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    PARAQUAT

    EXPLANATION

         Paraquat was evaluated for acceptable daily intake by the Joint
    Meetings in 1970, 1972, 1976, 1982, and 1985 (Annex 1, FAO/WHO, 1971a,
    1973a, 1977a, 1983a, and 1986a). A toxicological monograph was
    published after the 1970 Meeting (Annex 1, FAO/WHO, 1971b) and
    monograph addenda were published after the Meetings in 1972, 1976, and
    1982 (Annex 1, FAO/WHO, 1973b, 1977b, and 1983b). In 1970 the Meeting
    estimated an ADI of 0.001 mg/kg b.w. (as paraquat dichloride). The
    1982 Joint Meeting noted that the higher ADI established by the 1972
    Meeting (0.002 mg/kg b.w. as paraquat dichloride) was based on
    long-term studies conducted by Industrial Bio-Test Laboratories (IBT),
    for which no replacement studies, validations, or additional data had
    been submitted. Considering the evidence available, the 1982 Meeting
    recommended that a reduced ADI (0.001 mg/kg b.w. as paraquat
    dichloride) be retained on a temporary basis, pending receipt of
    further data.

         Data were submitted to the 1985 Meeting which met the 1982
    request. These data were reviewed by the 1985 Meeting, but logistical
    difficulties precluded their full evaluation, especially in the light
    of the considerable amount of information previously evaluated by the
    Joint Meeting. The 1985 Joint Meeting was aware that the 2-year study
    in rats that was submitted had been considered by 1 national authority
    to indicate a possible oncogenic potential in the rat. The Meeting
    also noted differing interpretations of the observed lesions by
    different pathologists. The Meeting therefore recommended that a
    complete evaluation of all valid data available should be undertaken
    by the 1986 Joint Meeting. In addition, it requested submission of
    full discriptions of the lung lesions seen in the new long-term rat
    study and of historical control data on all lung lesions in the strain
    of rats utilized in the study in the laboratory in which it was
    conducted. The Joint Meeting extended the existing temporary ADI until
    1986.

         This monograph incorporates the relevant studies summarized in
    earlier monographs and monograph addenda, the studies submitted for
    consideration by the 1985 Joint Meeting, and the studies required by
    the 1985 Joint Meeting, all of which were reviewed by the 1986
    Meeting.

    IDENTITY AND PROPERTIES

    CHEMICAL NAMES      1,1'-dimethyl-4,4'-bipyridylium ion
                        1,1'-dimethyl-4,4'-bipyridinium ion
                        1,1'-dimethyl-4,4'-dipyridylium ion
                        N,N'-dimethyl-gamma,gamma-dipyridylium ion

                        Present as the dichloride.

    SYNONYMS            Methyl viologen, PP-148, Gramoxone, Gramoxone S,
                        Gramoxone ZU, Dextrone X, Esgram, Dexuron,
                        Tota-Col, Gramuron, Simpar, Toxer Total, PP-910,
                        Para-Col, Pathclear, Gramonol, Cleansweep,
                        Terraklene, Actar, Priglone, Preeglone, Mofisal,
                        Sweep, Crisquat, Herboxone, Pillarquat,
                        Pillarxone, Duanti, Dukatalon, Frankol Prompt,
                        Gramazin, Gramixel, Katalon, Ortho Paraquat CL,
                        Ortho Spot Weed & Grass Killer, Orvar, Paradi,
                        Seythe, Spray Seed, Tryquat, Weedrite, Crisquat,
                        Goldquat-276, Paraquat CL.

    STRUCTURAL FORMULA
    CHEMICAL STRUCTURE 4

    EMPIRICAL FORMULA

                        [C12H14N2]2+

    MOLECULAR WEIGHTS

                        186.2 (ion)
                        257.2 (dichloride)

    PHYSICAL STATE*     Colorless crystalline solid.

    MELTING POINT       Decomposes at about 300C.

    VAPOUR PRESSURE     Not measurable.

    SOLUBILITY          Very soluble in water, slightly soluble in lower  
                        alcohols, insoluble in hydrocarbons.

    STABILITY           Stable in acid or neutral solutions, unstable in
                        alkaline solutions. Inactivated by inert clays,
                        anionic surfactants, and ultraviolet light.

    OTHER PROPERTIES    Solutions of paraquat become intensely purple on
                        reduction, due to the formation of a water
                        soluble, relatively stable free radical, which
                        absorbs at 400 nm. The unreduced form absorbs at
                        258 nm. The extinction coefficients of the reduced
                        and the oxidized paraquat at these absorption
                        maxima are xi mM400 = 46.0 and xi mM258 =
                        53.6, respectively (Autor, 1977). Vigorous
                        reduction gives tetrahydro derivatives and
                        ultimately the fully saturated base. The redox
                        potential (-446 mV) is independent of pH.
                        Concentrated aqueous solutions of paraquat are
                        corrosive to metal.

    FORMULATIONS        These include aqueous concentrates (100 - 240 g/l)
                        and water-soluble granules (24 g/kg) of paraquat
                        dichloride.

    COMBINATIONS        These include mixtures of paraquat with diquat
                        (e.g., Weedol), diuron (e.g., Dexuron),
                        monolinuron (e.g., Gramonol), and simazine
                        (e.g., Terraklene).

    * All chemical properties are for the dichloride.

    ANALYTICAL METHODS  These include spectrophotometric, gas chromato-
                        graphic and radioimmunoassay methods. They
                        have been extensively reviewed by WHO (1984).

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

         The absorption, distribution, and excretion of paraquat in
    experimental animals have been reviewed by WHO (1984).

         Following oral single-dose administration of 4 - 6 mg/kg b.w.
    14C-paraquat dichloride to rats, 99 - 102% of the administered dose
    was found in the faeces (93 - 96%) and in the urine (6%) within 3
    days. This information, together with the absence of significant
    biliary excretion, provided evidence that paraquat is poorly absorbed
    from the gut (Daniel & Gage, 1966).

         The low rate of paraquat absorption by the gut was confirmed in
    experiments in which rats, guinea pigs, and monkeys, orally
    administered with LD50 doses of 14C-paraquat, had low peak serum
    concentrations (2.1 - 4.8 mg/litre). The radioactivity levels reached
    a maximum 30 - 60 minutes after administration and then remained
    relatively constant for 32 hours (Litchfield et al., 1973; Conning
    et al., 1969).

         A dose of 126 mg/kg b.w. paraquat resulted in a maximum rat serum
    level of 4.8 mg/litre (Murray & Gibson, 1974).

         In fasting dogs, low oral doses of paraquat were rapidly but
    incompletely absorbed, the peak plasma concentration being attained 75
    minutes after dosing. After an oral dose of 0.12 mg/kg b.w., 46 - 66%
    was absorbed in 6 hours. After doses of 2 and 5 mg/kg b.w., only 22 -
    38% and 25 - 28% of the doses were absorbed, respectively (Bennett
    et al., 1976).

         Dose-dependent data from dogs and whole-body autoradiography seem
    to suggest that absorption is facilitated in the small intestine
    (WHO, 1984).

         The pulmonary absorption of 14C-paraquat after an intratracheal
    injection of 1.86 nmol/lung was investigated in the isolated perfused
    rat lung. The efflux of 14C-paraquat was diphasic, with a
    rapid-phase half-life of 2.65 minutes and a slow-phase half-life of
    356 minutes. It was suggested that the slow phase represented a
    storage pool, possibly responsible for the pulmonary toxicity of
    paraquat (Charles et al., 1978).

         Various doses of 3H-paraquat (1 pg - 10 g) in 0.1 ml saline
    were introduced directly into the left bronchus of rats. Fifteen
    minutes after instilling 10 ng of 3H-paraquat, 90% of the ion could
    be accounted for in the tissues and urine, 50% being present in the
    lung. With doses at or greater than 10 g, pathological changes were
    seen in the lung that were similar to those seen after systemic
    poisoning (Wyatt et al., 1981).

         Paraquat absorption through animal and human skin has been
    studied using an in vitro technique. Human skin was shown to be
    impermeable to paraquat, having a very low permeability constant of
    0.73. Furthermore, human skin was found to be at least 40 times less
    permeable than that of the animals tested, including rats, rabbits,
    and guinea pigs (Walker et al., 1983).

         Observations of dose-related dermal toxicity in experimental
    animals and human percutaneous poisoning suggest that paraquat
    absorption is markedly increased in damaged or occluded skin
    (WHO, 1984).

         High concentrations and retention of paraquat were found in lung
    tissue, relative to other tissues, following oral, i.v., i.p., s.c.,
    and intrabronchial routes of administration in rats, guinea pigs,
    rabbits, and monkeys (Sharp et al., 1972; Ilett et al., 1974;
    Murray & Gibson, 1974; Maling et al., 1978; Kurisaki & Sato, 1979;
    Waddell & Marlowe, 1980; Wyatt et al., 1981. Some of these data are
    summarized in Tables 1 and 2.

         An association between paraquat concentrations in the lung and
    degree of toxicity or lung injury has been reported (Sharp et al.,
    1972; Ilett et al., 1974; Waddell & Marlowe, 1980; Wyatt et al.,
    1981).

         In 1 study toxic doses of 14C-paraquat were administered orally
    and i.v. to rats. Paraquat concentrations in the whole blood were
    similar to those in the plasma. The distribution of the herbicide in
    various tissues was then followed for up to 10 days. The initial and
    secondary half-lives of paraquat in plasma following i.v.
    administration were 23 minutes and 56 hours, respectively. The
    concentration in the kidney, lung, and muscle declined at the same
    rate as in the plasma initially, but the rapid phase in the lung ended
    after 20 minutes (compared with 1 - 4 hours in other organs), after
    which it declined, with a half-life of 50 hours. The lung had the
    greatest retention and consequently contained the highest
    concentration 4 hours after dosing. Four to 10 days after dosing, the
    paraquat concentration in the lung was 30 - 80 times higher than in
    the plasma (Sharp et al., 1972).

