First draft prepared by
    Laboratory for Toxicology, National Institute of Public Health
    and Environmental Protection, Bilthoven, Netherlands

    Biological data
         Biochemical aspects
         Absorption, distribution, and excretion
         Endogenous synthesis of nitrate
    Toxicological studies
         Acute toxicity studies
         Short-term toxicity studies
         Long-term toxicity/carcinogenicity studies
         Reproductive toxicity studies
         Special studies on embryotoxicity/teratogenicity
         Special studies on genotoxicity/mutagenicity
         Special studies on the effects of nitrate on
           the thyroid
         Special studies on the effects of nitrate on gastric
         Special studies on the effects of nitrate on
         Observations in humans
              Relationship between nitrate and nitrite intake,
                   the subsequent endogenous formation of
                   N-nitroso compounds and possible risk of
                   (stomach) cancer in humans
              Relationship between nitrate intake and
                   genotoxic effects
              Relationship between nitrate intake and
                   teratogenic effects
              Relationship between nitrate intake and
                   thyroid effects


         Nitrate was considered at the sixth, eighth and seventeenth
    meetings of the Committee (Annex 1, references 6, 8, and 32). At the
    sixth meeting, an ADI of 0-5 mg/kg bw, expressed as sodium nitrate,
    was allocated. This ADI was based on a NOEL for sodium nitrate of
    500 mg/kg bw/day derived from a long-term toxicity study in rats and a
    short-term toxicity study in dogs together with a safety factor of
    100. Growth depression was observed at higher dose levels. The ADI of
    0-5 mg/kg bw was retained at the eighth and seventeenth meetings.

         Since the previous evaluation, new toxicological and
    epidemiological data have become available, which were reviewed at
    the present meeting. The Committee noted that nitrate  per se can
    generally be considered to be of relatively low toxicity. However, it
    was aware that nitrite is formed in the human body by reduction of
    nitrate and that N-nitroso compounds can also be formed from nitrite
    and N-nitrosatable compounds under certain conditions. Thus, the
    assessment of the health risk of nitrate to humans should encompass
    the toxicity of both nitrite and N-nitroso compounds, and the animal
    species used for safety evaluation should be closely related to humans
    with respect to the toxicokinetics of nitrate and the conversion of
    nitrate to nitrite. Furthermore, in the toxicological evaluation of
    nitrate, it should be considered in conjunction with nitrite and
    potential endogenously formed N-nitroso compounds.

         The following monograph summarizes relevant information from the
    previous monographs and the information that has become available
    since the previous evaluation.


    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion  Animals

         Uptake of nitrate from the upper respiratory tract occurred
    within 5 minutes after intratracheal administration in mice and
    rabbits (Parks  et al., 1981).

         After intravenous injections of 13N-labelled nitrate in mice
    and rabbits, an equilibrium with extracellular fluid was obtained
    within 5 minutes (Parks  et al., 1981).

         Intratracheal instillation of 13N-labelled nitrate in mice and
    rabbits gave very similar results (Parks  et al., 1981). After 20
    minutes, 16% of the radioactivity from intravenously injected 13NO3
    was found in the stomach and intestines of rats, 7% in the liver,
    kidney and bladder, and 70% in the eviscerated carcass (Witter
     et al., 1979b). Salivary glands were not examined.

         Ingested nitrate is rapidly absorbed from the rat upper small
    intestine with little if any absorption from the stomach and lower
    intestine (terminal ileum, caecum and proximal colon). About 50% of
    the radioactive label was detected in the eviscerated rat carcass
    within 1 h after oral gavage of 13NO3 (Witter  et al., 1979a,b;
    Balish  et al., 1981; Hartman, 1982; Fritsch  et al., 1979; Walker,
    in press).

         Nitrate from blood is selectively distributed to the salivary
    glands and actively secreted in saliva in humans and most laboratory
    animals, but not in rats (Fritsch  et al., 1985; Nighat  et al.,
    1981; Witter & Balish, 1979; Walker, in press). The transport of
    nitrate from blood to saliva is competitively mediated by active
    carriers that are shared by iodide and thiocyanate (NAS, 1981;
    Edwards  et al., 1954; Brown-Grant, 1961; Burgen & Emmelin, 1961).
    This active transport system is lacking in rats (Cohen & Myant, 1959;
    Mirvish 1983; Vitozzi, 1993; Walker, in press). However, the kinetics
    of nitrate secretion in rat saliva appear to have been less well
    studied than in humans, and even less is known concerning salivary
    secretion in mice. This poses difficulties in interpreting the
    significance for humans of toxicological studies conducted in these
    species (Walker, in press). In addition to the saliva, secretion of
    nitrate occurs at other sites in the GI tract leading to reduction by
    the gut flora. Thus in the rat, absorbed nitrate is secreted in
    gastric and intestinal secretions, including bile (Witter  et al.,
    1979a; Fritsch  et al., 1979; Walker, in press). Unlike humans, rats

    can actively secrete nitrate into the lower intestinal tract (Witter &
    Balisch, 1979; Walker, in press). Absorbed nitrate may re-enter the
    stomach and intestinal lumen directly via the bloodstream and via
    secretions. Secretion of nitrate into the stomach may be mediated by
    active carriers similar to those in the salivary glands (Edwards
     et al., 1954). Nitrate in the lower intestine of rats was shown to
    originate directly from the blood or intestinal secretions rather than
    from the passage of gastric contents or secretions of bile and
    pancreatic juice (Witter  et al., 1979a). However, rats may be
    exceptional in this respect as they are able to excrete iodide into
    the small intestine whereas this is unlikely to occur in other animal
    species (Brown-Grant, 1961; NAS, 1981). In the dog, in addition to
    strong salivary secretion, large quantities of nitrate were excreted
    in the bile following i.v. administration of nitrite, thus confirming
    this pathway of excretion as well as oxidation of nitrite  in vivo
    (Walker, in press).

         Nitrate levels were elevated in milk of lactating rats and cows
    given high nitrate doses (Ariga  et al., 1984; Nijhuis  et al.,
    1982). Nitrate is also frequently detected in normal cows' milk (NAS,
    1981). However, the nitrate concentration in milk did not exceed the
    plasma nitrate level in a beagle dog after intravenous nitrate
    injection indicating that unlike salivary secretion, nitrate transport
    in milk is not an active process (Green  et al., 1982).

         Nitrate excretion in urine generally reflects nitrate intake.
    However, various authors have reported that urinary nitrate excretion
    may exceed nitrate intake if the latter is low, as a consequence of
    endogenous nitrate formation (see Section 2.1.3).

         In conventional flora (CV) rats, approximately 55% of orally
    administered 15N-labelled nitrate was excreted unaltered in urine,
    and 11% was present as urinary ammonia and urea. Nitrate was not
    excreted in the faeces of CV or germ-free (GF) rats thus leaving 34%
    of the dose unaccounted for (Green  et al., 1981a,b; Schultz  et al.,

         In ferrets, urinary nitrate excretion amounted to 36% of an
    ingested dose. Other nitrogen compounds were not monitored (Dull &
    Hotchkiss, 1984).

         After absorption, nitrate rapidly equilibrates in body fluids
    (Ishiwata  et al., 1975a; Walker, in press). Low levels of nitrate are
    normally present in body fluids and tissues of laboratory animals
    (Witter & Balish, 1979; Fritsch  et al., 1985). Normal plasma nitrate
    levels in mongrel dogs were 6-10 mg/litre, equal to 0.1-0.15 mmol/litre
    (Fritsch  et al. (1985).

         Fritsch  et al. (1985) found that nitrate could be excreted in
    the saliva and bile of dogs in concentrations similar to plasma
    nitrate values.

         In cattle, nitrate was absorbed from the rumen. Peak blood
    nitrate levels occurred 4 h after intraruminal gavage. When the same
    amount of nitrate was fed in hay, absorption was slower due to
    the lower rate of uptake and nitrate levels in blood remained
    substantially lower. The extent of uptake did not change (Wright &
    Davison, 1964).

