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OCR for page 43
Thianiin
lansen and Donath (1926) identified thiamin as the
active factor in rice polishings and rice bran that pre-
vents the disease beriberi in humans. In later studies,
Kinnersly and Peters (1928) isolated thiamin from yeast
and wheat germ. A synthetic process was developed for
the production of this vitamin in 1936 (Robinson, 1966~.
Thiamin is a white hydroscopic crystalline compound
that is stable at temperatures up to 100°C and is readily
soluble in water. l humid consists ot a pyr~m~ne nu-
cleus and a thiazole ring linked by a methylene bridge
(Williams and Cline, 1936) (see Figure 101.
NUTRITIONAL ROLE
Dietary Requirements of Various Species
Thiamin synthesis occurs only in plants and microbes;
therefore, virtually all animals have nutritional require-
ments for this vitamin. There are a number of factors
that can affect an animal's dietary requirement for the
vitamin. Adult ruminants and horses can obtain ade-
quate quantities of thiamin from bacteria in the rumen
or cecum (Bechdel et al., 1926; McElroy and Gross,
1941; Kon and Porter, 1947; Hotzel and Barnes, 1966;
Poe et al., 1972~. However, young ruminants between
the ages of 2 to 7 months can, under certain circum-
stances, develop polioencephalomalacia (cerebrocorti-
cal necrosis) in which thiamin deficiency plays an
essential role (Edwin and fackman, 1981/19821. This
disease appears to result from either the ruminal de-
struction of formed thiamin or from the presence of anti-
thiamin compounds there (Edwin and lackman,
1981/1982).
Bacterial synthesis of thiamin in the cecum of nonru-
minant animals other than the horse can also occur. Rab
bits and rats, which practice coprophagy, can obtain
significant quantities of thiamin by this route. A defi-
ciency state can be induced by feeding a thiamin-free or
thiamin-inadequate diet, however (Wostmann et al.,
1958; Reid et al., 1963; Bitter et al., 1969; Loew and
Yert, 1976~. Other factors such as age of the animal
(Draper, 1958; Lazarov, 1977) and composition of the
diet (Stirn et al., 1939; Wainio, 1942; Ellis and Madsen,
1944; Dicksen and Dahme, 1971; Holler et al., 1978)
may also affect the thiamin requirement level of an ani-
mal. The thiamin requirements for most domestic ani-
mals, with the exception of horses and ruminants, range
from 1 to 10 mg/kg of diet.
Biochemical Functions
The enzyme thiamin pyrophosphokinase and adeno-
sine triphosphate (ATP) convert thiamin into its meta-
bolically active coenzyme form, thiamin pyrophosphate
(TPP) (Sauberlich, 1967~. In the form of TPP, thiamin
functions in the oxidative decarboxylation of a-keto ac-
ids, such as pyruvate and o`-ketoglutarate. In addition,
TPP functions in the transketolase reaction of the pen-
tose phosphate pathway. Thiamin plays a very impor-
tant role in glucose metabolism. Therefore, it is not
surprising that the first signs of thiamin deficiency are
usually of neurological origin. The thiamin status of an
animal can also be determined by measurement of
transketolase activity in erythrocytes or other tissues
and of percentage of stimulation of that activity by exog-
enous TPP.
Thiamin also appears to be involved in nerve trans-
mission and/or excitation, but whether this role involves
TPP is not clear (Waldenlind, 1978~. It is this function
that appears to be related to the toxicity of thiamin (Ito-
kawa, 19781.
43
OCR for page 44
44 Vitamin Tolerance of Animals
NH2-HCl CH3
1
NICHE Now |
CH3 N
+ )=:CH2- CH2- OH
Thiamin Chloride-Hydrochloride
FIGURE 10 Chemical structure of thiamin hydrochloride.
FORMS OF THE VITAMIN
Thiamin is found in most animal tissues predom
.
nately in phosphorylated forms (e.g., thiamin mono-, di-,
and triphosphates). In cereals and legumes it is present
in a nonphosphorylated form. It is located predomi-
nately in the scutellum and germ of cereal grains and is,
therefore, removed by milling. Thiamin hydrochloride
and thiamin mononitrate are synthesized for commer-
cial use in animal feeds. Thus, thiamin is found in the
diet in one of three forms: free thiamin, phosphorylated
thiamin, and protein-phosphate complexes.
ABSORPTION AND METABOLISM
In the gastrointestinal tract, the bound forms of thia-
min are cleaved and the free form is absorbed primarily
in the proximal small intestine (Sklan and Trostler,
1977~. Thiamin absorption appears to be passive at high
or pharmacological concentrations and active, by a
carrier-mediated system, at low or physiological con-
centrations (Hoyumpa et al., 1975; Hoyumpa, 1982~.
Thiamin's absorption mechanism has only been studied
in laboratory animals and humans; however, the absorp-
tion mechanism in domestic animals is assumed to be
essentially the same.
The tissue distribution of thiamin appears to be fairly
uniform, with higher concentrations found in the liver
and kidney (Cohen et al., 1962; Hammarstrom et al.,
1966; Ensminger et al., 1983a). Nervous tissues gener
ally have low levels of thiamin. These tissues are able to
conserve or maintain their thiamin more rigorously than
other tissues, however (Robinson, 1966; Spector, 1982~.
In the human body, approximately 80 percent of the
thiamin present is stored as TPP,10 percent is stored as
the triphosphate form, and the remainder is stored as
the monophosphate form (Ensminger et al., 1983a). Thi-
amin is one of the most poorly stored of the vitamins.