        Table 1. Paraquat distribution in tissues*
                                                                                                                      

    Route              Dose         Species     Time             Tissue         Concentration        Reference
    of                                          after
    entry                                       treatment
                                                                                                                      

    Intrabronchial     10 ng        rat         60 min           plasma         0.0092 g/l           Wyatt et al.,
                                                                 lung           5.2 ng               1981
                                                                 kidney         0.052 ng
                                                                 liver          not measured
                                                                 heart          not measured
                                                                 brain          not measured

    I.v.               20 mg/kg     rat         24 h             plasma         0.07 mg/l            Sharp et al.,
                                                                 lung           6.00 mg/kg           1972
                                                                 kidney         1.45 mg/kg
                                                                 liver          0.48 mg/kg
                                                                 heart          1.20 mg/kg
                                                                 brain          not measured

    I.v.               20 mg/kg     rat         24 h             plasma         not measured         Ilett et al.,
                                                                 lung           11.36 mol/kg         1974
                                                                 kidney         1.93 mol/kg
                                                                 liver          0.90 mol/kg
                                                                 heart          1.13 mol/kg
                                                                 brain          0.87 mol/kg
                                                                                                                      
    *   From WHO, 1984

    Table 1. (cont'd).
                                                                                                                       

    Route              Dose         Species     Time             Tissue         Concentration        Reference
    of                                          after
    entry                                       treatment
                                                                                                                       

    I.v. cont'd.       20 mg/kg     rabbit      24 h             plasma         0.28 mol/l
                                                                 lung           7.90 mol/kg
                                                                 kidney         5.25 mol/kg
                                                                 liver          1.59 mol/kg
                                                                 heart          1.52 mol/kg
                                                                 brain          0.49 mol/kg

    I.p.               15 mg/kg     rat         24 h             plasma         0.32 mol/kg          Maling et al.,
                                                                 lung           26.28 mol/kg         1978
                                                                 kidney         10.40 mol/kg
                                                                 liver          5.04 mol/kg
                                                                 heart          4.59 mol/kg
                                                                 brain          1.22 mol/kg

    Oral               126 mg/kg    rat         16 h             plasma         0.9 mg/l             Murray &
                                                                 lung           5.0 mg/kg            Gibson, 1974
                                                                 kidney         7.0 mg/kg
                                                                 liver          2.1 mg/kg
                                                                 heart          2.7 mg/kg
                                                                 brain          not measured

                       22 mg/kg     guinea      16 h             plasma         0.03 mg/l
                                    pig                          lung           1.29 mg/kg
                                                                 kidney         1.99 mg/kg
                                                                 liver          0.08 mg/kg
                                                                 heart          0.31 mg/kg
                                                                 brain          not measured
                                                                                                                       

    Table 2.  Paraquat distribution in tissues (in mg/kg (mean) tissue)*
                                                                                                             

    Route     Dose       Species   Time       Lung    Kidney    Liver    Heart    Plasma    Reference
    of        mg/kg                after
    entry     body                 dosing
              weight
                                                                                                             

    Oral      126        rat         1 h       3.3    27.5      2.0      1.8      4.7       Murray & Gibson,
                                     4 h       3.7     4.5      4.4      0.9      0.8       1974
                                    32 h      13.6     9.4      5.7      2.8      1.1
                                    64 h       1.7     1.0      7.7      0.2      0.1

    I.v.      20         rat         1 h       9.0    25.0      5.0      -        6.0       Sharp et al.,
                                     4 h       8.0     6.0      2.0      -        0.3       1972
                                    24 h       6.0     1.0      0.4      -        0.07
                                     2 d       4.0     0.8      0.3      -        0.05
                                                                                                             
    *    From WHO, 1984
             The high lung tissue concentrations of paraquat were confirmed in
    another study in rats and rabbits after i.v. injection of 20 mg
    14C-paraquat/kg b.w. Although the herbicide showed a selective
    localization in the rabbit lung, the concentration decreased far more
    rapidly in the rabbit lung than in the rat lung. The rabbit, unlike
    the rat, did not show any histological or biochemical signs of lung
    damage. No preferential subcellular localization of paraquat was found
    in the lungs of either species. No evidence of covalent binding of
    paraquat in lung tissue was found. After thorough washing of tissue
    precipitate with dilute trichloracetic acid, only insignificant
    amounts of 14C-paraquat were detected in protein from the brain,
    heart, kidney, liver, lung, and plasma (Ilett et al., 1974).

         Autoradiographic studies using 14C-paraquat have been carried
    out on mice and rats. Paraquat was observed in nearly all organs 10
    minutes after i.v. injection of 20 mg/kg b.w. (Litchfield et al.,
    1973).

         Autoradiographic results similar to those above were obtained in
    mice after i.v. injection of 288 - 338 g/kg b.w. of 3H-paraquat
    dichloride. Cellular resolution autoradiography showed that paraquat
    was confined almost entirely to cells having the distribution of
    alveolar Type II cells. The authors suggested that it was unlikely
    that the radioactivity was bound to cellular constituents. The Type II
    cells were found to be susceptible to the toxicity of paraquat
    (Waddell & Marlowe, 1980; Kimbrough & Gaines, 1970).

         No paraquat was detected in the kidney, brain, liver, or lungs
    when administered in the diet to rats at a concentration of 50 ppm for
    a period of 8 weeks. At 120 ppm it was found at low concentrations in
    the lung, kidney, gastrointestinal system, and brain. When
    administered at 250 ppm, it was detected in the tissues within 2
    weeks. No sex differences or any clear pattern of accumulation were
    noted throughout the 8-week study. Within 1 week of return to a normal
    diet, no paraquat was detected in any tissue examined. Histological
    changes were observed in all lungs of animals fed paraquat at 250 ppm
    in the diet (Litchfield, et al., 1973).

         Rose et al. (1974) demonstrated an energy-dependent
    accumulation of paraquat in slices of rat lung that obeyed saturation
    kinetics. The same investigators later examined the ability of
    paraquat to accumulate in tissue slices from other organs in vitro.
    The uptake of the herbicide in brain, adrenal gland, and kidney slices
    was less than 10% of that observed in lung slices. The authors
    established the uptake of paraquat by the lung in various species
    (rat, rabbit, dog, monkey, and man). The human lung accumulated
    paraquat as readily as that of the rat. Indeed, the kinetics (Vmax
    and Km) of the process were found to be very similar in the 2
    species. Moreover, there was a relationship between the concentration
    of paraquat in the different lung areas and the development of
    microscopic lung lesions (Rose et al., 1976a; Rose & Smith, 1977).

         It has been demonstrated that the rate of paraquat efflux from
    lung tissue is less than its rate of accumulation in lung slices.
    Efflux from lung slices, prepared from rats dosed i.v. with the
    herbicide, was found to be biphasic. There was a fast component
    (half-life of 20 minutes), followed by a first-order slow component
    characterised by a half-life of 17 hours. The half-life in vitro was
    similar to that seen in vivo following i.v. administration to rats
    (Smith et al., 1981). These results are partially consistent with
    those obtained by Charles et al. (1978) in the isolated perfused rat
    lung.

         A biphasic elimination of paraquat from the plasma of rats after
    i.v. injection has been reported. The initial rapid phase had a 20 -
    30 minute half-life, and the slower phase a half-life of 56 hours
    (Sharp et al., 1972).

         Prolonged paraquat disappearance from serum following a rapid
    initial decline was also found after oral administration to rats,
    guinea pigs, and monkeys. Both the urinary and faecal routes were
    important in all species studied. In rats 32 hours after dosing, 52%
    of the administered paraquat was found in the gastrointestinal tract
    and 17 and 14% were excreted in the faeces and urine, respectively. No
    radioactivity was found in the expired air. The paraquat in the faeces
    was due primarily to elimination of unabsorbed paraquat. The prolonged
    elimination of paraquat in all animals tested indicated retention of
    the herbicide in the body (Murray & Gibson, 1974).

         Following i.v. administration of paraquat to rats, 75 - 79% of
    the dose was excreted in the urine within 6 hours. In this study, the
    plasma disappearance of 5 mg/kg paraquat was fitted to a 3-compartment
    model. Total body clearance was estimated to be 8.39  0.54 ml/kg
    /minute. The relatively high concentration of paraquat found in the
    duodenal and jejunal walls suggested biliary secretion of the
    herbicide. The authors' hypothesis was later supported by the
    observation of radioactivity in the intestines of mice injected i.v.
    with 14C-paraquat in whole-body autoradiographic studies (Maling
    et al., 1978; Waddell & Marlowe, 1980).

         The dog was used as a model to evaluate the influence of
    paraquat-induced renal failure on the kinetics of paraquat
    elimination. After i.v. injection of a trace dose of 14C-paraquat
    (30 - 50 g/kg b.w.), the kinetics of distribution was described by a
    3-compartment model. To obtain a good fit of the curve, it was
    necessary to sample the central (plasma) compartment for at least
    24 hours after dosing. Simulation of paraquat levels in the peripheral
    compartments suggested the existence of a compartment with rapid
    uptake and removal (kidney) and another with slow uptake (lung). The

    renal clearance of paraquat approximated total body clearance,
    indicating that paraquat elimination occurs through renal excretion.
    The urinary excretion rate of an i.v. dose was rapid, approximately 80
    - 90% of the dose being eliminated during the first 6 hours.
    Intravenous injection of a large toxic dose of paraquat (20 mg/kg
    b.w.), however, brought about a marked decrease in renal clearance,
    from 73 ml/minute to 18 ml/minute after 2.5 hours and 2 ml/minute
    after 6 hours. These data suggest that kidney damage could contribute
    to paraquat accumulation in the lung (Hawksworth et al., 1981).

    Metabolism

    Rats, dogs, and guinea pigs

         After oral administration of 14C-paraquat to rats, dogs, and
    guinea pigs, most of the radioactivity was excreted in 4 days, mainly
    in the faeces as unchanged paraquat. The remaining label was present
    in urine, which contained 12% (rats), 45% (dogs), and 9% (guinea pigs)
    of the dose administered. Paraquat was the main radioactive component
    of rat and dog urine, with monquat and the dipyridone of paraquat
    accounting for 0.4%, 0.3%, and 0.1% of the administered dose in rat
    urine, and 0.4%, 0.5%, and 0% of the dose in dog urine. After s.c.
    administration of 14C-paraquat to rats, over 90% of the administered
    radioactivity was excreted in the urine in 4 days. While the excretion
    produce was mainly paraquat, chromatography indicated that monoquat
    (1.9%), paraquat monopyridone (3.2%), and paraquat dipyridone (1.1%)
    were also present. Although traces of monoquat and paraquat
    monopyridone were also found in rat faeces, there was no evidence of
    extensive metabolism of paraquat by the gut microflora. Intestinal
    bacteria from rat caecal contents did not degrade paraquat in vitro
    to any measurable extent (Annex 1, FAO/WHO, 1977b).

         These conclusions were in contrast with the results of other
    studies previously evaluated which indicated that when paraquat
    (50 mg/kg b.w. of 14C-labelled dichloride salt) was given to rats,
    25% of the radioactivity excreted in the faeces could be attributed to
    products of metabolism by gut microflora. Examination of extracts
    indicated the presence of only 1 metabolite in addition to paraquat.
    Thirty percent of the paraquat was broken down when incubated
    anaerobically with rat caecal contents; the metabolites were not
    identified. Urine from rats injected i.p. with 14C-methyl-labelled
    paraquat contained 87% of the administered radioactivity in 24 hours,
    which was entirely unchanged paraquat (Plant Protection Ltd, 1972).