         The elimination of nitrate from plasma varied considerably
    between species. The elimination half-life of nitrate resulting from
    nitrite injection was 45 h in dogs and 4 h in sheep and ponies
    (Schneider & Yeary, 1975).  Humans

         Nitrate is primarily absorbed from the upper part of the human
    digestive tract (Bartholomew & Hill, 1984; Witter  et al., 1979a).
    Absorption is rapid: within 1-3 h after ingestion of nitrate in food
    or drink, peak levels of nitrate were observed in serum, saliva and
    urine by various investigators (Bartholomew & Hill, 1984; Ellen
     et al, 1982; Spiegelhalder  et al., 1976; Turek  et al., 1980;
    Fritsch & de Saint Blanquat, 1992).

         An average 25-fold increase in plasma nitrate was found 10
    minutes after ingestion of nitrate (470 mmol/kg bw). The concentration
    of nitrate rose to a peak level of 1.83 mmol/litre in 40 minutes, a
    value 49 times the pre-load level. Erythrocyte-nitrate followed a
    similar pattern, but remained at about 2/3 of the plasma values
    (Cortas & Wakid, 1991).

         Absorbed nitrate is rapidly distributed to the salivary glands
    and probably to other exocrine glands. After 1-3 h from ingestion, a
    peak value of nitrate was observed in saliva and sweat. The increase
    in the amount of nitrate secreted by the salivary glands was directly
    related to the amount of nitrate ingested, although there were
    marked inter-individual and diurnal variations (Walker, in press;
    Spiegelhalder  et al., 1976; Bartholomew & Hill, 1984; Stephany &
    Schuller, 1980; Tannenbaum  et al., 1976; Cortas & Wakid, 1991).
    On average, 25% of oral nitrate intake was secreted in the saliva
    (Stephany & Schuller, 1980; Walker, in press).

         The transport of nitrate to the salivary glands is probably
    mediated by active carriers. Edwards  et al. (1954) reported
    substrate inhibition of active iodide secretion in saliva by nitrate,
    and also by thiocyanate (SCN-) and perchlorate (C104-). Thus,
    SCN-, iodide and C104- would also be able to inhibit nitrate
    secretion in saliva. This may be of importance for smokers who have
    SCN- levels 3 to 4 times higher than non-smokers (Boyland & Walker,
    1974). Forman  et al. (1985) actually found lower nitrate levels in
    the saliva of smokers than of non-smokers.

         Salivary nitrate levels were found to be generally higher with
    increasing adult age (Forman  et al., 1985). However, salivary nitrate
    levels depend largely on nitrate intake. Salivary concentrations
    reported for adults ranged from less than 0.1 mmol/litre after low
    nitrate intake (Turek  et al., 1980), to over 40 mmol/litre after a
    high-nitrate dose (Ellen  et al., 1982). Average salivary nitrate
    level reported for a group of breast- and bottle-fed infants was
    0.5 mmol/litre (range 0.1-1.0 mmol/litre) (Turek  et al., 1980). In
    healthy volunteers administered 10 mg sodium nitrate, the cumulative
    salivary nitrate excretion, over 24 h expressed as percentage of the
    ingested dose, was 28% (Kortboyer  et al., in press).

         After i.v. administration of 13N-labelled nitrate in one
    volunteer, the label was rapidly distributed in the bloodstream
    throughout the body. The radioactivity accumulated almost linearly
    with time in a small region of the abdomen, which was probably due to
    the swallowing of salivary nitrate (Witter  et al., 1979a). In a
    study with healthy volunteers administered 10 mg sodium nitrate/kg bw,
    the plasma nitrate half-life was approximately 6.5 h and the volume of
    distribution was approximately 33 litres (Kortboyer  et al., in

         Nitrate may be present in human milk. Levels of up to 5 mg
    NO3-/kg milk were reported (Sukegawa & Matsumoto, 1975). However,
    nitrate levels in milk from lactating women after a normal evening
    meal did not exceed the corresponding elevated plasma nitrate levels
    (Green  et al., 1982).

         Single oral doses of 25-170 mg potassium nitrate gave an urinary
    nitrate excretion of 65-70% irrespective of the dose. Excretion was
    maximal 5 h after ingestion and returned to baseline levels within
    18 h. Reported urinary nitrate baseline levels in fasting subjects
    were 10-20 mg/litre (Bartholomew & Hill, 1984; Tannenbaum & Green,
    1981; Wagner  et al., 1983a).

         Small amounts of 15N-labelled ammonia and urea were found in
    the urine after ingestion of 15N-labelled nitrate (Wagner  et al.,

         Large single oral doses of ammonium nitrate (7-10.5 g) resulted
    in an average urinary nitrate excretion of 75% within 24 h, with small
    amounts of nitrite detected in only 26% of the samples. In this study,
    nitrate baseline levels in urine were higher (2.4-9.3 mmol/l, equal to
    149-577 mg/l), probably because the subjects were not submitted to
    dietary restrictions. The mean nitrate clearance after an oral dose of
    NaNO3 of 470 µmol/kg bw was 25.8 ml/minute corrected for a body area
    of 1.73 m2. The urinary nitrate/creatinine ratio increased 25 to 70
    times after dosing. These results indicated a predominantly tubular
    excretion of nitrate (Ellen  et al., 1982).

         Urinary nitrate excretion in infants was reported to be 80-100%
    of the average intake, but no specific data were given for exposure
    levels (Turek  et al., 1980).

         In another study with healthy infants, the urinary excretion of
    nitrate (316 mg, average 8.7 mg NO-3/day) was as high or higher
    than the average (low) intake of 2-7 mg of NO-3 plus NO-2 per
    day. It was concluded that excretion probably included endogenously
    synthesized nitrate (Hegesh & Shiloas, 1982).

         Low levels of nitrate and nitrite were detected in the faeces of
    humans on a 'Western diet' with unknown nitrate content (Saul  et al.,
    1981). Less than 0.1% 15N-labelled nitrate was found in the faeces
    of 12 volunteers ingesting 298 mg of 15N-labelled sodium nitrate.
    15N-labelled ammonia and urea were also detected in small quantities
    (Wagner  et al., 1983b).

         Incubation of nitrate with fresh human faeces under anaerobic
    conditions resulted in a rapid conversion of nitrate by the faecal
    microflora, suggesting that faecal excretion of nitrate may be higher
    than the amount detected (Archer  et al., 1981; Saul  et al., 1981).

    2.1.2  Biotransformation  Animals

         The most important metabolite of nitrate is nitrite. However,
    nitrite is converted rapidly and may not be readily detected.
    Therefore, methaemoglobin formation, which is caused by nitrite (see
    monograph on nitrite and section on methaemoglobin formation
    in this monograph), is often used as an indicator for nitrite
    formation although it may not be a very sensitive indicator (Ward
     et al., 1986). Nitrate is metabolized to nitrite and in addition it
    can (via nitrite) be broken down to hydroxylamine, ammonium and
    ultimately to urea (Mascher & Marth, 1993).

         Part of ingested nitrate in CV rats, but not in GF rats, was
    reported to be metabolized to NH4+ and urea (Green  et al.,
    1981a,b; Schultz  et al., 1985). Bacterial reduction is an important
    mechanism for nitrate conversion in mammals (Witter & Balish, 1979;
    Green  et al., 1981a; Schultz  et al., 1985). Nitrate reductase is
    present in many bacteria and other microorganisms normally present in
    the GI tract (WHO, 1985).

         Turek  et al. (1980) observed that nitrate reduction by faecal
    flora of pigs under anaerobic conditions was more rapid after a
    prolonged high-nitrate diet, suggesting the possibility of bacterial
    selection or induction. Wise  et al. (1982) observed a several-fold
    increase in nitrite production in the rat caecum when adding 5% pectin
    to the diet. According to the authors, this increase could not be
    attributed to overall differences in the diversity or number of
    microorganisms but was likely to be due to bacterial enzyme induction.

         Nitrate reductase activity has been demonstrated in various rat
    tissues (WHO, 1985; Ward  et al., 1986). In rats, 90% of total
    mammalian tissue nitrate reductase activity was present in the liver
    (Schultz  et al., 1985). The same authors calculated from the urinary
    nitrate excretion in CV and GF rats after intraperitoneal nitrate
    injection that approximately half of the metabolized nitrate in CV
    rats was metabolized by mammalian processes and the other half by
    enteric bacteria.

         In ferrets, 67% of a large single oral 15NO3- dose was
    metabolized (Dull & Hotchkiss, 1984). The ferret may be a more
    suitable experimental animal than the rat because its basal stomach
    acidity and gastric morphology are more similar to those of humans.

