient goats, however, gave birth to years (Table 2). It was shown that the feed intake by significantly more female kids. the growing young goats was significantly (11%) The 5-year average showed that lithiurn-deficient lower in comparison to the control goats. The adult goats produced 20% Iess milk than the control ani- lithium-deficient goats compensated this low feed mals. intake in the second year of life. The kids of lithium- Long-term lithium deficiency experiments with deficient goats had a 9% Iower birth weight than female goats allowed an analysis of the influence of those of control goats. lithium-poor nutrition on the life expectancy of the Moreover, Iithium-poor nutrition caused reproduc- animals. The investigations showed that 41% of the tive disorders in goats and rats. Lithium-poor feeds of lithium-deficient goats and 7% of the control animals female goats did not have an effect on the intensity of died during the first year of the experiments. Skin estrus behavior. The first mating, however, produced lesions occurred in individual animals with lithium- a significantly worse rate of conception in these ani- poor feeds (Figure 3). In the meantime, it was shown mals. Repeated services at the following ovulations that lithium was also effective in the treatment of improved the conception rate of lithium-deficient herpes virus infections and of seborrheic dermatitis in goats. The difference between the groups remained humans [28]. 172 Biorned Res Trace Elements 16(3) : 169-176, 2005

Table 2 Influence of lithium-poor nutrition on feed intake, growth, reproduction performance, milk production, mortality, and serum enzyme activity of goats

1)Control goats 100 % lithium deficrent goats x% p2) srgmficance level Student test

Lithium deficiency did not affect the biochemical Influence of the geological origin of the soil on the blood profile, but it changed the activity of several lithium content of the vegetation serurn enzymes. As a rule, Iithium deficiency reduced The Earth's crust contains 50-65 mg Li/kg [3l] . The the serum enzyme activity, mainly the enzymes of the geological origin of the soil is reflected in its lithium citrate cycle (ICDH, isocitric acid dehydrogenase ; content (Table 3). The plants of the sandstone weath- MDH, malate dehydrogenase), of glycolysis (ALD), ering soils of the Cretaceous formation, slate, Keuper, and of nitrogen (GLDH, glutamine dehy- gneiss, Muschelkalk and Bunter are richer in lithium drogenase), for which significant differences between than those of diluvial and alluvial formations (Table control and lithium-deficient goats were observed. 4) [2l]. Only creatine kinase activity, a stress indicator enzyme, was significantly increased in lithium- Lithium intake by humans deficient goats. The lithium intake by adult humans v~ith mixed Owing to the particular role of monoamine oxidase diets was systematically investigated in 10 test popu- (MAO) in manic-depressive diseases, chronic schizo- lations (each from different regions of Germany) of phrenia, and unipolar depression, this enzyme was seven women and seven men each, aged between 20 also investigated in the liver of control and lithium- and 69 years (Table 5) [32]. deficient goats. MAO activity in the hepatic tissue of Men and women consumed the same amount of the latter group was reduced to 28%. lithium-rich and lithium-poor food and beverages. The Abnormal behavior was observed in lithium- lithium intake by both sexes doubled after the deficient rats, and this disappeared after lithium sup- reunification of Germany and with worldwide trade. plementation. This assessment is interesting in so far Since men consume 24% more dry matter than as the MAO hypothesis is discussed as a biochemical women, they take in more lithium than women. Adults mechanism of a lithium therapy in humans. of both sexes with mixed diets consurned significantly In brief, the results of lifelong lithium-poor nutrition more lithium with increasing age. On average, elderly over > 15 generations of goats show that lithium may test persons consumed 30-46% more lithium. They be essential to the fauna, and thus, to hurnans as well clearly preferred lithium-rich foodstuffs. In Germany, [29, 30]. the individual lithium intake per day on the average of a week varies between 128 pg/day and 1802 pg/day in women and 139 and 3424 pg/day in men. Worldwide, Recent progress in exploring the essentiality of the ultratrace element lithium to the nutrition of animals and man 173

lithium intakes between 4 and 2392 pglday on the 1.0 to 7.0 mg Li/kg food DM. Tomatoes are especially average of populations are reported [30, 33, 34, 35] In rich in Li (7.0 mg Li/kg DM). By contrast, anirnal Germany, 70 women and 70 men consumed, on the foodstuffs are generally lithium-rich. On average, only average of 7 days, > 100pg Li/day. butter, fish, cheese and broiler meat contain > 3.0 mg Li/kg DM (Table 6). Poultry, beef, pork and mutton Lithium contents of the foodstuffs contain lithium concentrations increasing in that A11 sugar- and starch-rich cereals, pasta, bread, order. Most lithium is delivered to humans by eggs cakes and pastries generally contain little lithium (0.2 and milk (> 7000 pglkg DM). In Germany, the lithium to 1.0 mglkg food DM). Fruits and vegetables supply content of drinking water varies between 4 and 60 pgl

30 18 17 25 16 e~~ 14 :~. 20 ~ 12 :b C o O 10 ce = = 15 10 10 ,r ~ ~'aO 8 tb 8 ~ 7 O ~. 10 ~ 6 c' a: ~i a, 4 5 ~ 2 3 3 2 1 1 1 ~ ~ 21 2 1 1 O o ~SO~~~sg)Ss~)SsC)Sss~~!~s~SssSSSCSO~~~SS)SS~)SS~~S~)SSScSsgS~~~~)CS~)~~ ¥~~ ¥SP ~P ~S) SS~ ~~ ~) ICfS) ~S) ~:~~~b¥~~~¥~~¥~~~~~~~~¥~P¥~C~)¥f~¥~~~~ In;~~ L~ ~ n) tS b~ ~5 ~S 4: ~S (~¥~S¥~¥'p~f~~b~¥~5~:~5¥~t¥~5¥q~n)~5ln;~~ LWlium intake mglday (on the average of a week) Lhhlum httlK' mgld'y (on the 'v'r'g' of I w'et)

Figure 4 Frequency distribution of the daily lithium Figure 5 Frequency distribution of the daily lithium intake by women intake by men

Table 3 The correlation of the lithium contents of two plant species of the same location (x = first species ; y = second species)

nl) = Number; p2) Significance level of the t-test according to Student; r3) Correlation coefficient

Table 4 Influence of the geological origin of the site on the lithium content of the flora in Central Europe (n 2551)

S i te Relative index Sandstone weathering soils ofthe Cretaceous formation l OO Slate weathering soils 94 Keuper weathering soils 94 Gneiss weathering soils 92 Muschelkalk weathering soils 83 Bunter weathering soils 83 Rotliegende weathering soils 70 Diluvial sands 72 Granite weathering soils 72 Loess 71 Syenite weathering soils 68 Phyllite weathering soils 65 Bog, peat soil 58 Boulder clay 54 Alluvial riverside soils 51 174 Biomed Res Trace Elements 16(3) : 169-176, 2005

Table 5 Lithium intake by adult Germans with mixed and ovolacto-vegetarian diets depending on time and gender (pg/day), on the average of a week (n=980)

1) Women = 100 %, men = x %･ 2) A = 100%; B = x %･ 3) Fp = Significance level in one- or multi-factorial variance analysis; 4) s = Standard deviation; 5) x = Arithmetic mean; 6) n = Number

Table 6 The lithium contents of several groups of foodstuffs (n 575)

1) SD = Standard deviation

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