    Hens

         When a single oral dose of 14C-methyl-labelled paraquat was
    administered to hens, all of the dose was recovered quantitatively in
    the faeces within 3 days. At least 98% of the recovered radioactivity
    was unchanged paraquat. Analysis of the tissues of hens after about 3
    weeks of dosing with 14C-paraquat (6 ppm in the total diet)
    indicated that it did not accumulate in the hens (Hemingway & Oliver,
    1974).

         Continuous dosing of hens with radiolabelled paraquat for up to
    22 days, at rates up to 30 ppm in the diet, resulted in total
    radioactive residues in the eggs of up to approximately 0.05 mg/kg
    paraquat ion equivalent. At least 80% of the radioactivity was due to
    unchanged paraquat. The residue was almost entirely in the yolk rather
    than in the albumin (Hemingway & Oliver, 1974; Hendley et al.,
    1976a).

    Pigs

         Pigs excreted an oral dose of paraquat principally in the faeces
    as unchanged paraquat. Two pigs were dosed with 14C-labelled
    paraquat for 7 consecutive days at a rate equivalent to 50 ppm in
    the diet. One was dosed with 14C-methyl- and the second with
    14C-ring-labelled paraquat. The pigs were sacrificed 2 hours after
    receiving the final dose. By this time 69 - 73% of the administered
    residue had been recovered in the faeces and approximately 3% had been
    recovered in the urine. More than 90% of the radioactivity in the
    faeces was present as unchanged paraquat. Total radioactive residues
    in the tissues were low. More than 90% of these residues were due to
    unchanged paraquat, except in liver, where approximately 70% was due
    to unchanged paraquat and 4 - 7% was due to monoquat ion (Leahey
    et al., 1976; Spinks et al., 1976).

    Goats

         14C-ring-labelled paraquat was administered to a goat in
    mid-lactation twice daily for 7 days at a dose equivalent to 100 ppm
    in the diet. Total radioactive residues in the milk were less than
    0.01 mg/kg paraquat ion equivalent; 76% was unchanged paraquat. Total
    radioactive residues were 0.74, 0.56, and 0.1 mg/kg in kidney, liver,
    and muscle, respectively. There was no significant metabolism of
    paraquat, except in the liver, where 50% of the residue was paraquat
    and about 5% was each of the metabolites monoquat ion and monopyridone
    ion (Hendley et al., 1976b).

    Sheep

         A dose of 14C-methyl-labelled paraquat administered to a sheep
    via a rumen fistula was recovered quantitatively within 10 days.
    Approximately 4% of the dose was excreted in the urine and the
    remainder in the faeces. More than 95% of the radioactivity in urine
    and faeces was present as unchanged paraquat. Small amounts of
    monoquat ion (1%) and monopyridone ion (2.3%) were also detected
    (Hemingway et al., 1972).

         When injected s.c., paraquat was also excreted rapidly in the
    urine (over 80% of the dose), 69% within the first day after
    treatment. Unchanged paraquat accounted for most (90%) of the
    radioactivity; the monopyridone derivative was present as 2 - 3% of
    the dose and monoquat was a trace metabolite. This pattern of
    metabolism was virtually identical to that seen in the urine following
    dosing via the rumen (Hemingway et al., 1972).

    Cows

         When cows were given single oral doses of 14C-methyl paraquat
    at 8 mg/kg, 96% of the radioactivity was recovered in the faeces
    during the following 9 days; 0.7% was recovered in the urine.
    Unchanged paraquat accounted for most of the radioactivity in the
    faeces (96%) and urine (62 - 90%), but traces of the monoquat ion and
    monopyridone ion were also detected in the urine. Only 0.003 - 0.004%
    of the radioactivity was recovered in milk; the maximum radioactive
    residue (0.005 mg/kg, paraquat ion equivalent) was observed on the day
    after dosing. About 15% of this radioactivity was present as unchanged
    paraquat. Monoquat ion and monopyridone ion (3 - 25%) were also found
    in the milk. The radioactivity not identified as paraquat, monoquat,
    or monopyridone was incorporated into natural constituents of milk
    resulting from the anabolism of the radioactive methyl group cleaved
    from paraquat (Hemingway et al., 1974).

         Cows were fed for 3 months diets containing 24, 80, or 170 ppm
    paraquat ion (equivalent to 0.8, 2.5, or 5.5 mg/kg b.w./day). The
    paraquat was present as a residue in dried grass obtained from a
    pasture that had been sprayed with Gramoxone and subsequently
    weathered. The diet was accepted satisfactorily and no toxicological
    effects were observed during the trial. Pathological examination of
    tissues from animals slaughtered within 24 hours of the end of the
    feeding trial showed no toxic effects attributable to paraquat. The
    tissue residues, including muscle and liver, determined in cows at the
    2 higher dose rates, varied between 0.01 and 0.09 mg/kg except in the

    kidney, where 0.21 - 0.31 mg/kg was found. These fell to low
    (0.04 mg/kg in the kidney) or non-detectable levels in an animal fed
    the high-paraquat diet for 30 days and then maintained on an untreated
    diet for 12 days before slaughter. Very low residues of paraquat were
    present in milk samples taken weekly during the trial (121 samples
    ranging from 0.0001 - 0.0006 mg/kg; 1 sample = 0.001 mg/kg)
    (Edwards et al., 1974).

    Effects on enzymes and other biochemical parameters

         Several reviews or monographs have summarised the biochemical
    mechanism of paraquat toxicity in plants (Calderbank, 1968), bacteria
    (Fridovich & Hassan, 1979), and animals (Bus et al., 1976; Autor,
    1977; Smith et al., 1979; Smith, 1985). The mechanism of the toxic
    action of paraquat has also been extensively reviewed by WHO (1984).

         Paraquat has long been known to participate in cyclic
    reduction-oxidation reactions in biological systems. The compound
    readily undergoes a single electron reduction in tissues, forming a
    free radical. In an aerobic environment, the free radical is
    immediately oxidised by molecular oxygen, generating the superoxide
    anion radical. The reoxidized paraquat is capable of accepting another
    electron and continuing the electron transfer reactions in a catalytic
    manner (Figure 1).

    CHEMICAL STRUCTURE 5

         Research into the mechanism of paraquat toxicity has identified
    at least 2 partially toxic consequences of the redox cycling reaction:
    a) generation of the superoxide anion radical, and b) oxidation of
    cellular NADPH, which is the major source of reducing equivalents for
    the intracellular reduction of paraquat. Generation of the superoxide
    anion radical can lead to the formation of more toxic forms of reduced
    oxygen, hydrogen peroxide (H2O2), and hydroxyl radicals. Hydroxyl
    radicals have been implicated in the initiation of membrane damage by
    lipid peroxidation, depolymerization of hyaluronic acid, inactivation
    of proteins, and damage to DNA. Depletion of NADPH, on the other hand,
    may disrupt important NADPH-requiring biochemical processes such as
    fatty acid synthesis (Hassan & Fridovich, 1980; Smith et al., 1979).

         The importance of molecular oxygen and the potential role of
    superoxide anion radical generation in mediating paraquat toxicity
    have been implicated in studies on plants, bacteria, and in vitro
    and in vivo mammalian systems. In cultures of E. coli, Hassan &
    Fridovich (1977, 1978, & 1979) demonstrated that paraquat stimulated
    cyanide-resistant respiration, which could be almost entirely
    accounted for by the NADPH-dependent formation of the superoxide anion
    radical.

         The possibility that formation of the superoxide anion radical
    might be responsible for the toxicity of paraquat in bacteria is
    supported by observations that bacteria containing elevated activities
    of superoxide dismutase, an enzyme that detoxifies the superoxide
    anion radical, were resistant to paraquat toxicity (Hassan &
    Fridovich, 1977, 1978; Moody & Hassan, 1982).

         In vitro studies on lung and liver preparations from various
    animal species have supported the hypothesis that paraquat redox
    cycling and associated superoxide anion radical and H202
    generation also occur in mammalian systems (Gage, 1968; Ilett
    et al., 1974; Montgomery, 1976, 1977; Steffen & Netter, 1979;
    Talcott et al., 1979).

         Bus et al. (1974) reported that the single electron reduction
    of paraquat in mammalian systems was catalysed by microsmal cytochrome
    P-450 reductase and NADPH. The observation that the in vivo toxicity
    of paraquat in animals is markedly potentiated by exposure to elevated
    oxygen tensions further supports the potential role for molecular
    oxygen in mediating toxicity (Fisher et al., 1973; Autor, 1974;
    Bus & Gibson, 1975; Witschi et al., 1977; Kehrer et al., 1979;
    Keeling et al., 1981; Selman et al., 1985).

         The results of in vivo studies conducted by Bus et al. (1974)
    suggest that stimulation of lipid peroxidation, which is dependent on
    paraquat redox cycling and associated superoxide anion radical
    generation, might be an important toxic mechanism in mammalian
    systems. Consistent with this hypothesis, animals fed diets deficient

    in selenium or vitamin E in order to diminish cellular antioxidant
    defenses were significantly more sensitive to paraquat toxicity than
    control animals (Bus et al., 1975a; Omaye et al., 1978). Moreover,
    selenium deficiency potentiated paraquat-induced lipid peroxidation in
    isolated perfused rat lung (Glass et al., 1985). In contrast to
    these studies, a number of studies have shown that paraquat inhibited
    in vitro microsomal lipid peroxidation (Ilett et al., 1974;
    Montgomery & Niewoehner, 1979; Steffen & Netter, 1979; Kornburst &
    Mavis, 1980). Subsequent studies have indicated, however, that
    paraquat would stimulate microsomal lipid peroxidation when an
    adequate supply of electrons (NADPH) and in vitro oxygen tension
    were maintained (Trush et al., 1981, 1982).

         Despite the evidence described above, the hypothesis that lipid
    peroxidation is the underlying toxic mechanism functioning in vivo
    has not been conclusively demonstrated. Direct quantification of
    paraquat-induced lipid peroxidation damage in vivo by analysis of
    tissue malonadialdehyde levels or ethane exhalation, both markers of
    peroxidation injury, has been largely unsuccessful (Reddy et al.,
    1977; Shu et al., 1979; Steffen et al., 1980), although
    significant increases of serum malondialdehyde levels have been
    recently reported in patients with paraquat poisoning (Yasaka
    et al., 1986). Furthermore, attempts to counteract paraquat
    toxicity by administration of various antioxidants have also been
    unsuccessful (Fairshter, 1981).

         Superoxide radicals generated in paraquat redox cycling may
    induce biochemical changes other than the initiation of the
    peroxidation reaction. Ross et al. (1979) demonstrated that paraquat
    increased DNA strand breaks in cultured mouse lymphoblasts. Paraquat
    was also reported to induce a superoxide-dependent stimulation of
    guanylate cyclase activity in rat liver (Vesely et al., 1979) and
    guinea pig lung (Giri & Krishna, 1980). These investigators postulated
    that increased cyclic-GMP might stimulate the pulmonary fibroproli-
    ferative changes characteristic of paraquat toxicity. In other
    studies, paraquat has also been found to increase collagen synthesis
    in the rat lung (Greenberg et al., 1978; Thompson & Patrick, 1978;
    Hussain & Bhatnagar, 1979).