         Nitrate reduction in humans, and probably in most animal species,
    takes place for the largest part in the oral cavity (saliva). It may
    also occur throughout the GI tract; however, the conversion is
    pH-dependent and therefore does not occur in the stomach of most
    monogastric animals (Wright & Davison, 1964; Mirvish, 1975; Walker, in
    press). The rumen of ruminants and the enlarged caecum and colon of
    horses are especially suited for nitrate reduction due to the dense
    microbial population and the relatively high pH (Wright & Davison,
    1964; Sen  et al., 1969; Mirvisch  et al., 1975).

         In rabbits and ferrets, the average gastric pH is low and
    therefore considered to be similar to that of humans (Sen  et al.,
    1969; Dull & Hotchkiss, 1984); in cats, rats and dogs it is higher,
    2.9, 4-5 and 5.4-7.4, respectively (Sen  et al., 1969). In GF rats,
    the pH of various parts of the GI tract is significantly higher than
    in CV rats (Ward  et al., 1986).

         Salivary nitrate reduction is almost absent in rats (Witter
     et al., 1979a; Til, 1986; Vittozzi, 1992) which is probably due to
    the low salivary nitrate secretion in this species.

         Although nitrate reduction in the lower part of the gut is higher
    in the rat than in humans, the less efficient absorption of formed
    nitrite makes the rat (and probably the mouse) different with respect
    to the toxicokinetics of nitrate and thus less suitable as a model for
    nitrate toxicity in humans (Vittozzi, 1992; Speijers, in press). This
    conclusion is supported by comparing the NOAEL in rat studies and the
    reported (sub)acute toxic effect level in humans which is 10-60 times
    lower than the NOAEL in rats (Speijers, in press).  Humans

         Nitrate is converted to nitrite by microorganisms in the saliva.
    About 4-7% of ingested nitrate was detected as nitrite in the saliva
    (Eisenbrand  et al., 1980; Spiegelhalder  et al., 1976; Stephany &
    Schuller, 1980; Speijers  et al., 1987; Brüning-Fann & Kaneene,
    1993). Kortboyer  et al. (in press) found in human volunteers
    administered 10 mg sodium nitrate/kg bw (twice the ADI) that 8% of the
    ingested nitrate was converted to nitrite. The reduction of nitrate in
    the saliva accounts for 70-80% of the nitrite exposure (Bos  et al.,
    1985). The ratio of nitrite/nitrate in the saliva 1-2 h after intake
    of various nitrate doses was remarkably constant within one individual
    but differed greatly between individuals (from 0.06 to 3.6)
    (Bartholomew & Hill, 1984; Ellen  et al., 1982). The major site for
    this reduction appears to be at the base of the tongue where a stable,
    nitrate-reducing microflora is established (Walker, in press).

         The concentration of salivary nitrite was directly related to
    orally ingested nitrate (Stephany & Schuller, 1978; Spiegelhalder
     et al., 1976; Harada  et al., 1975; Ishiwata  et al., 1975a,b,c).
    However, Tannenbaum  et al. (1976) suggested that the reduction
    process may become saturated at high nitrate intakes. Oral reduction
    of nitrate is the most important source of nitrite for humans and most
    species (except the rat and probably the mouse) which possess an
    active salivary secretory mechanism of nitrate (Stephany & Schuller,
    1980; Walker, in press).

         Factors that may influence the oral microbial flora are, for
    example, nutritional status, infection, environmental temperature and
    age. A sudden drop of temperature resulted in a dramatic fall of
    salivary nitrite levels, but this may have been caused by increased
    salivary flow as well as reduced microbial activity (Eisenbrand
     et al., 1980). Salivary nitrite levels were generally higher in
    older age groups, although considerable variation between individuals
    was noted (Eisenbrand  et al., 1980; Forman  et al., 1985).

         A low pH (1-2) in the fasting stomach is considered normal for
    adults, and under these conditions bacterial nitrate reduction does
    not take place because of poor bacterial growth. High gastric pH
    values and sometimes correspondingly high nitrite levels were observed

    in achlorhydric man, stomach cancer and gastric ulcer patients, in
    patients with atrophic gastritis and patients treated with cimetidine
    and antacids (Correa  et al., 1975; Ruddell  et al., 1976; Schlag
     et al., 1982; Bartsch  et al., 1984; Sen  et al., 1969; Mirvish,
    1975; Wright & Davison, 1964; Walker, in press). In human volunteers
    administered omeprazole (pH elevating drug) followed by 10 mg
    sodium nitrate/kg bw, the gastric pH was increased and the nitrite
    concentration in gastric juice was approximately 6 times higher
    (Kortboyer  et al., in press). Studies on ileostomy patients given
    a conventional or high nitrate/nitrite meal indicated that the type
    of foodstuff ingested can significantly alter levels of nitrite
    and nitrate in the distal ileum and is a factor in determining
    nitrite/nitrate input into the proximal colon (Radcliffe  et al.,

         Infants younger than 3 months are highly susceptible to gastric
    bacterial nitrate reduction because they have very little production
    of gastric acid (Ellen & Schuller, 1983; Kross  et al., 1992).
    Gastrointestinal infections, which frequently occur in infants may
    produce an additional increase in the reduction of nitrate to nitrite.

         Contrary to the usual assumption that the normal gastric pH is
    low, a high proportion of normal healthy adults (30-40%) were found to
    have a fasting gastric pH >5 which was relatively stable over a
    prolonged period with correspondingly high bacterial activity and high
    nitrite levels (Ruddell  et al., 1976; Müller  et al., 1984). In one
    third of 15 healthy volunteers, major variations of the fasting
    gastric pH occurred occasionally, with corresponding changes in the
    bacteriological parameters (Müller  et al., 1984).

         Schultz  et al. (1985) developed a model for the fate of nitrate
    in humans based on various human data tested in rats. The model
    suggested that the bacteria of the large intestine were responsible
    for about half of the extrarenal removal of nitrate from the body.
    Ascorbic acid did not affect nitrate plasma levels nor the amount of
    nitrate excreted in urine, faeces or saliva, indicating that ascorbic
    acid does not interfere with nitrate metabolism (Wagner  et al.,

         The half-life of nitrate in the body after ingestion was
    approximately 5 h (Wagner  et al., 1983b). Nitrite was not detected
    in any of the body fluids studied except saliva where it appeared to
    increase as nitrate levels decreased (Cortas & Wakid, 1991).

         The  in vivo conversion of nitrate to nitrite is complex and the
    quantitative aspects are difficult to clarify because of nitrate and
    nitrite endogenous synthesis, and the oxidation to nitrate of other
    nitrogen-containing compounds (e.g., ammonia, hydroxylamine). In
    addition, once nitrite is formed, it has a short biological half-life,

    being rapidly oxidized to nitrate in the blood. Nitrate undergoes
    active secretion in humans not only in the salivary duct cells but
    also in the gastric pariental cells and, in passive equilibration with
    other intestinal secretions, occurs at a number of other sites leading
    to enterosystemic cycling of nitrate and nitrite. Because of this
    complex biotransformation, the literature on nitrate provides only
    qualitative or at best semi-quantitative information on nitrate
    reduction, nitrite formation, and circulating methaemoglobin
    levels which represent a dynamic equilibrium between oxidation of
    oxyhaemoglobin by nitrite and reduction by methaemoglobin reductase.
    Moreover, there are marked interspecies variations in the activity of
    this enzyme in the erythrocytes (Walker, in press).

     Methaemoglobin formation

         As described above, nitrate is reduced to nitrite, which in
    turn causes the oxidation of oxyhaemoglobin to methaemoglobin.
    Methaemoglobin formation by nitrite is discussed in the monograph on
    nitrite. A few studies dealing with nitrate intake and MetHb formation
    are discussed here.