Mammals can exhaust their body stores within 1 to 2
weeks (Ensminger et al., 1983b). The pig, however, is
an exception to this general rule. It can s' e large quan
tities of thiamin in skeletal muscles (Wilson et al., 1979~.
In mammals, excess thiamin is primarily eliminated by
way of the urine in unaltered form (Kraus and Mahan,
1979~. Nonetheless, a number of different metabolites
of thiamin have been noted in rat and human urine (Neal
and Pearson, 1964; Balaghi and Pearson, 1966;
Sauberlich, 1967; Ariaey-Nejad et al., 1968~.
HYPERVITAMINOSIS
The effects of excessive intakes of thiamin have been
studied only in laboratory animals, dogs, and rabbits
(Table 11~. Lethal doses (i.e., LD~oo levels) of thiamin by
intravenous injection are 80 mg/kg of BW in mice, 180
mg/kg of BW in rabbits, and 50 to 125 mg/kg of BW in
dogs (Haley and Flesher, 1946; Smith et al., 1947; Ha-
ley, 1948~. Molitor (1942) has reported that lethal doses
of thiamin in rats are 170 mg/kg of BW by intravenous
administration and 9.5 g/kg of BW by oral administra-
tion. Furthermore, the LD50 values of thiamin in rats are
500 mg/kg of BW by subcutaneous administration and 6
g/kg of BW by oral administration (Molitor, 1942~. The
studies of Molitor are reported only in a review and
consequently need to be confirmed. Nevertheless, it is
obvious that the lethal effects of the vitamin are only
produced at levels at least 1,000 times (by intravenous
administration) that of the dietary requirement. In these
studies, toxic levels of thiamin produced a wide variety
of pharmacological effects in the animals. It appears
that most of these toxic effects are produced only when
the vitamin is administered acutely (Unna, 1972; Ito-
kawa, 1978~. There is virtually no information available
to indicate any cumulative effects of thiamin adminis-
tered chronically at levels below those that are acutely
toxic.
In acute toxicity studies, excess thiamin appears to
block nerve transmission, producing curare-like signs
in the treated animal (Haley and Flesher, 1946; Smith et
al., 1947, 1948; Haley, 1948; Hayashi et al., 1965~.
These general signs include restlessness, epileptiform
convulsions, cyanosis, and labored respiration. Death
from thiamin toxicity results from respiratory paralysis,
usually accompanied by cardiac failure. In studies with
dogs, artificial respiration applied after intravenous in-
jection of a lethal dose of thiamin was partially effective
in overcoming thiamin toxicity (Smith et al., 1948~. The
mechanism whereby high levels of thiamin block nerve
transmission remains to be determined.
It should be noted that the majority of the studies
conducted on the acute toxicity of parenterally adminis-
tered thiamin have used the hydrochloride form of the
vitamin. Therefore, it is possible that the observed tox-
icity signs may involve an altered acid-base balance due
OCR for page 45
Thiamin 45
TABLE 11 Research Findings of High Levels of
Thiamin in Animals
. .
Species and Age or Amount
No. of Animal Weight (mg/kg of BW) Reference
Dogs 50
Dogs, 12 ~ 125
Mice, 150 22-42 g 80-92
Mice, 150 22-42 g 380-400
Rabbits, 5 3.2-4.7 kg 99-137
Rabbits, 5 1.5-1.9 kg 180-240
Smith et al., 1948
Smith et al., 1947
Haley, 1948
Haley, 1948
Haley, 1948
Haley and Flesher, 1946
NOTE: In all cases, the form was thiamin hydrochloride, the route
was intravenous, a single dose was administered, and there was 100
percent mortality.
to the administration of excess chloride. This possibility
requires further study.
The effect of varying levels of intake of thiamin on
tissue levels of the vitamin has been studied only in the
rat. In that species, thiamin concentrations in the brain,
heart, and liver increased with thiamin intakes of as
much as 1.5 to 2.0 mg/kg of BW/day, after which there
were no further increases (Gubler and Murdock, 1982~.
PRESUMED UPPER SAFE LEVELS
The maximum tolerable level of thiamin administered
by either oral or parenteral routes has yet to be deter-
mined in most domestic animal species. In dogs, 100 to
115,ug of thiamin/kg of BW/day (oral route, Noel et al.,
1977) and in sheep, 50 mg thiamin/head/day (intramus-
cular route, Yano and Kawashima, 1977) appeared safe.
In rats, oral intakes of 50 to 100 mg/kg of diet appeared
safe for periods up to 12 weeks Morrison and Sarett,
1959; Schumacher et al., 1965; Itokawa and Fujiwara,
1973~. Presently, it appears that for most species, di-
etary intakes of thiamin up to 1,000 times the require-
ment are apparently safe.
SUMMARY
1. There is little published information concerning
thiamin tolerances and toxicity in domestic animal spe-
cies.
2. Studies in laboratory animals, rabbits, and dogs
indicate that parenteral administration of thiamin hy-
drochloride may be the only route by which signs of
thiamin toxicity can be produced. In laboratory animals,
rabbits, and dogs, thiamin toxicity is characterized by a
depression of the respiratory center; however, the
mechanism of this effect is unknown.
3. Acutely toxic levels of thiamin for laboratory ani
mals given the vitamin parenterally range from approxi
mately 80 to 400 mg/kg of BW.
4. Dietary intakes of thiamin up to 1,000 times the
requirement level are apparently safe for most animal
species.
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OCR for page 46
46 Vitamin Tolerance of Animals
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Representative terms from entire chapter:
thiamin toxicity