         Redox cycling of paraquat has also been proposed to lead to
    increased oxidation of cellular NADPH (Brigelius et al., 1981;
    Keeling et al., 1982). The activity of pentose shunt enzymes in the
    lung rapidly increased in rats treated with paraquat, which suggested
    an increased demand for NADPH (Fisher et al., 1975; Rose et al.,
    1976b). The observation that paraquat decreased fatty acid synthesis
    in lung slices (Smith et al., 1979) further supported this
    hypothesis, since fatty acid synthesis requires NADPH. Direct analysis
    of NADPH in the lung has long confirmed that paraquat treatment
    decreases the NADPH content in rat lung (Witschi et al., 1977;

    Smith et al., 1979). More recently, both oxygen consumption and
    NADPH oxidation in lung microsomes were found to be significantly and
    specifically stimulated by the addition of paraquat (Rossouw et al.,
    1984). The above observations led Smith et al. (1979) to propose
    that oxidation of NADPH might interrupt not only vital physiological
    processes, such as fatty acid synthesis, but also may render tissues
    more susceptible to lipid peroxidation by decreasing the equivalents
    (NADPH) necessary for functioning of the antioxidant enzyme
    glutathione peroxidase (Figure 2). Indeed, a significant increase
    (589%) in lung-oxidized glultathione (GSSG) content was found over
    control levels after perfusion of isolated rabbit lung with a 0.4 mM
    paraquat solution. This effect was significantly increased (225%) by
    hyperoxia (Dunbar et al., 1984).

    Toxicological studies

    Special studies on carcinogenicity

    Mice

         Groups of 60 male and 60 female Alderly Park SPF mice were fed
    diets containing 0 (2 groups), 12.5, 37.5, or 100/125 ppm paraquat
    cation for 97 - 99 weeks. The initial top dose of 100 ppm was
    increased to 125 ppm at week 36 in order to evoke a toxic effect. The
    study was terminated at weeks 97 - 99 when 80% mortality was reached
    in a female control group and was approaching 80% overall. Clinical
    observations, body-weight gain, food consumption, and urinary paraquat
    were measured throughout the study. Histopathological examination of
    approximately 40 tissues was performed on animals killed or dying
    during the study and at termination. Further groups of 10 males and 10
    females were fed the same dose levels as above for 52 weeks for
    measurement of paraquat concentrations in the kidney, lung, and plasma
    at termination.

         Mortality ranged from 32 - 55% at 80 weeks and from 58 - 87% at
    termination and was higher in the 37.5 ppm and 125 ppm groups than in
    the combined controls. Effects due to treatment were renal lesions in
    both sexes at 100/125 ppm and, in males, at 37.5 ppm; lung lesions in
    both sexes at 100/125 ppm; and decreased food consumption and
    body-weight gain and increased mortality in females at 100/125 ppm.
    Histopathologically, the treatment-related renal lesions were manifest
    as mild dilatation and degenerative changes in the tubules. The
    incidences of tubular degeneration (with and without dilatation) in
    male mice dying during the study were 31/48 at 100/125 ppm, 15/47 at
    37.5 ppm, 9/45 at 12.5 ppm, and 8/45 and 3/35 in controls. The
    paraquat-induced lung lesions noted at 100/125 ppm included focal
    pneumonitis/alveolitis and hypercellularity of the alveolar walls.
    Statistically-significant increases in the incidence of fatty changes
    of the liver were reported at 37.5 and 100/125 ppm in males, when
    compared to controls. Other hepatic changes were noted, with a
    significantly-higher incidence in treated compared to control mice.

    These changes, however, were not considered by the authors of the
    study to be treatment-related. There were no effects observed at
    12.5 ppm. Histopathological examination showed no clear evidence of
    treatment-related neoplastic changes in these mice. The incidence of
    pulmonary tumours in both males (7/24) and females (8/20) in the
    100/125 ppm dose group dying from 79 - 98 weeks was somewhat higher
    than in controls (5/37 in males and 6/39 in females). However, the
    incidences of pulmonary tumours in the animals of the same groups
    surviving to termination were lower than in controls.

         The authors of the study concluded that paraquat was not
    oncogenic to the mouse. Based on the renal lesions, the no-effect
    level of paraquat cation for Alderley Park SPF mice in this study was
    12.5 ppm, equal to 1.4 mg/kg b.w./day in males and 37.5 ppm, equal to
    4.3 mg/kg b.w./day in females.

    Rats

         Groups of 80 male and 80 female Fisher SPF rats were maintained
    on diets containing 0, 7.2, 22, 72, or 217 ppm paraquat cation for 104
    weeks. Eight rats/sex/group were sacrificed after urinalysis at 26,
    52, and 78 weeks and were subjected to haematological examination. All
    surviving animals were sacrificed at 104 weeks and, among these, 10
    rats/sex/group were subjected to haematological and biochemical
    examination. All animals, including those killed on schedule and those
    found moribund and killed during the study, were autopsied and
    subjected to gross necropsy and histopathological examination of
    approximately 30 tissues.

         Mortality was increased in female rats of the 217 ppm group from
    week 66 to week 74 when compared with that of other groups, including
    controls. Both male and female rats at the 217 ppm dietary level
    showed a marked statistically-significant reduction in body-weight
    gain when compared to control groups. Food consumption, efficiency of
    food utilisation, and water consumption were also statistically-
    significantly lower in these rats when compared to control animals.

         Haematological examination showed a statistically-significant
    reduction in total white cell count in male rats of the 217 ppm group,
    when compared to controls, at 26, 52, and 78 weeks, but not at 104
    weeks. This change was not considered by the authors of the study to
    be attributable to the administration of paraquat. Biochemical
    examination indicated a statistically-significant reduction in
    globulin in male rats of the 217 ppm group at 26, 78, and 104 weeks
    when compared to controls. Clinical observations, RBC counts,
    haemoglobin, mean red-cell volume (MCV), mean cell hamoglobin (MCH),
    mean cell haemoglobin concentration (MCHC), platelet counts,
    differential WBC counts, plasma alkaline phosphatase, lactic acid

    dehydrogenase, blood urea nitrogen, glucose, total cholesterol, GOT,
    GPT, total and direct bilirubin, GGPT, calcium, total protein,
    albumin, and urinalysis indicated no significant effects attributable
    to the administration of paraquat at any dose levels.

         Throughout the entire administration period, a statistically-
    significant reduction was found in the absolute weights of various
    organs of male and female rats of the 217 ppm group at interim
    sacrifices. This change was considered by the authors of the study
    to be related to the reduction in body weight observed in these
    animals. Histological examination of the lung at termination showed a
    marked, treatment-related, statistically-significant increase in the
    incidence of proliferation of interalveolar septum cells and of
    hyperplasia of alveolar epithelium in both male and female rats at 217
    ppm and in male rats at 72 ppm, when compared to controls. There was
    a marked, statistically-significant increase in the incidence of
    cataract in male and female rats of the 217 ppm group killed or found
    dead after week 79. This treatment-related change was reported to be
    the same microscopically as that observed in the tissues collected
    from those control rats which had spontaneous, age-related cataracts.
    Male rats of the 217 ppm group also showed a statistically-significant
    increase in the incidence of local atrophy of renal tubules when
    compared to controls. Females of the same dietary group had a
    statistically-significant increase in the overall incidence of
    diffusive fatty changes of the liver and pulmonary fibrosis when
    compared to controls. Kidney and liver lesions were not considered by
    the authors of the study to be attributable to the administration of
    paraquat. A significant increase (details of statistical analysis were
    not available) in the incidence of pulmonary adenoma (7/80) was found
    in female rats of the 217 ppm group when compared to controls (1/80).
    There was no significant increase in the incidence of lung adenoma in
    male rats, but a few of them had lung adenocarcinoma (1 in each of the
    22 and 72 ppm groups, 3 in the 217 ppm group, and none in the
    controls). The authors noted that, although the historical incidence
    of pulmonary adenoma in rats of this strain is reportedly rather low
    (about 2%), 6/80 (7.5%) of the control rats developed pulmonary
    adenoma in a 24-month chronic toxicity study carried out separately in
    their laboratory. Based on these considerations, the authors of the
    study concluded that the incidence of pulmonary adenoma found in the
    present paraquat study in female rats in the 217 ppm group did not
    exceed the background incidence of pulmonary adenoma in rats of this
    strain. On the basis of the lung and eye lesions the no-effect level
    of paraquat cation determined in this study for Fisher SPF rats after
    104-week treatment was 22 ppm, equal to 0.77 mg/kg b.w./day in male
    rats and 72 ppm, equal to 3.12 mg/kg b.w./day in female rats
    (Yoshida et al., 1982).

    FIGURE 1

         Historical control incidence data of neoplasia in F-344 rats in
    the laboratory in which the preceding study was conducted were made
    available and are summarized in Table 3.

    Table 3.  Spontaneous lung tumours observed in F-344 rats at the
              Institute of Environmental Toxicology from 1980 to 19831
                                                                        

                                   No. of tumour-bearing animals (%)2
                                                                      

                                   Males              Females
                                                                        

    Adenoma                        40 (4.2%)          21 (2.2%)
    Adenocarcinoma                  5 (0.5%)           1 (0.1%)
    Bronchial gland adenoma         1 (0.1%)             -

    Total                          46 (4.8%)          22 (2.3%)
                                                                        

    1    From Maita, 1986
    2    These data were taken from 12 studies that included 960 male and
         959 female F-344/DuCrj rats.

         Groups of 60 male and 60 female Fischer 344 rats were maintained
    on diets containing paraquat cation at 0 (2 groups), 25, 75, or
    150 ppm for at least 113 weeks (males) or 122 weeks (females). Further
    groups of 10 rats/sex/group received the same diets for 1 year. All
    animals were studied for mortality, food and water consumption, and
    body weight, and were subjected to periodical ophthalmoscopic and
    haematological examinations throughout the study.

         The distribution of mortality was unaffected by treatment. There
    was approximately 50% mortality in all groups at the end of the study.
    At 150 ppm, statistically-significant reductions in body-weight gain,
    food consumption, and efficiency of food utilisation in both sexes
    were observed. There was a statistically-significant depression of
    body-weight gain in the first year of the study in males receiving
    75 ppm paraquat. Water consumption was not significantly affected at
    any dietary level tested. Paraquat accelerated, in a dosage-dependent
    manner, the onset and progression of cataract changes, ranging from
    minor opacity to total cataract in both males and females.
    Treatment-related ocular lesions were first seen at 52 weeks.
    Thereafter, ophthalmoscopy revealed a statistically-significant
    dosage-related increase in the incidence, progression, and severity of
    lenticular cataract in the 150 ppm group and, toward the end of the
    study (103 weeks), in the 75 ppm group. There was evidence of
    paraquat-dependent ocular effects in all treatment groups of both
    sexes at termination. A statistically-significant higher incidence of
    secondary eye lesions was found at termination in females receiving 75

    or 150 ppm paraquat when compared to controls. Haematological
    investigation (RBC counts, total and differential leucocyte counts,
    haemoglobin, haematocrit, mean cell volume, mean cell haemoglobin
    concentration, platelet and reticulocyte counts, and prothrombin and
    partial thromboplastin times) and blood biochemistry (urea, glucose,
    ALT, and AST) indicated no significant effects attributable to
    paraquat administration. Urinalysis did not reveal any treatment-
    related changes. Reductions in liver and testicular weights were noted
    at termination in the 150 ppm dietary group.