         Normal MetHb levels in human blood range from 1%-3%. Reduced
    oxygen transport was noted clinically when MetHb concentrations
    reached 10% or more (Canada, 1992; Speijers, in press). The
    relationship between blood nitrate and MetHb formation is not linear
    at lower nitrate concentrations. A minimum amount of nitrite must
    enter the bloodstream before a measurable increase in MetHb
    concentration can be detected (Kross  et al., 1992). Infants younger
    than 3 months are particularly susceptible to nitrate poisoning
    because fetal Hb is more readily oxidized to MetHb and as mentioned
    before, under certain conditions the reduction of nitrate to nitrite
    can be high. Pregnant women, persons with genetically controlled
    deficiencies of the enzymes glucose-6-phosphate dehydrogenase or MetHb
    reductase and probably the elderly are also more vulnerable to the
    toxic effects of nitrate and nitrite (Corre & Breimer, 1979; Canada,
    1992; Speijers, in press). Nitrates in water supplies at concentrations
    above 45 mg/l as NO3- have led to numerous cases of infant
    methaemoglobinaemia, particularly in infants up to 6 months of age
    (Van Went & Speijers, 1989), although the role of microbial infections
    may also be important (ECETOC, 1988; Van Went & Speijers, 1988;
    Gangolli  et al., 1994).

    2.1.3  Endogenous synthesis of nitrate  Animals

         When nitrate intake is low, urinary nitrate excretion usually
    exceeds the intake. This was demonstrated to be the case in CV and GF
    rats suggesting that nitrate was synthesized in the animals.
    Furthermore, the high excretion in GF as well as in CV rats showed
    that bacterial activity was not obligatory for this synthesis (Green
     et al., 1981a).

         The inhalation of nitrogen oxides from air could account for, at
    most, 1% of the excess excreted nitrate (Green  et al., 1981a).

         Proof of nitrate biosynthesis was supplied by Dull & Hotchkiss
    (1984) for ferrets and by Saul & Archer (1984), Wagner  et al.
    (1983a) and Wishnok  et al. (in press) for rats. Ingestion of
    15N-labelled ammonium salts was invariably followed by the urinary
    excretion of small amounts of 15N-labelled nitrate. It was proposed
    that ammonia is at first oxidized to hydroxylamine, catalyzed by the
    generation of free radicals, which is then further oxidized to yield
    nitrate (Wagner  et al., 1983a). This hypothesis was confirmed by the
    experimental  in vivo synthesis of nitrate from hydroxylamine and the
    enhanced synthesis of nitrate from ammonia by rats treated with an
    endotoxin-inducing free radical formation (Saul & Archer, 1984; Wagner
     et al., 1983a).

         Urinary nitrate excretion increased 9 times after intraperitoneal
    injection of  E. coli lipopolysaccharides (Wagner  et al., 1983a).
    Stuehr & Marletta (1985) found that infection with  Mycobacterium
     bovis could increase the urinary nitrate excretion of mice from
    3.6 to 164 mg/kg bw. Both studies indicated that endogenous nitrate
    synthesis may increase considerably under inflammatory conditions.  Humans

         Various authors reported an excess urinary nitrate excretion
    (0.3-1.9 mmol/day) at low nitrate intake (<0.25 mmol/day) in humans
    (Bartholomew & Hill, 1984; Green  et al., 1981b; Lee  et al., 1986;
    Tannenbaum & Green, 1981; Wagner  et al., 1983b; Gangolli  et al.,
    1994; Wishnok  et al., in press). When large amounts of 15N-labelled
    nitrate were ingested (up to 3.5 mmol), urinary excretion of unlabelled
    nitrate was still considerable (0.7-1.3 mmol/day) (Green  et al.,

         Ellen & Schuller (1983) calculated that up to 20% of this excess
    excretion could have originated from the inhalation of NO2- and
    NO3- from indoor and outdoor air and cigarette smoke. The
    remaining excess urinary nitrate, up to 1 mmol/day, most probably
    originates from endogenous synthesis.  In vivo nitrate synthesis from

    ammonia and hydroxylamine was confirmed in rats and ferrets (see
    section Although bacterial activity is not obligatory for
    this synthesis in animals it may enhance nitrate biosynthesis and the
    occurrence of GI infections may thus be important. Considerably
    increased urinary nitrate excretion was found in infants with acute
    diarrhoea (from 8.7 to 39 mg NO3- per 24 h), at low intake of
    NO3- and NO2- of 2-7 mg/day (Hegesh & Shiloah, 1982).

         A major pathway for endogenous nitrate production is the
    conversion of arginine by macrophages to nitric oxide and citrulline,
    followed by oxidation of the nitric oxide to N2O3 and the reaction
    of N2O3 with water to yield nitrite. Nitrite is rapidly oxidized
    to nitrate through reaction with haemoglobin. In addition to
    macrophages, many cell types can form nitric oxide, generally from
    arginine. The question of whether the arginine-nitrate pathway can be
    associated with increased cancer risk via exposure to endogenously
    formed N-nitroso compounds remains open. Nitric oxide is mutagenic
    toward bacteria and human cells in culture, it causes DNA strand
    breaks, deamination (probably via N2O3), oxidative damage, and can
    activate cellular defense mechanisms. In virtually all cases, the
    biological response is paralleled by the final nitrate levels. Thus,
    while endogenously-formed nitrate itself may be of relatively minor
    toxicological significance, the levels of this substance may
    potentially serve as integrators for these potentially important
    nitric oxide-related processes (Wishnok  et al., in press; Gangolli
     et al., 1994).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         Oral LD50 values were 2480-6250 mg sodium nitrate/kg bw in
    mice, 4860-9000 mg/kg bw in rats and 1600 mg/kg bw in rabbits. Female
    rats seemed to be more sensitive than males (Mammalian Toxicity Array,
    1982; Corré & Breimer, 1979).

         A lethal dose of 300 mg sodium nitrate/kg bw has been reported in
    pigs. The LD50 in cows following a single oral administration was
    estimated to be 450 mg sodium nitrate/kg bw (Bradley  et al., 1942),
    whereas the LD50 was 970-1360 mg/kg bw when the total dose was
    administered over a 24 h period (Crawford, 1960). The lethal dose in
    cows appeared to be ten times lower than in non-ruminants (Gwatkin &
    Plummer, 1946; Emerick, 1974). Acute intoxication occurred in cattle
    when rations with 6% or more nitrate in dry matter were fed. Fatal
    intoxications in cattle were also reported at dose levels of 1.5% in
    feed (Bradley  et al., 1942), whereas hay with 0.75% nitrate as dry
    matter revealed no adverse effects (Geurink & Kemp, 1983).

         Signs of acute nitrate intoxication varied with animal species.
    Generally ruminants display methaemoglobinaemia, while monogastric
    species develop severe gastritis (Brüning-Fann & Kaneene, 1993).

    2.2.2  Short-term toxicity studies  Mice

         In a 15-day study, male C57B1 mice received i.p. injections
    of 0, 50 or 100 mg sodium nitrate/kg bw/day. Cytogenetic and
    pathohistological changes of the spleen, liver and kidneys were
    examined. A moderate increase in the number of macrophages was
    observed in the spleen after nitrate treatment. The kidneys showed
    alterations such as damaged small canals in the cortical part
    reflected by dystrophic cells, cytoplasm filled with small grains and
    missing or limited nuclei. In the liver, cell effects analogous to the
    ones in the kidney were observed. These slight histopathoiogical
    effects were reversible (Rasheva  et al., 1990).  Rats

         In a 4-week study, rats (10/sex/group) were fed diets containing
    0, 1, 2, 3, 4 or 6% potassium nitrate or 5% sodium nitrate, equivalent
    to 0, 500, 1000, 1500, 2000 or 3000 mg potassium nitrate/kg bw/day,
    and 2500 mg sodium nitrate/kg bw/day. Two types of diet were used: a
    cereal basal and a semi-purified diet. At 3% potassium nitrate, the
    female rats had slightly elevated methaemoglobin levels and the male
    rats showed increased relative kidney weights. No effects were
    observed at 1% and no important differences were found between the two
    types of diets (Til  et al., 1985a,b).

         F344 rats (10/sex/group) were fed diets containing 0, 1.25, 2.5,
    5, 10 or 20% sodium nitrate, equivalent to 0, 625, 1250, 2500, 5000 or
    10 000 mg/kg bw/day for 6 weeks. There was a slight or moderate
    reduced weight gain in rats of the two highest dose groups. At autopsy
    the abnormal colour of the blood and spleen due to methaemoglobin was
    marked in rats of the two highest dose groups. From these results it
    was determined that the maximum tolerated dose was 5% in the diet
    (Maekawa  et al., 1982).

         In a 12-week study, rats were administered by gastric intubation
    0 or 1/20 of the LD50 of sodium or calcium nitrate. The energy
    conversion processes, such as the glycolysis and the pentose phosphate
    cycle, were reported to be altered after nitrate treatment. Changes in
    the glutathione-ascorbinate system of the liver and brain tissues were
    also reported (Diskalenko  et al., 1972a,b; cited in WHO, 1978).

         In a 14-month study, rats (10/sex/group) received drinking-water
    containing 0 or 4000 mg sodium nitrate/litre, equivalent to 0 or
    400 mg/kg bw/day. The methaemoglobin levels in the nitrate group were
    the same as in the control animals. Nitrate had a moderate effect on
    plasma vitamin E level and on the incidence of chronic pneumonitis
    (Chow  et al., 1980).  Rabbits

         In a 4-week study, rabbits (6 males/group) received 0, 200, 400
    or 600 mg potassium nitrate/kg bw/day in a pulse dose via gelatin
    capsules. The rabbits of all nitrate-treated groups showed
    intoxication symptoms within 2 weeks, including significant weight
    reduction, tachycardia, polyuria and weakness (Nighat  et al., 1981).  Dogs

         Three dogs (2 females, 1 male) were fed a diet containing 2%
    sodium nitrate, equivalent to 500 mg/kg bw/day for 105-125 days. No
    adverse effects were observed (Lehman, 1958).  Cattle

         In an 8-week study, calves (12 males/group) received artificial
    milk containing 18 (control group), 400, 2000, 5000 or 10 000 mg
    NO3-/kg of milk. No adverse effects were observed on growth
    pattern, weight gain, food conversion, biochemical blood parameters,
    or morphology of the liver and kidneys (Berende  et al., 1977).

    2.2.3  Long-term toxicity/carcinogenicity studies  Mice

         Mice (10/sex/group) received for more than 1 year diets
    containing 0, 25 000 or 50 000 mg sodium nitrate/kg of feed. No
    difference in tumour incidences were observed in the animals
    (Greenblatt & Mirvish, 1973; Sugiyama  et al., 1979, abstract only).

         In an 18-month study, mice (100/group) received 0, 100 or 1000 mg
    nitrate/litre of drinking-water. The concentration of urea increased
    with time and nitrate dose. The mice at the high-dose group lost
    weight and died prematurely. At 100 mg nitrate/l, no changes were seen
    in biochemical parameters, including liver and kidney function, total
    iron, ammonium, total protein and electrophoresis of the various serum
    proteins and N-glycolneuraminic acid as a tumour marker (Mascher &
    Marth, 1993).  Rats

         In a 2-year study, rats (20/sex/group) were fed a diet containing
    0, 0.1, 1, 5 or 10% sodium nitrate. At the 5% dose level a slight
    growth inhibition was observed, whereas inanition was noticed at the
    10% dose level. Complete histopathological examination, including
    tumour incidences, was performed. No abnormalities or increased tumour
    incidence were found. The NOEL in this study was 1%, equivalent to
    500 mg sodium nitrate/kg bw/day, or 370 mg/kg bw/day expressed as
    nitrate ion (Lehman, 1958; Annex 1, references 6 & 33).

         In a carcinogenicity study, rats (15/sex/group) received 0 or 5%
    sodium nitrate/l of drinking-water for 84 weeks and were killed 20
    weeks later. Histopathological examination did not reveal any increase
    in tumour incidence. (Lijinsky  et al., 1973).

         In a 2-year carcinogenicity study, F344 rats (50/sex/group)
    received diets containing 0, 2.5 or 5.0% sodium nitrate, equivalent to
    0, 1250 or 2500 mg sodium nitrate/kg bw/day, or 0, 910, or 1820 mg/kg
    bw/day expressed as nitrate ion. No carcinogenic effects were detected.
    This strain of rats is known to have a high incidence of mononuclear
    leukemia which was higher in controls than in the experimental
    groups (Maekawa  et al., 1982).

    2.2.4  Reproductive toxicity studies  Guinea-pigs

         Groups of female guinea-pigs received during 143-204 days 0
    (4 animals), 300 (6), 2500 (3), 10 000 (3) or 30 000 (3) mg potassium
    nitrate/l in drinking-water, equal to 0, 12, 102, 507 or 1130 mg
    potassium nitrate/kg bw/day. The mating behaviour was highly impaired
    at 30 000 mg/l and the number of pregnant animals was seriously
    reduced. The fertility of the animals of other nitrate groups was not
    reduced since pregnancy occurred in all groups. Weight gain and food
    and water intake were normal at all concentrations. No macroscopic or
    microscopic alterations were observed in the reproductive organs
    (Sleight & Atallah, 1968).  Rabbits

         Rabbits were given 0, 250 or 500 mg nitrate/l during 22 weeks. No
    detrimental effects on reproductive performances were found after
    successive gestations. Measures of reproductive performance included
    fertility, litter size or weight at birth and at weaning, plasma
    retinol and progesterone concentration and Hb level. However, a
    decrease in retinol concentration in the liver of progeny of exposed
    rabbits (themselves exposed for 5 weeks to nitrate in drinking-water)
    was observed. Hb level was slightly decreased in dams given 500 mg/l
    (Kammerer, 1993; Kammerer & Siliart, 1993).  Sheep

         Sheep (5/group) were fed a diet containing 0.3, 0.6 or 1.2%
    NO3- in drinking-water from day 21-49 of pregnancy till parturition
    (for a total of 41-74 days). These doses were high enough to induce
    severe methaemoglobinaemia, however, no changes in abortion rates were
    observed (Davison  et al., 1965).  Cattle

         In a 7-month study, 15 heifers were fed a diet containing 445 or
    665 mg NO3-/kg of feed from 2 months of pregnancy until birth. No
    treatment-related changes in pregnancy were observed, although the
    dose levels selected led to 20-50% methaemoglobinaemia. Macroscopical
    examinations revealed no abnormalities in the newborn animals (Winter
    & Hokanson, 1964).

         The effect of high-nitrate oat hay on late-gestating (46 days
    prior to parturition) crossbred beef cows (8 cows/group) and their
    subsequent calves was studied over a 92-day period. The results of the
    study suggested that up to 1.4% KNO3 in the diet may not cause
    abortions in cows during late gestation when fed under controlled
    conditions. However, this level of nitrate appeared to cause loss of
    cow body weight (Hixon  et al., 1992).

    2.2.5  Special studies on embryotoxicity/teratogenicity

         No data available

    2.2.6  Special studies on genotoxicity/mutagenicity

         Nitrate did not induce mutagenic effects in bacterial tests with
     Salmonella typhimurium. When tested under aerobic and anerobic
    conditions in  Escherichia coli, mutagenicity was only found under
    anaerobic conditions. The mutations, however, were probably due to the
    reduction of nitrate to nitrite under the test conditions (Konetzka,

         In an  in vitro chromosome aberration test with hamster cells,
    sodium nitrate revealed mutagenic effects, whereas with potassium
    nitrate negative results were obtained. Sodium chloride - in contrast
    to potassium chloride - was also positive at high concentrations in
    the same test system (Ishidate  et al., 1984). It is likely that
    interactions may have taken place between the chromosomes and elevated
    concentrations of the sodium ions which subsequently led to chromosome
    aberrations (Ashby, 1981).

         In acute experiments, mice were treated intragastrically with
    doses of 79, 236, 707 or 2120 mg sodium nitrate/kg bw. An increase in
    chromosome aberrations was found at only one dose (707 mg/kg bw) and
    the number of micronuclei was enhanced at 79 and 236 mg/kg bw. At
    doses of 707 mg/kg bw and higher, cytotoxicity occurred in the bone
    marrow as shown by a concomitant depression of the bone marrow. In
    contrast, acute treatment of rats with doses up to 2120 mg/kg bw did

    not show chromosome abnormalities in the bone marrow. However, rats
    subacutely treated with the same doses of sodium nitrate, showed a
    significantly enhanced number of chromosome aberrations in bone
    marrow. According to the authors, it cannot be excluded that formation
    of N-nitroso compounds was responsible for the bone marrow damage
    (Luca  et al., 1985).