         Macroscopic examination at necropsy revealed a treatment-related
    increase in the incidence of focal subpleural changes in animals
    killed at termination in all dietary groups. This effect was most
    marked in females receiving 75 ppm and in both sexes receiving 150 ppm
    paraquat. Microscopic examination of lung tissues indicated that
    treatment with paraquat at 150 ppm, in both sexes, and possibly at
    75 ppm in males, was associated with proliferative lesions of the
    alveolar epithelium. These lesions were not easily classified into
    non-neoplastic or neoplastic, nor into adenoma or carcinoma. This
    study provided strong evidence for the induction by paraquat of a
    proliferative lesion of the alveolar epithelium and some controversial
    evidence for the induction of lung adenomas in female Fischer 344
    rats. There was no treatment-related increase in the incidence of lung
    adenocarcinoma at any dose level in either sex. At 25 ppm, significant
    increases in the incidence of proliferative lung lesions, compared to
    the controls, were not observed. Microscopic examination of the eyes
    confirmed a dose-related effect of paraquat on the onset and
    progression of cataract lesions normally present in both male and
    female F-344 rats. Slight dilation of the fourth ventricle of the
    brain was evident in females receiving 150 or 75 ppm paraquat, but not
    in males at these dosages or in either sex at 25 ppm. A statistically-
    significant increase in the incidence of apparent degeneration of
    occasional/several sciatic nerve fibers was noted in decedent males
    receiving 75 or 150 ppm paraquat. Both hydrocephalus and nervous
    tissue changes were considered by the authors of the study possibly
    to be associated with paraquat treatment. Pathology summaries
    indicate that atrophy of the testes was recorded in the high-dietary
    group (5/33) but not in controls at termination, and moderate lymphoid
    hyperplasia was observed in the respiratory epithelium of males
    receiving 75 and 150 ppm paraquat and dying between 52 weeks and
    termination.

         The authors of the study concluded that "a wide range of tumour
    types was observed in treated and control animals, and there was no
    evidence that treatment with paraquat resulted in a marked change in
    the group distribution of any of these tumours". A no-effect level for
    paraquat was not found in this study due to the higher incidence of

    cataract observed in animals of the 25 ppm group when compared to
    controls. Paraquat accelerated, in a dosage-dependent manner, the
    onset and progression of cataract change in F-334 rats. The authors
    considered 25 ppm to be near the no-effect level for this change at
    the end of the study (Ashby et al., 1983; Busey, 1986; Ishmael &
    Godley, 1983).

         Data on the historical incidence of lung neoplastic lesions in
    F-344 rats from 7 studies performed in the laboratory in which the
    preceding study was conducted were made available and are summarised
    in Table 4.

    Table 4.  Spontaneous lung tumours observed in F-344 rats at Life
              Science Research1
                                                                        

                                     No. of tumour-bearing animals (%)2
                                                                        

                                     Males             Females
                                                                        

    Adenoma                          6/357 (1.7%)      4/363 (1.1%)
    Carcinoma                        3/357 (0.8%)      0/363 (0%)

        Total pulmonary tumours      9/357 (2.5%)      4/363 (1.1%)
                                                                        

    1    From Ashby et al., 1983
    2    The range (% incidence) of adenoma was 0 - 4.4% in males and
         0 - 4.0% in females; the range of carcinoma was 0 - 4.0% in
         males.

    Special studies on embryotoxicity and teratogenicity

    Mice

         The teratogenicity and fetal toxicity of paraquat were examined
    after oral (20 mg/kg b.w./day) or i.p. (1.67 or 3.35 mg/kg b.w./day)
    administration of paraquat to pregnant mice during the period of
    organogenesis (days 8 - 16 of gestation). The oral dose (which was
    equal to 1/10 of the oral LD50/day) did not produce significant
    maternal toxicity, but at the higher of the 2 i.p. doses (which was
    equal to 1/10 of the i.p. LD50/day) a significant maternal mortality
    (5/7) and a statistically-significant increase of resorption rate,
    when compared to controls, were observed. Paraquat did not
    significantly increase the incidence of gross, soft-tissue, or
    skeletal abnormalities. At the lower i.p. dose and after oral
    administration of paraquat, there was a slight but non-significant

    increase in the number of fetuses with absent or non-ossified
    sternebrae. However, a significant difference was observed in the
    incidence of abnormal sternebrae between the 2 control groups (6.9 
    3.2% in the i.p. control group and 13.2  5.8% in the oral control
    group). The authors of the study concluded that the potential for
    paraquat as a teratogen appeared to be minimal (Bus et al., 1975b).

         The same authors examined the effects of paraquat dichloride on
    the development of Swiss-Webster mice when administered in the
    drinking water at concentrations of 0, 50, or 100 ppm. Paraquat was
    given to pregnant mice from day 8 of gestation and administration was
    continued to the newborns until 42 days after birth, when both the
    control and paraquat-treated mice were sacrificed and subjected to
    histopathological examination of the lungs, liver, and kidneys. A
    significant increase in postnatal mortality in mice receiving 100 ppm
    paraquat was observed. Histopathological examination of the lungs of
    these mice showed extensive alveolar consolidation and collapse, and
    areas of thickening of intra-alveolar septa. No significant
    pathological changes were seen in the lungs of the 50 ppm or control
    mice, nor in the liver or kidneys of mice of any treatment group.
    There were no treatment-related effects on the number of live fetuses
    nor on postnatal growth rate at either treatment level (Bus & Gibson,
    1975).

         Four groups of at least 20 pregnant SPF Alderley Park mice were
    given orally 0, 1, 5, or 10 mg/kg b.w./day of paraquat cation during
    days 6 to 15 of pregnancy, inclusive. On day 18 the animals were
    killed, their uteri were examined, and the fetuses were removed,
    weighed, sexed, and observed for gross abnormalities. There was some
    evidence of maternal toxicity in the form of slight reductions in
    body-weight gain at 5 and 10 mg/kg b.w./day, although only that of the
    middle-dose group was statistically significant. There were no
    clinical signs nor pathological changes in maternal animals
    attributable to paraquat administration. Water and food consumption
    were not quantified in this study. Numbers of implantations, viable
    fetuses and resorptions, sex ratios, and fetal and litter weights
    showed no significant differences between treated and control groups.
    There were no increases in fetal external or soft-tissue abnormalities
    which could be associated with paraquat treatment. There were
    occasional statistically-significant differences in ossification of
    individual bones between treated and control groups, but no
    dose-related trend indicating either retardation of ossification or
    increased abnormalities was observed. The authors of the study
    concluded that paraquat was not teratogenic and had no significant
    influence on embryonic or fetal development of the mouse at levels up
    to and including 10 mg/kg b.w./day (Hodge et al., 1978a).

    Rats

         The teratogenic effects of paraquat were studied in 4 groups of
    at least 20 pregnant SPF Alderley Park rats after oral administration
    of 0, 1, 5, or 10 mg/kg b.w./day of paraquat cation during days 6 to
    15 of pregnancy, inclusive. On day 21 the animals were killed. There
    were clear clinical signs of maternal toxicity at 5 and 10 mg/kg
    b.w./day. Apparently, 6 rats at the highest-dose level and 2 at the
    middle-dose level died or became moribund during the experiment.
    Histological changes found in the lungs and kidneys of the animals
    receiving 10 mg/kg b.w./day paraquat which died or became moribund
    were those known to be associated with oral paraquat poisoning. Slight
    fetotoxicity was seen at 5 and 10 mg/kg b.w./day, as shown by a
    statistically-significant reduction in fetal weight and retardation in
    ossification, and by a decrease in the number of viable fetuses per
    number of implants. According to the authors of the study, these
    effects were probably associated with maternal toxicity. There were no
    effects on embryonic or fetal survival and increases in fetal
    abnormalities were not observed. The authors of the study concluded
    that paraquat was not teratogenic when administered orally to rats,
    even when there was clear evidence of maternal toxicity. However, it
    did cause slight fetotoxicity at the 2 highest-dose levels (Hodge
    et al., 1978b).

    Special studies on eye irritation

         The effects of paraquat on the eye have been reviewed by WHO
    (1984). The instillation of diluted paraquat (up to 500 g/litre) in
    rabbits' eyes induced inflammation within 24 hours, and this continued
    for 96 hours (Clark et al., 1966). In another experiment, 62.5, 125,
    250, 500, or 1000 g/litre of paraquat was introduced into the eyes of
    rabbits. Concentrations of 62.5 and 125 g/litre caused severe
    conjunctival reactions; higher levels (250 - 500 g/litre) provoked
    ititis and pannus, while at the 500 g/litre concentration corneal
    opacification, iritis, and conjunctivitis occurred. All rabbits
    receiving 0.2 ml of paraquat at 1000 g/litre in 1 eye or 0.2 ml of
    500 g/litre paraquat in both eyes died within 6 days of application
    (Sinow & Wei, 1973).

    Special studies on mutagenicity

         In a review of published mutagenicity data (WHO, 1984) it was
    noted that paraquat had been found to have minimal to no genotoxic
    activity when evaluated in a variety of in vitro and in vivo test
    systems. In in vitro studies producing weakly positive results,
    paraquat genotoxicity was accompanied by high cytotoxicity (Moody &
    Hassan, 1982; Parry, 1973 & 1977; Tweats, 1975; Benigni et al.,
    1979; Bignami & Grebelli, 1979). Moody and Hassan (1982) have shown
    that the mutagenicity of paraquat in bacterial test systems

    (Salmonella typhimurium TA98 and TA100) was mediated by the
    formation of superoxide. More recently, paraquat was found to induce
    superoxide dismutase, chromosomal aberrations, and sister-chromatid
    exchange in Chinese hamster fibroblasts, suggesting that superoxide
    production is responsible for the chromosomal damage (Nicotera
    et al., 1985). Other investigators (Anderson et al., 1972; Levin
    et al., 1982) have not found mutagenic activity in bacterial test
    systems. Furthermore, paraquat was not mutagenic when evaluated in
    human leukocytes nor in in vivo cytogenic tests on mouse bone marrow
    (Selypes & Paldy, 1978) or in dominant lethal tests on mice
    (Pasi et al., 1974; Anderson et al., 1976).