         Oral administration of 500 mg sodium nitrate/kg bw to pregnant
    Syrian hamsters on days 11 or 12 of gestation did not lead to an
    increase in gene mutations, chromosome abnormalities, micronuclei or
    morphological transformation in cells cultured from the hamster
    embryos (Inui  et al., 1979). However, Rasheva  et al. (1990) found
    induction of chromosome aberrations in male C57B1 mice after 5 and 15
    day treatment with 50 or 100 mg sodium nitrate/kg bw.

         UDS was determined in leucocytes of 10 human subjects after the
    consumption of meals containing varying amounts of nitrate, nitrite or
    nitrosamines. In 6/10 subjects, UDS was significantly increased but no
    correlation was found with dietary nitrate, nitrite and nitrosamine
    levels or with blood nitrosamine levels (Kowalski  et al., 1980). In
    addition, Miller (1984) did not observe any effect of ingested
    nitrate/nitrite (from lettuce) on UDS in leucocytes of human subjects
    after consumption of an amine-containing meal (fish).

    2.2.7  Special studies on the effects of nitrate on the thyroid

         In rats, doses of 40-4000 mg NO3-/l in drinking-water for 100
    days had no effect on the serum iodine level or protein-bound iodine.
    Minor changes were reported in 131I uptake by the thyroid, thyroid
    weight and the histology of the thyroid. These effects were seen at all
    dose levels, but there was no dose-response relation (Höring, 1985;
    Höring  et al., 1988; Seffner, 1985).

         Potassium nitrate was administered to 56-day old pigs at a
    dietary concentration of 3% for 2 days or 6 weeks (equivalent to
    730 mg/kg bw/day expressed as nitrate ion). Levels of MetHb, serum
    T4 ,T3, nitrate and somatomedin were determined. Sufficient iodine
    uptake by mothers prevented a decrease in T4 levels after
    administration of KNO3 for 2 days. After 6 weeks of treatment,
    however, the decrease in T4 level could not be prevented by
    supplementing the diet with 0.5 mg iodine/kg bw. A decrease in serum
    somatomedin activity due to nitrate administration was also observed
    which correlated with a decreased body-weight gain in pigs (Jahreis
     et al., 1987).

    2.2.8  Special studies on the effects of nitrate on gastric epithelium

         In a 19-month study, Wistar rats were fed twice a week a dose of
    0.1 of the LD50 of nitrate. Ultrastructural examination showed that
    sodium nitrate alone or in combination with saphrol caused atypical
    changes in the gastric epithelium (Ptashekas, 1990).

    2.2.9  Special studies on the effects of nitrate on behaviour

         The development of sensoro-motor functions and adult learning
    behaviour was studied in rats exposed to nitrate. Pregnant and
    lactating dams (50/group) and their offspring were supplied with
    drinking-water containing 0, 1.12 or 2.24 mmol KNO3/litre (equal to
    0, 113 or 226 mg/l). Postnatal maturation of reflexes, that of sensory
    and somatic parameters and motor activity, the acquisition of one-way
    avoidance and rewarded discriminative learning behaviour in adulthood
    were examined. Reflexes (righting, cliff avoidance) and hearing
    startle reaction maturated earlier in the nitrate treated groups. Open
    field motor activity was higher at days 5, 7, and 10 after birth, but
    hypoactivity ensued after day 20. A marked learning deficit was
    observed both in punished and in rewarded learning tests. The results
    indicated a nitrate-induced deviation in behavioural development, and
    an impairment in learning behaviour, particularly of the discriminative
    type (Markel  et al., 1989).

    2.3  Observations in humans

         The toxicity of nitrate in humans, as well as in animals, depends
    on the conversion of nitrate to nitrite. For this reason infants and
    patients with hypo- or achlorhydria and/or stomach lesions are to be
    considered as special risk groups. These patients might also be more
    susceptible to the toxicity of nitrate (Speijers  et al., 1987;
    Brüning-Fann & Kaneene, 1993; Speijers, in press).

         Human lethal doses of 4-50 g NO3- (equivalent to 67-833 mg
    NO3-/kg bw) have been reported. Toxic doses - with methaemoglobin
    formation as a criterion for toxicity - ranged from 2 to 5 g (Corré &
    Breimer, 1979) and 6 to 9 g of NO3- (Fassett, 1973). These values
    are equivalent to 33-83 and 100-150 mg NO3-/kg bw, respectively.
    Fassett (1973) reported a rapidly occurring severe gastroenteritis
    with abdominal pain, blood in the urine and faeces as symptoms of
    acute nitrate intoxication. Repeated doses gave rise to dyspepsia,
    mental depression, headache and weakness. Farre  et al. (1982)
    reported on nine cases of mild methaemoglobinaemia which appeared as
    an outbreak in a group of 50 infants. The cause of intoxication was an
    excessive concentration of nitrate (76 mg/l) in well water.

         Eighty cases of acute nitrate poisoning were reported from 1973
    to 1989 by Gao & Guo (1991). The patients came to the emergency
    department of the hospital. Most patients were in shock with moderate
    respiratory distress, pallor or cyanosis in the mouth and extremities
    and abnormalities in mental status. RBC was normal lot all patients.
    WBC was temporarily higher in 16 cases. In 2 cases, ASAT and BUN
    levels were elevated. It was assumed that each patient ingested more
    than 2 g nitrate.

         The data on nitrate toxicity in humans originate partly from
    relatively old publications, some of which do not provide details on
    age or gastric conditions. The low values of these lethal and toxic
    doses are difficult to interpret. Contradicting these values are
    reports of absence of toxic symptoms in 12 volunteers receiving
    intravenously 9.5 g of sodium nitrate in 1 h, while in 2 of 12 other
    persons administered 7-10.5 g of ammonium nitrate orally in one dose,
    vomiting and diarrhoea occurred (Ellen  et al., 1982). The lethal
    dose of nitrate in adults is probably around 20 g NO3-, equivalent
    to 330 mg NO3-/kg bw (Leu  et al., 1986; Ellen, 1986). In infants
    under the age of 3 months the conversion of nitrate to nitrite and
    methaemoglobin formation is high as discussed previously in section and in the monograph on nitrite. Gastrointestinal disturbances
    play a crucial role, the reduction of nitrate to nitrite in the
    stomach being enhanced by bacterial growth at the high pH in the
    stomach of these infants. Toxic effects are therefore induced at a
    much lower dose of nitrate than in adults. According to Corré &
    Breimer (1979) assuming an 80% reduction of nitrate to nitrite in
    these young infants, the toxic dose was calculated to vary from
    1.5-2.7 mg NO3-/kg bw, using 10% formation of methaemoglobin as
    toxicity criterion (Winton  et al., 1971). In the same report a
    lethal dose for infants of 43.2 mg NO3-/kg bw was calculated based
    on haemoglobin/methaemoglobin transfer stoichiometry (WHO, 1985).
    However, in reported cases of infant methaemoglobinaemia, the amounts
    of nitrate ingested were higher: 37.1-108.6 mg/kg bw, with an average
    of 56.7 mg/kg bw.

         Acute intoxications have been reported due to drinking of well
    water containing high nitrate levels (WHO, 1978; NAS, 1981). Of all
    reported cases of infantile methaemoglobinaemia, 97.7% occurred in
    areas with a nitrate content in drinking-water of more than
    44.3-88.6 mg NO3-/1 (WHO, 1985). In the Netherlands, these
    intoxications have occurred sporadically in the last two decades.
    However, the evaluation of cases of infantile methaemoglobinaemia in
    relation to nitrate intake is difficult because of the frequent
    occurrence of simultaneous bacterial contamination of drinking-water
    and of bacterial infections in infants which may influence the
    reduction of nitrate to nitrite as well as the endogenous synthesis of
    nitrate. Hegesh & Shiloah (1982), for example, found a significantly
    increased nitrate blood content, paralleling an increased
    methaemoglobin content, in infants with acute diarrhoea, whereas the
    intake of nitrate and nitrite by these infants was low (2-7 mg/day)
    (See also section 2.1.3).