         A set of recently completed studies indicate that in most tests
    paraquat was not mutagenic (see Table 5). Clastogenic potential has
    been shown in vitro at very high concentration levels which were
    themselves cytotoxic. Paraquat was not found to be mutagenic
    in vivo.

    Special studies on reproduction

    Rats

         In a 3-generation study, groups of 15 male and 30 female (F0
    parents) weanling Alderley Park SPF rats were fed diets containing
    0, 25, 75, or 150 ppm paraquat cation. After 12 weeks, animals were
    mated to produce the first (F1a) litter and subsequently re-mated to
    produce a second (F1b) litter. The breeding programme was repeated
    twice with F1 parents selected from the F1b offspring and F2
    parents selected from the F2b offspring. Test diets were fed
    continuously throughout the study.

         There were no adverse effects on parental body weights or food
    consumption, and no treatment-related changes were found in the
    reproductive performance (male and female fertility, live-born and
    survival indexes, and litter size) or in the reproductive tract of
    parents or offspring. Development of the reproductive tract in all
    treated offspring was substantially comparable to that in controls.
    The mild atrophy of seminal tubules found in a few of the treated
    males of the F2b offspring at termination was considered by the
    authors of the study to have no toxicological significance. Lung
    changes due to paraquat administration occurred mainly in females
    receiving 150 ppm paraquat. One pulmonary adenoma was found in 1
    female receiving 150 ppm paraquat. Death resulting from severe, acute,
    or sub-acute lung damage was confined to females with litters of
    weaning age, and to 3 F0 females which died during the first 2 weeks
    of the study. There were dose-related increases in the incidence and

        Table 5.  Mutagenicity assays on paraquat
                                                                                                                           

    Test system        Test object          Concentration         Purity    Results               Reference
                                            used                  (%)
                                                                                                                           

    Ames test1         S. typhimurium       0.12, 0.6, 2.9,       99        Negative              Anderson, 1977
                       TA98                 14, 72, 361,
                       TA100                & 1807 g/plate
                       TA1535               (dissolved in
                       TA1538               H2O)

    Ames test1         S. typhimurium       0.4, 0.7, 3.6,        100       Negative, growth      Shirasu et al., 1978
                       TA98                 7, 36, 72, &                    inhibition at 72
                       TA100                360 g/plate                    at 72 & 360
                       TA1535               (dissolved in                   g/plate2
                       TA1538               H2O)

    Host-mediated      S. typhimurium       3.6 & 14 mg/kg        100       negative2             Shirasu et al., 1978
      assay            G 46 (host: male     (2 equal doses
                       ICR mice)            orally)

    Rec-assay          B. subtilis          14 - 361              100       negative2             Shirasu et al., 1978
                                            g/disk

    Mouse              L 5178 Y             23, 45, 90, 180,      99        ?                     Clay & Thomas, 1985
      lymphoma         mouse                & 361 g/ml
      test1            lymphoma
                       cells
                                                                                                                           

    Table 5.  (cont'd).
                                                                                                                           

    Test system        Test object          Concentration         Purity    Results               Reference
                                            used                  (%)
                                                                                                                           

    Clastogenic        Human                90, 903, & 1807       99.6      positive at 2         Sheldon et al., 1985a
      potential        lymphocytes          g/ml                           highest levels
      test1            in vitro                                             (also cytotoxic)

    Mouse              Male & female        51.7 & 82.8           99.4      negative              Sheldon et al., 1985b
      micronucleus     C 57/BL/6J/          mg/kg (single
      test             Alpk mice            dose orally)

    In vitro           Chinese              0.9, 1.8, 9, 18,      99.4      positive (reduced     Howard et al., 1985
      sister           hamster lung         90 & 177 g/ml                  with metabolic
      chromatid        fibroblasts                                          activation)
      exchange1

    Unscheduled        Hepatocyte           1 nM - 10 mM          99.6      negative              Trueman et al., 1985
      DNA              cultures             (0.19 ng/ml -
      synthesis        from male            1.86 mg/ml)
                       Alderley Park
                       albino rats
                                                                                                                           
    1    Both with and without metabolic activation
    2    Positive control compounds gave positive responses
        severity of focal alveolar histiocytosis in the lungs of male and
    female parents receiving 75 and 150 ppm paraquat. A mild perivascular
    inflammation was observed in the lungs of F1b pups receiving 150 ppm
    paraquat. No changes due to paraquat were seen in animals receiving
    25 ppm paraquat. The authors concluded that paraquat had no effect on
    reproductive performance or development of the reproductive organs of
    Alderley Park rats when administered at dietary levels up to 150 ppm
    over 3 generations (Lindsay et al., 1982).

         Groups of 12 male and 24 female rats were fed diets containing
    0, 30, or 100 ppm paraquat ion from 35 days of age. Three generations
    bred from these animals received the same diets during the whole
    period under test. Two litters were bred from each generation, and the
    effects on growth, food intake, fertility, fecundity, neonatal
    morbidity, and mortality were noted. No evidence was seen of damage to
    germ-cell production or of structural or functional damage in the
    animals. In this study, pregnant and young animals did not appear to
    be more vulnerable to paraquat than did adults. However, the incidence
    of renal hydropic degeneration in 3 - 4 week-old offspring was
    slightly increased in the 100 ppm group (Fletcher et al., 1972).

         In a 3-generation study with 2 litters per generation, groups of
    30 male and 30 female Sprague-Dawley rats (F0 parental generation)
    were given diets containing 0, 72, 145, or 290 ppm paraquat cation
    from 5 weeks of age (13 weeks prior to mating to obtain the first
    litter, F1a) until the end of the second lactation (lactation of
    F1b litters). In the second generation (F1b), 30 males and 30
    females per group were treated from immediately after weaning until
    the end of the second lactation (lactation of F2b litters). In the
    third generation (F2b), the same number of rats were treated
    immediately after weaning for at least 13 weeks. In a teratology study
    sub-group 5 pregnant females of the parental generation (F0) and 10
    pregnant females of the second generation (F1b) were killed on day
    20 of pregnancy and examined macroscopically. Fetuses were examined
    for number, sex, weight, external and internal abnormalities, and
    progress of ossification. Another subgroup was used as a postnatal
    investigation group, where natural parturition of pregnant females was
    permitted to occur. In this group the duration of gestation,
    parturition conditions, the number of live and still-born pups, sex,
    and external abnormalities were recorded. Live pups were investigated
    until weaning. Five male and 5 female rats per group of the first
    (F0) and second (F1b) generations and 10 male and 10 female rats
    per group of the F2b litters were subjected to histopathological
    examination of approximately 25 tissues.

         In the parental generation there were significant increases in
    mortality and clinical signs attributable to paraquat (asthmatoid
    wheezing) in several rats of the 290 ppm group of each generation from
    the early stage of the dosing period. There were 29 treatment-related

    deaths/moribund animals, all from the 290 ppm dietary level (5 among
    F1b animals and 24 among F2b animals), but only 4 deaths among
    control rats (1 among F0 female rats and 2 among F1b female rats
    at parturition and 1 among F2b rats during the dosing period).
    Histopathological examination of these dead or moribund F2b rats
    showed, in some cases, hyperplasia of the alveolar epithelium and, in
    most cases, diffuse thickening and fibrosis of the alveolar walls.
    There was a decrease in body-weight gain in both male and female rats
    of the F0 and F2b generations at 290 ppm during the early stage of
    the dosing period. Body-weight gain was also reduced in F1b females
    at 290 ppm during the gestation and lactation periods. Reductions in
    food consumption and efficiency of food utilisation were seen in F0
    and F2b females. There was a significant decrease in water
    consumption in F0 and F1b females during lactation. No effect of
    the compound was observed on the reproductive performance of parental
    rats. Macroscopic examination revealed an apparently higher incidence
    of white spots in the lungs of both male and female rats of the
    290 ppm group in all 3 generations. Treatment-related changes of the
    lung were confirmed by histopathology in rats of each generation.
    These lesions were dose-dependent and included zonal thickening and
    fibrosis of the alveolar walls, zonal atelectasis, and accumulation of
    foam cells. There were no treatment-related changes in organ weights.
    A treatment-related statistically-significant reduction in the
    lactation index was found in F1a and F1b litters of the 290 ppm
    group. A statistically-significant reduction in the lactation index
    was also observed in F2a litters of the 290 ppm group, but it was
    not clear to the authors of the report whether this change was
    attributable to treatment. There were no statistically-significant
    differences in lactation index between other treatment groups and
    controls nor in the number of still-births and live births, sex
    ratios, or viability indexes in any of the treated groups of both
    generations, when compared to controls. The prolonged duration of
    gestation in F0 rats of the parental group at 145 and 290 ppm was
    considered by the authors of the report to be accidental. The
    teratology phase showed a statistically-significant delay in
    ossification in F1b fetuses from F0 parents treated with 290 ppm
    paraquat and in F2b fetuses from F1b parents of all treated
    groups. It was not clear to the authors of the report whether the
    retarded growth was due to the treatment. There was a treatment-
    related statistically-significant higher incidence of female
    pups with retarded opening of the vagina in both F1b and F2b
    litters at 290 ppm. There was a statistically-significant decrease in
    body weight in male, but not in female, fetuses at 72 and 290 ppm.
    There were no statistically-significant differences between fetuses
    from treated rats and control fetuses in the number of corpora lutea
    or implantations, percentage of implantations, number of dead or live
    fetuses, sex ratios, or placental weights. No external or internal
    malformations were detected in fetuses of any treatment group.

         The authors of the report concluded that there was no evidence
    suggesting that paraquat was teratogenic and that the only treatment-
    related change which was enhanced by treatment of successive
    generations of Sprague-Dawley rats with paraquat was "an increase in
    death" at 290 ppm. A no-effect level for paraquat was not found in
    this study due to delayed ossification in F2b fetuses in all treated
    groups (Suzuki et al., 1983).

    Rabbits

         Forty rabbits received paraquat i.p. at total dosages of 2 to
    100 mg/kg b.w. in 1 to 5 separate administrations. Multinuclear giant
    cells were found in testicular tubules of 7/20 rabbits receiving
    50 mg/kg b.w. or more paraquat (Butler & Kleinerman, 1971). However,
    it has been reported that, when paraquat was orally administered at
    4 mg/kg b.w. to male rats for 60 days and testes were examined, there
    were no significant deviations in the spermatozoa count or motility,
    nor were there any biochemical changes in the several enzymes of
    testes homogenates. The histoenzyme activity of lactate dehydrogenase,
    succinate dehydrogenase, DPN-diaphorase, alkaline phosphatase, and
    acid phosphatase in the treated animals did not differ from those of
    the controls, nor did quantitative and qualitative histological
    examination of the testicular tubule cells reveal any abnormalities
    (WHO, 1984).

    Special studies on skin irritation

         The effects of paraquat on the skin have been reviewed by WHO
    (1984). Paraquat can provoke local irritation of the skin and eyes.
    Clark et al. (1966) found skin irritation in rabbits only when
    paraquat was applied beneath occlusive dressings in aqueous solutions
    (total doses 1.56, 5.0, and 6.25 mg ion/kg b.w.). In mice and rats,
    the application of solutions of 5 - 20g paraquat/litre in single and
    21-day repeated dermal toxicity tests provoked dose-related toxic
    dermatitis with erythema, oedema, desquamation, and necrosis (Bainova,
    1969). Doses from 1.56 to 50 mg/kg, in repeated 20-day studies using
    the occlusive technique (McElligott, 1972), resulted in local erythema
    and scab formation. The histological changes consisted of
    parakeratosis and occasional intra-epidermal pustules. A delayed
    skin-irritant action of the herbicide was reported by Fodri et al.
    (1977) in guinea pig studies.

    Acute toxicity

         The LD50 and LC50 values for paraquat in various species are
    given in Table 6.

        Table 6.  Acute toxicity of paraquat in various species
                                                                                              

                                            LD50           LC50
    Species       Route          Sex        (mg/kg b.w.)   (mg/l)    Reference
                                                                                              

    Mouse         oral           M          260            --        Shirasu & Takahashi, 1977
                                 F          210            --

                  i.p.           M & F      29-30          --        Shirasu & Takahashi, 1977
                                                                     Bus et al., 1975a

                  i.v.           --         50             --        Ecker et al., 1975

                  s.c.           M          30             --        Shirasu & Takahashi, 1977
                                 F          27             --

                  dermal         --         62             --        Bainova, 1971

    Rat           oral           M          161            --        Shirasu & Takahashi, 1977
                                 F          187            --

                                 M          110            --        Kimbrough & Gaines, 1970
                                 F          100            --

                                 --         126            --        Murray & Gibson, 1972

                                 --         200            --        Howe & Wright, 1965

                  i.p.           M          18             --        Shirasu & Takahashi, 1977
                                 F          19             --

                                 F          19             --        Clark et al., 1966

                  s.c.           M          19             --        Shirasu & Takahashi, 1977
                                 F          23             --

                                 --         22             --        Makovskii, 1972

                  dermal         M          90             --        Kimbrough & Gaines, 1970
                                 F          80             --

                                 --         350            --        Makovskii, 1972
                                                                                              

    Table 6.  (cont'd).
                                                                                              
                                            LD50           LC50
    Species       Route          Sex        (mg/kg b.w.)   (mg/l)    Reference
                                                                                              

                  inhalation     M & F      --             10        Bainova & Vulcheva, 1972

                                 --         --             1         Gage, 1968

                                 --         --             6         Makovskii, 1972

    Guinea        oral           M          30             --        Clark et al., 1966
    pig
                                 --         40-80          --        Howe & Wright, 1965

                                 --         22             --        Murray & Gibson, 1972

                                 --         42             --        Makovskii, 1972

                  i.p.           F          3              --        Clark et al., 1966

                  s.c.           --         5              --        Makovskii, 1972

                  dermal         --         319            --        Makovskii, 1972

                  inhalation     --         --             4         Makovskii, 1972

    Cat           oral           F          35             --        Clark et al., 1966

                                 --         40-50          --        Howe & Wright, 1965

    Hen           oral           --         300-380        --        Howe & Wright, 1965

                                 --         262            --        Clark et al., 1966

    Turkey        oral           --         250-280        --        Smalley, 1973

                  i.p.           --         100            --        Smalley, 1973

                  i.v.           --         20             --        Smalley, 1973

                  dermal         --         375            --        Smalley, 1973

    Monkey        oral           --         50             --        Murray & Gibson, 1972

    Sheep         oral           --         50-75          --        Howe & Wright, 1965

    Cow           oral           --         50-75          --        Howe & Wright, 1965
                                                                                              
    
         Following a single high dose of paraquat to animals, the earliest
    ultrastructural changes were observed in the Type I alveolar
    epithelial cells, approximately 4 - 6 hours after treatment, and were
    usually characterised by cellular and mitochondrial swelling,
    increased numbers of mitochondria, and the appearance of dark granules
    in the cytoplasm. When a high dose was given (equal to approximately
    the LD50 or greater), the lesions in the Type I cells often
    progressed to the point of complete cellular disintegration, leaving
    areas of exposed basement membrane (Kimbrough & Gaines, 1970;
    Smith et al., 1973; Smith & Heath, 1974; Vijeyaratnam & Corrin,
    1971; Klika et al., 1980). In contrast to the effects on Type I
    pneumocytes, however, the capillary endothelial cells were remarkably
    resistant to the toxic effects of paraquat (Sykes et al., 1977).

         Ultrastructural lesions in the alveolar Type II pneumocytes were
    also observed shortly after single-dose paraquat exposure, although,
    generally, these lesions were not apparent until after the first
    lesions were seen in the Type I cells (Kimbrough & Gaines, 1970).
    Swollen mitochondria and damage to the lamellar bodies usually
    occurred between 8 and 24 hours after a high dose of paraquat
    (Robertson, 1973; Robertson et al., 1976). Progressive deterioration
    of the Type II cells continued, resulting in completely denuded
    alveolar basement membranes and debris-filled alveolar spaces
    (Vijeyaratnam & Corrin, 1971). Infiltration and proliferation of
    fibroblasts may produce fibrosis that obliterated the alveolar
    structure (Smith & Heath, 1974).

         Vijeyaratnam & Corrin (1971) observed that less-severely affected
    parts of the lung appeared to undergo epithelial regeneration 7 - 14
    days after a single dose of paraquat. Electron microscopic examination
    revealed the alveoli to be lined with cuboidal epithelial cells that
    closely resembled Type II pneumocytes, except for a general lack of
    lamellar bodies. Similar phenomena have also been noted by other
    investigators who administered paraquat in the diet (Kimbrough &
    Linder, 1973) or as repetitive i.p. administrations (Smith et al.,
    1974). Thus, in animals where the paraquat dose was sufficient to kill
    only the Type I pneumocytes, the surviving Type II cells repaired the
    damaged epithelium by proliferating and subsequently differentiating
    into Type I epithelial cells. Inhaled paraquat in aerosol produced
    initial necrosis of the epithelia and Type II pbeumocyte hyperplasia,
    fibroblast proliferation, and increased synthesis of collagen in mice
    (Popenoe, 1979).

         The pathogenesis of the paraquat lung lesion has been well
    characterised, and has been reviewed by Smith & Heath (1976). The
    acute pulmonary toxicity of paraquat in animals has been described as
    occuring in 2 phases. In the initial "destructive" phase, alveolar
    epithelial cells were extensively damaged and their subsequent
    disintegration often resulted in a completely denuded alveolar

    basement membrane. Pulmonary oedema was also a characteristic of the
    destructive phase, and was frequently of sufficient severity to result
    in the death of the animals. Animals surviving the initial destructive
    phase, which occurred in the first 1 - 4 days after acute paraquat
    overexposure, progressed to what has been termed the "proliferative"
    phase. In this phase, the lung was infiltrated with prolifroblastic
    cells that rapidly differentiated into fibroblasts which, in some
    cases, progressed to fibrosis. The histopathological outcome of the
    second phase may be influenced by the treatment regimen, however.
    Administration of repeated low doses of paraquat, which less-severely
    damaged the alveolar epithelial cells, was also able to induce a
    hyperplasia of the Type II cells. This response may represent an
    attempt by the lung to repair the damaged epithelium (WHO, 1984).

         When rabbits were injected i.p. with total doses of paraquat from
    2 - 100 mg/kg b.w., thymic atrophy was observed, but most lungs showed
    only occasional and small histological deviations that were poorly
    correlated with the clinical signs of paraquat intoxication. These
    results confirmed the resistance of the rabbit to paraquat-induced
    lung lesions (Butler & Kleinerman, 1971).

         According to Murray & Gibson (1972) and Hundsdorfer & Rose
    (1980), guinea pigs treated with paraquat either orally or s.c. did
    not develop the same type of progressive pulmonary fibrosis as
    paraquat-intoxicated rats. In hamsters, a single administration of
    paraquat did not induce lung damage, but prolonged exposure resulted
    in lung fibrosis (Butler, 1975).

         In conclusion, from lung toxicity studies, a characteristic
    dose-related pulmonary fibrosis can be induced in rats, mice, dogs,
    and monkeys, but not in rabbits, guinea pigs, or hamsters.

         In paraquat toxicity, kidney damage often precedes signs of
    respiratory distress (Clark et al., 1966; Butler & Kleinerman, 1971;
    Murray & Gibson, 1972). Paraquat is excreted primarily via the urine
    and the concentrations of the herbicide in the kidneys are relatively
    high (see Table 1). Gross pathological and histological examination of
    paraquat-poisoned rats, guinea pigs, rabbits, and dogs revealed
    vacuolation of the convoluted renal tubules and proximal tubular
    necrosis (Murray & Gibson, 1972). The nephrotoxicity caused by
    paraquat is pronounced and appears to be restricted to the proximal
    nephron (Ecker et al., 1975; Gibson & Cagen, 1977; Lock & Ishmael,
    1979; Purser & Rose, 1979). The degeneration of the proximal tubular
    cells has also been confirmed by electron-optical studies (Fowler &
    Brooks, 1971; Marek et al., 1981).

         In contrast with lung and kidney damage, liver damage in
    experimental animals has not been severe and serum enzyme activities
    (SGOT, SGPT, LAP) only increased when large amounts of paraquat were
    given (Girl et al., 1979). Recently, electron microscopic
    examination of the liver of paraquat-treated rats showed early,
    localised changes (degranualtion of the RER, proliferation of the SER,
    and mitochondrial swelling) in hepatocytes within 2 layers around the
    central vein (Matsumori et al., 1984).

    Short-term studies

    Mice

         Groups of 20 male and 20 female ICR-CRJ SPF mice were maintained
    on diets containing 0, 7.2, 22, 72, or 217 ppm paraquat cation for 13
    weeks. At the 217 ppm dietary level 2 female mice died from pulmonary
    damage. Both males and females in this group showed significantly
    reduced body-weight gain and a slight reduction in efficiency of food
    utilisation. Food intake and water intake were not affected. No
    abnormalities considered related to paraquat treatment were seen
    during haematological, blood biochemistry, or urine analysis. A few
    statistically-significant changes in absolute and relative organ
    weights were seen at termination, mainly in males and females of the
    217 ppm group. However, only an increase in lung weight of females in
    the 217 ppm group was reported by the authors of the study to coincide
    with histopathological changes of the same organ, namely eosinophilic
    swelling of the alveolar epithelium walls which was observed in both
    sexes at this dietary level. The no-effect level in this study with
    respect to pulmonary damage and other parameters was 72 ppm, equal to
    12 (males) and 14 (females) mg/kg b.w./day (Malta et al., 1980a).