         In healthy infants 11 days to 11 months of age, oral treatment
    for several days with 50 or 100 mg NO3-/kg bw increased
    methaemoglobin levels (5.3-7.5%) but no cyanosis was seen. In 6-7 week
    old infants just recovering from previous methaemoglobinaemia after
    administration of 100 mg NO3-/kg bw, cyanosis and increased
    methaemoglobin concentrations (up to 11%) were found. Details of
    individual infants age and days of treatment were not given (Cornblath
    & Hartmann, 1948).

    2.3.1  Relationship between nitrate intake, the subsequent endogenous
           formation of N-nitroso-compounds and possible risk of (stomach)
           cancer in humans

         Several authors have suggested that the risk for the development
    of stomach cancer is positively correlated with three factors: 1) the
    nitrate level of the drinking-water, 2) the urinary excretion of
    nitrate and 3) the occurrence of atrophic gastritis.

         During the last three decades the incidence of stomach cancer has
    been decreasing. It has been suggested that this was caused by factors
    such as the significant reduction of nitrate and nitrite concentrations
    in cured meat, and the increasing use of refrigerators and freezers
    (Hartman, 1983).

         The incidence of gastric cancer is still high in countries with
    frequent consumption of salted fish (Japan, Iceland, Chile), and in
    countries with long winters and consequently prolonged food
    preservation (Eastern Europe, Russian Federation, China).

         Siddiqi  et al. (1992) presented analytical data on aliphatic
    amines and nitrate from the most commonly used fresh and sun-dried
    vegetables, red chillies and salted tea from a high risk area for
    oesophagal and gastric cancer in Kashmir. Exposure estimates for the
    adult population showed high nitrate intake (237 mg/day) and
    exceptionally high exposure to N-nitrosatable compounds such as
    methylamine (1200 µ/day), ethylamine (14 320 µg/day), diethylamine
    (400 µg/day), dimethylamine (150-280 µg/day), pyrrolidine (517 µg/day)
    and methylbenzylamine (40 µg/day).

         The daily nitrate intake seemed to be associated with the
    development of gastric cancer in a number of epidemiological and
    related studies (Weisburger & Raineri, 1975; Fraser  et al., 1980;
    NAS, 1981; Dutt  et al., 1987). Fine  et al. (1982) suggested an
    association between nitrate intake and gastric cancer mortality by
    combining previously published data on daily nitrate intake in
    different countries with gastric cancer mortality rates (r = 0.88).

         Based on the available results of epidemiological and related
    research concerning the association between food components and the
    development of stomach cancer two hypotheses have been proposed
    (Joossens & Geboers, 1981; Food Council, 1986): (i) The salt
    hypothesis, in which a large intake of salt is considered to be an
    important factor and (ii) the nitrate/nitrite hypothesis as discussed
    in this section. Since nitrate and other salts are present in the
    diet, a combination of both hypotheses is likely (Correa  et al.,
    1975; Weisburger  et al., 1981).

         Several factors or conditions can influence the formation of
    gastric tumours (Speijers  et al., 1987; Moller, in press). The
    correlation between nitrate intake and tumour incidence involves
    several factors which influence the reduction of nitrate to nitrite.
    These factors, discussed in detail in section 2.1.2, involve the
    biotransformation of nitrate, the presence of thiocyanate (smokers
    versus non-smokers), iodide, age (increasing salivary nitrate and
    nitrite levels with increasing age), conditions for bacterial growth
    in the GI tract (pH of the stomach or type of indigestible material in
    the diet), and antacid medication (Armijo  et al., 1981a,b; Boyland &
    Walker, 1974; Eisenbrand  et al., 1980; Forman  et al., 1985;
    NAS, 1981; Reed  et al., 1981b; Ruddell  et al., 1978; Tannenbaum
     et al., 1979; Ward, 1984).

         Factors influencing the formation of carcinogenic N-nitroso
    compounds are also important in correlating nitrate or nitrite intake
    with gastric tumour incidence. Factors influencing nitrosation of
    amines and amides were discussed in the Monograph on nitrite and
    include the role of thiocyanate, high salt intake, pH of the stomach,
    vitamin C or other dietary components, medication (cimetidine and
    other antacid), and gastric lesions or disorders (Armijo  et al.,
    1981a,b; Forman  et al., 1985; Mirvish, 1985; Risch  et al., 1985).
    These factors are discussed in many epidemiological and related
    studies concerning nitrate or nitrite intake and the occurrence of
    gastric tumours (Speijers  et al., 1987; Brüning-Fann & Kaneene,

         Some studies support the claim that there is evidence for a
    correlation between gastric cancer and nitrate (nitrite) intake. On
    the other hand there are also studies which do not support an
    association between high nitrate levels and increased incidence of
    gastric cancer. The majority of the studies were inconclusive or in
    some cases revealed a negative correlation between nitrate intake and
    gastric cancer (Speijers  et al., 1987; Forman, 1987; Forman  et al.,
    1988; Hansson  et al., 1994; Bruning-Fann & Kaneene, 1993;
    Moller et al., 1994; Gangolli  et al., 1994; Speijers  et al., in
    press). Epidemiological studies (on cancer) in general are hindered by
    a variety of factors such as the multiplicity of gastric cancer
    etiological factors and the time lag between exposure and the
    development of cancer (Brüning-Fann & Kaneene, 1993; Gangolli  et al.,

         A high intake of certain vegetables, although an important source
    of nitrate, seemed to be associated with a lower risk of gastric
    cancer. Protective factors such as ascorbic acid simultaneously
    present in these foods may be involved (Buiatti  et al., 1989, 1990;
    Boeing  et al., 1991; Gangolli  et al., 1994; Moller, in press).

         Epidemiological studies have been carried out in several
    countries on the relationship between gastric cancer and nitrate
    exposure via drinking-water. Salivary nitrite levels in volunteers
    were strongly increased after consumption of drinking-water containing
    200 mg NO3-/l in comparison with 50 mg NO3-/l (WHO guideline
    value). However, in studies of large populations in Chile, Denmark,
    England, France, Hungary and the USA no correlation was found between
    nitrate in drinking-water and stomach cancer. This still held true
    when the analysis was restricted to urban areas with nitrate levels
    above the 50 mg/l (Hart & Walters, 1983; Hill  et al., 1973; Zaldivar
    & Wetterstrand, 1978; Juhasz  et al., 1980; Davies, 1980; Jensen,
    1982; Vincent  et al., 1983; Beresford, 1985; WHO, 1985; Rademacher
     et al., 1992).

         The originally reported positive association in females in the
    mining town of Worksop (Hill  et al., 1973) was no longer significant
    after correction for mining area and social class (Davies, 1980).

         No association between nitrate concentration in food alone or in
    combination with drinking-water was found in Chile and England, when
    populations from high- and low-risk areas for stomach cancer were
    compared (Armijo  et al., 1981b; Forman  et al., 1985).

         Exposure from environmental pollution sources or from food via
    natural fertilizers in Chile led to a significant association between
    nitrate load and gastric cancer (Armijo & Coulson, 1975; Zaldivar,
    1977; Speijers  et al., 1987; Moller, in press).

         Studies of gastric cancer mortality in occupationally-exposed
    fertilizer workers did not show any evidence of an excess gastric
    cancer rate (Fraser  et al., 1982; Al-Dabbagh  et al., 1986;
    Rafnsson and Gunnardottir, 1990; Hagmar  et al., 1992; Fandrem  et al.,
    1993; Speijers  et al., 1987). In addition no increase in lung or
    prostate cancer was found in nitrate fertilizer workers (Hagmar
     et al., 1991; Rafnsson & Gunnarsdottir, 1990).

         A study of 556 grinders occupationally exposed from 1958 to 1976
    to cutting fluids containing nitrite and amines, did not reveal an
    increased risk of cancer (Järvholm  et al., 1986).

         Individuals with an achlorhydric stomach, and persons on
    cimetidine and antacid medication do present a special risk group.
    Chronic gastritis, especially the atrophic form seems to be an
    important intrinsic factor in the genesis of stomach cancer (Cuello
     et al., 1976; Rufu  et al., 1984).

         Atrophic gastritis is a relevant factor in determining the
    gastric nitrite level, because nitrate administered to subjects with
    this type of gastritis results in a ten times higher nitrite
    concentration than that found in subjects with a normal mucosa (see
    section 2.1.2). A given nitrate dose may be harmless to normal
    subjects, but harmful to a patient with atrophic gastritis, especially
    in the presence of precursors of N-nitrosamines or nitrosamides in the
    diet (see also Monograph on nitrite - endogenous nitrosation).

         According to Ruddell  et al. (1978), iron deficient patients
    with gastric lesions and patients with pernicious anaemia (PA) are
    predisposed to stomach cancer and also have a high reduction rate of
    nitrate to nitrite. The reduction rates in PA patients were nearly
    50-fold higher than of matched controls, as was the number of bacteria
    (Ruddell  et al., 1978; Reed  et al., 1981).

    2.3.2  Relationship between nitrate intake and genotoxic effects

         In an attempt to apply genetic biomarker analysis to improve the
    basis for risk assessment with respect to nitrate contamination of
    drinking-water, a study evaluated peripheral lymphocyte chromosomal
    damage in human populations exposed to low-, medium- and high-nitrate
    levels in private water wells in the Netherlands. It was shown that
    nitrate contamination of drinking-water caused dose-dependent
    increases in nitrate body loads as monitored by 24-h urinary nitrate
    excretion in female volunteers, but this appeared not to be associated
    with peripheral lymphocytes sister chromatid exchange frequencies
    (Kleinjans  et al., 1991).

    2.3.3  Relationship between nitrate intake and teratogenic effects

         The relationship between maternal exposure to nitrates in
    drinking-water and risk of delivering an infant with CNS malformation
    was examined in a case-control study in New Brunswick, Canada.
    Exposure to nitrate levels of 26 mg/l from private well water sources
    was associated with a moderate but not statistically significant
    increase in risk for CNS malformation If the source of drinking-water
    was a municipal distribution system or a private spring, an increase
    in nitrate exposure was associated with a decrease in risk of
    delivering a CNS-malformed infant. However, these estimates of effects
    were not statistically significant (Arbuckle  et al., 1988).

         To investigate the relationship between community drinking-water
    quality and spontaneous abortion, trace element levels in the
    drinking-water of 286 women having a spontaneous abortion through 27
    weeks of gestation with that of 1391 women having live births were
    compared. After adjustment for potential confounders, a decrease in
    the frequency of spontaneous abortion was associated with high levels
    of alkalinity and sulfate, and any detectable level of nitrate
    (Aschengrau  et al., 1989).

         The relationship between community drinking-water quality and the
    occurrence of late adverse pregnancy outcomes was investigated by
    conducting a case-control study among women who delivered infants
    during August 1977 through March 1980 at Brigham and Women's Hospital
    in Massachusetts. The water quality indices were compared among 1039
    congenital anomaly cases, 77 stillbirth cases, 55 neonatal death
    cases, and 1177 controls. There was no relationship between nitrate
    levels and late adverse pregnancy outcomes or neonatal death cases
    (Aschengrau  et al., 1993).

    2.3.4  Relationship between nitrate intake and thyroid effects

         Van Maanen  et al. (1994) studied the effect of nitrate
    contamination of drinking-water on volume and function of the thyroid
    in human populations exposed to different nitrate ion levels in their
    drinking-water. No iodine deficiency was observed in any of the
    nitrate exposure group. A dose-dependent difference in the volume of
    the thyroid was observed between low-and medium- versus high-nitrate
    exposure groups, showing development of hypertrophy at nitrate levels
    exceeding 50 mg/l. An inverse relationship was established between the
    volume of the thyroid and serum thyroid stimulating hormone (TSH)
    levels. These effects are supported by similar findings in rats and
    pigs (see 2.2.7).


         As the toxicity of nitrate results from its conversion to nitrite
    and the possible endogenous formation of N-nitroso compounds, and the
    toxicokinetics and biotransformation of nitrate in the rat are
    different from those in humans, rats are less suitable than rabbits,
    dogs and pigs for use in assessing the toxicity of nitrate in humans.
    However, the toxicological data are too limited to allow a safety
    evaluation on the basis of the results of studies on these species.
    For these reasons both the toxicity studies on nitrate in laboratory
    animals and those on nitrite in combination with data on the
    conversion of nitrate to nitrite were considered by the Committee.

         The possible endogenous formation of N-nitroso compounds from
    nitrite and N-nitrosatable compounds as precursors has already been
    discussed in the Monograph on nitrite. No evidence of an association
    between nitrate exposure and the risk of cancer was found in either
    the toxicological or epidemiological studies, and nitrate was not

         In two long-term toxicity studies in rats, one old and one
    recent, doses of 370 and 1820 mg/kg bw/day, expressed as nitrate ion,
    respectively failed to produce any effects. However, the second of
    these was solely a carcinogenicity study, in which the highest dose
    level of 1820 mg nitrate ion/kg bw/day could not be considered as a
    NOEL because complete histopathological examinations were not

         The experimental design of a recent study in rats on possible
    behavioural effects of nitrate was considered to be inappropriate for
    safety evaluation purposes.

         A short-term toxicity experiment in pigs indicated that a daily
    dose level of 3% potassium nitrate, equivalent to 730 mg/kg bw/day
    expressed as nitrate ion, inhibited the functioning of the thyroid.
    This finding was supported by an epidemiological cohort study in
    which enlargement of the thyroid and decreased levels of serum
    thyroid stimulating hormone were seen at high nitrate levels in


         In the light of the overall information on the toxicity of
    nitrate, the NOEL of 370 mg nitrate ion/kg bw/day was considered to be
    the most appropriate for safety evaluation.

         If the proportion of nitrate converted to nitrite in humans is
    taken as 5% (mol/mol) for normally responding individuals and 20% for
    those showing a high level of conversion and the NOEL for nitrite
    (6 mg/kg bw/day expressed as nitrite ion) is used, the "transposed"
    NOELs for nitrate, expressed as nitrate ion, would be 160 and 40 mg/kg
    bw/day, respectively. As these figures are derived in part from human
    pharmacokinetic data, the use of a safety factor of less than 100
    is justified. If the data on individuals showing a high level of
    conversion are used, a safety factor of 10 would be justified because
    intraindividual differences have already been taken into account.

         Since uncertainties still exist with respect to the possible
    endogenous formation of N-nitroso compounds after nitrate exposure,
    the most appropriate approach at present is to derive an ADI based on
    the most sensitive toxicity criteria for nitrite in rats and the
    toxicokinetics of nitrate in humans, in addition to deriving an ADI
    directly from toxicity studies with nitrate.

         On the basis of the NOEL of 370 mg of nitrate ion/kg bw/day in
    the long-term study in rats and a safety factor of 100, an ADI of
    0-5 mg/kg bw, expressed as sodium nitrate, or 0-3.7 mg/kg bw,
    expressed as nitrate ion, could be allocated. On the basis of the
    "transposed" NOEL for nitrate of 160 mg/kg bw/day for normally
    responding individuals in the human population (5% rate of conversion)
    and a safety factor of 50, an ADI of 0-3.2 mg/kg bw, expressed as
    nitrate ion, could be allocated. Both ways of deriving an ADI for
    nitrate thus give similar figures. The Committee therefore retained
    the previous ADI of 0-3.7 mg/kg bw, expressed as nitrate ion. This ADI
    is expressed to two significant figures because rounding up was not
    considered to be justified on the basis of the value of 3.2 mg/kg bw
    derived from conversion of nitrate to nitrite.

         Because nitrate may be converted to nitrite in significant
    amounts and infants below the age of 3 months are more vulnerable to
    the toxicity of nitrite than adults, the ADI does not apply to such

         In deriving an ADI for nitrate the Committee took a cautious
    position. It was aware that vegetables are an important potential
    source of intake of nitrate. However, in view of the well-known
    benefits of vegetables and the lack of data on the possible effects of
    vegetable matrices on the bio-availability of nitrate, the Committee
    considered it to be inappropriate to compare exposure to nitrate from
    vegetables directly with the ADI and hence to derive limits for
    nitrate in vegetables directly from it.

         Submission of the results of studies in humans exposed to nitrate
    from different sources (vegetables and drinking-water), including the
    toxicokinetics and relevant toxicodynamic parameters such as thyroid
    function and adrenal cortex function, is desirable. The results should
    be analyzed by means of physiologically based pharmacokinetic (PBPK)


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    See Also:
       Toxicological Abbreviations
       Nitrate (JECFA Food Additives Series 50)
       NITRATE (JECFA Evaluation)