    Rats

         Groups of 20 male and 20 female Fischer 344 rats were maintained
    on diets containing 0, 7.2, 22, 72, or 217 ppm paraquat cation for 13
    weeks. During the study there were no deaths. Body-weight gain was
    reduced markedly in both sexes at the 217 ppm dietary level, at which
    level food consumption, efficiency of food utilization, and water
    consumption were also reduced. Histopathological examination revealed
    swelling of alveolar epithelium cells in males and increased deposits
    of brown pigment in the spleen of females at the 217 ppm dietary
    inclusing level. No abnormalities considered attributable to paraquat
    administration were observed during heamatological, blood
    biochemistry, urine, organ weight, or gross necropsy investigations.
    The no-effect level in this study with respect to lung lesions and
    other parameters was 72 ppm, equal to 6.5 (males) and 7.1 (females)
    mg/kg b.w./day (Malta et al., 1980b).

    Dogs

         Groups of beagle dogs, 3 males and 3 females per group, received
    diets containing 0, 7, 20, 60, or 120 ppm paraquat cation for 13
    weeks. Two males and 2 females in the 120 ppm group showed marked
    paraquat toxicity and were killed in extremis between days 16 and
    23, having shown marked dyspnoea and body-weight loss. Both surviving
    dogs at 120 ppm also showed body-weight loss. A slight overall
    reduction in body-weight gain among the females of the other treatment
    groups was not considered by the authors of the study to be
    treatment-related. Lung weights were increased in all animals in the
    120 ppm group and in 2 animals from the 60 ppm group. All other organ
    weights were in the normal range. Distinct gross and histological
    treatment-related lung lesions were seen in all dogs in the 60 and
    120 ppm groups. Minor renal lesions (swelling of the cortical tubules)
    were also found histologically in a few of these animals. There were
    no discernible gross or histological treatment-related pulmonary
    lesions in the dogs of the 7 or 20 ppm groups. The focal pulmonary
    lesions in these animals were of a type and incidence similar to those
    found in the controls. Microscopic examination of 34 other tissues
    from each animal showed no treatment-related changes. There were no
    treatment-related effects on food intake except for 1 surviving
    high-dose female which showed a loss of appetite from week 8 onward.
    There were no distinct treatment-related changes in any of the
    haematological (RBC counts, mean cell volume, haemoglobin, total and
    differential white cell counts, platelets, prothrombin, and partial
    thromboplastin time), biochemical (glucose, cholesterol, blood urea
    nitrogen, bilirubin, total and partial protein, GOT, GPT, ALP, and
    CPK), or urinary parameters examined. Slight haemoconcentration was
    seen in 1 high-dose dog at termination. The no-effect level in this
    study after administration of paraquat for 13 weeks to beagle dogs, on
    the basis of lung and kidney lesions, was considered to be 20 ppm,
    equal to 0.57 mg/kg b.w./day (Sheppard, 1981).

    Long-term studies

         See also under "Special studies on carcinogenicity".

    Mice

         Groups of 60 male and 60 female JCL:ICR mice were maintained on
    diets containing 0, 1.4, 7.2, 22, or 72 ppm paraquat cation for 104
    weeks and then killed and examined. Further groups of 10 males and 10
    females receiving the same diets were sacrificed after 26 weeks or 52
    weeks of treatment. Animals in each group, including the control
    groups, showed approximately 60 - 70% mortality at the end of the
    study. Haematological changes, attributed by the authors of the study
    to the administration of paraquat, included reduced erythrocytes,

    hematocrit, and haemoglobin at the 72 ppm level in both sexes. Total
    serum protein was decreased and blood glucose increased at the 72 ppm
    dietary level in both sexes. Various rumours, mostly malignant, were
    observed in all groups in this study, the main types being lung
    adenocarcinoma in males and leukaemia in females. However, no tumour
    type showed a higher incidence in the treated groups than in controls
    and no correlations between tumour incidence and concentration of the
    test substance were observed. No effects attributable to paraquat were
    observed in absolute or relative organ weights, urinalysis,
    body-weight gain, food consumption, efficiency of food utilization, or
    water intake. Based on the haematological and blood biochemistry
    changes observed, the no-effect level for paraquat after 104 weeks of
    administration to JCL:ICR mice in this study was 22 ppm (as paraquat
    cation), equal to 2.8 mg/kg b.w./day (Toyoshima et al., 1982a).

    Rats

         Groups of 50 male and 50 female JCL:Wistar rats were maintained
    on diets containing 0, 4.3, 22, 72, or 217 ppm paraquat cation for 104
    weeks and then killed and examined. Further groups of 6 males and 6
    females receiving the same diets were sacrificed after 26 or 52 weeks
    of treatment. There was 38 - 66% mortality in all groups at the end of
    the study. The distribution of mortality and of abnormalities were not
    significantly affected by treatment. Females in the 217 ppm group
    showed a transient tendency to lower body-weight gain, compared to
    controls, at weeks 34, 42 - 48, and 54. Food consumption, efficiency
    of food utilization, and water consumption were not affected by
    paraquat administration. Haematological changes attributed by the
    authors of the study to paraquat administration at the 217 ppm level
    included reduced erythrocytes and haemoglobin in both sexes and
    decreased haematocrits and increased reticulocytes in males after 26
    weeks. Total serum protein was slightly but constantly decreased at
    the 217 ppm level in both sexes.

         During histopathological examination of approximately 20 tissues,
    various rumours were observed in this study in all groups, the main
    types being benign pituitary tumours in males and benign mammary
    rumours in females. However, none of the tumours were present at a
    significantly-higher incidence in the treated groups than in controls.
    Body weight, food consumption, food efficiency, water intake,
    leucocyte counts, platelet counts, prothrombin time, GOT, GPT,
    alkaline phosphatase activity, blood glucose, blood urea nitrogen,
    cholesterol, Na+, K+, C1-, creatine, and brain, serum, and
    corpuscular cholinesterase activities, as well as ophthamological
    examination indicated no significant effects attributable to paraquat
    at any dose level. Based on the haematological and blood biochemistry
    changes the no-effect level of paraquat after 104 weeks of
    administration to JCL:Wister rats in this study was 72 ppm (as
    paraquat cation) equal to 3.0 (males) and 3.7 (females) mg/kg b.w./day
    (Toyoshima et al., 1982b).

    Dogs

         Groups of 6 male and 6 female beagle dogs received diets
    containing 0, 15, 30, or 50 ppm paraquat cation for 1 year. During the
    study there were no deaths. No effects due to paraquat were observed
    on body weight. The reduced food consumption of 1 male and 1 female
    dog, both in the 50 ppm group, was considered by the authors of the
    study to be treatment-related. There was clinical evidence of
    respiratory dysfunction (hyperpnoea) in some dogs fed 50 ppm paraquat.
    Mean lung weights of male and female dogs fed 50 ppm paraquat were 35
    and 60% higher than those of controls, respectively. Histopathological
    examination of the lungs showed a statistically-significant increase
    in the incidence of chronic pneumonitis in both sexes at the 30 and
    50 ppm dietary levels when compared to controls. This lesion consisted
    of interstitial fibrosis, alveolar epithelialization, and mononuclear
    cell infiltration. No other toxicologically-significant treatment-
    related effects were seen during clinical observations, haemotological
    or biochemical investigations, or during gross and microscopic
    examination of approximately 40 tissues from each animal at
    termination. On the basis of the pulmonary changes, the authors of
    this study concluded that the dietary no-effect level for paraquat in
    dogs over 1 year of treatment was 15 ppm, equal to 0.45 (males) and
    0.48 (females) mg/kg b.w./day (Kalinowski et al., 1983).

    Observations in humans

         Information on the effects of paraquat in humans has been
    obtained from occupational exposure studies (epidemiological data and
    case reports), descriptions of accidental or suicidal poisonings, and
    volunteer studies. These data have been extensively reviewed by WHO
    (1984).

         In 1965, a study was carried out on a team of 6 sprayers, and in
    1967 on 4 teams in Malaysian rubber plantations, to estimate the
    efficacy of individual protective measures. The operators used a spray
    dilution containing paraquat at 0.5 g/litre for 12 weeks. Attention
    was paid to personal hygiene. Each man was given a thorough physical
    examination, and urine samples were taken before spraying began and at
    weekly intervals throughout the study. Chest X-rays were taken before
    the study started and at the end of the 6th and 12th weeks. In the 2
    studies, a total of 528 urine samples were examined. Paraquat was
    found on 131 occasions (78/134 and 53/394 in the 2 studies,
    respectively), the maximum concentration detected being 0.32 mg/litre
    in the first study and 0.15 mg/litre in the second. Average urine
    levels of paraquat of 0.04 mg/litre were found in the 1965 study and
    of 0.006 mg/litre in the 1967 study. After spraying ceased, these
    levels declined steadily to become undetectable within a week, with 1

    exception. Both trials showed that about half of the men had suffered
    mild irritation of the skin and eyes, but had recovered rapidly with
    treatment. Two cases of scrotal dermatitis occurred in workers wearing
    trousers that were continuously soaked by the spray solution. There
    were also 2 cases of epistaxis. All chest radiographs were normal
    (Swan, 1969).

         Studies performed over a period of several years on 296 Trinidad
    sugar estate workers drew attention to nail damage that ranged in
    severity from localized discoloration to nail loss following gross
    contamination with paraquat at 1 - 2 g/litre. The typical distribution
    of the lesions, affecting the index, middle, and ring fingers of the
    working hand, suggested that they had occurred through leakage from
    the knapsack sprayer and inadequate personal hygiene. Apart from 2
    cases of contact dermatitis of the hands, no skin, eye, or nose
    irritation was reported, nor were there any systemic effects (Hearn &
    Keir, 1971).

         Similar data were obtained on several groups of workers spraying
    paraquat as an herbicide and dessicant in cotton fields during the hot
    season. These workers were exposed to paraquat aerosol concentrations
    of 0.13 - 0.55 mg/m3 air. Dermal exposure was low, not more than
    0.05 - 0.08 mg paraquat on the hands and face. There were no
    complaints, nor did the clinical and laboratory examinations of the
    workers demonstrate any significant deviations from the matched
    control groups (Makovskii, 1972).

         In the USA, the exposure of field workers operating
    tractor-mounted spray equipment in orchards was determined. About
    4.6 litres of paraquat liquid concentrate (291 g/litre) was used in
    935 litres of water per hour. In addition, exposure from yard and
    garden applications were studied in volunteers using pressurized hand
    dispensers containing paraquat solution (4.4 g/litre). Dermal
    contamination was measured by adsorbent cellulose pads attached to the
    worker's body or clothing, and by hand-rinsing in water in a
    polyethylene bag. Special filter pads were used in the filter
    cartridges of the respirators worn by the subjects under study. In
    all, 230 dermal and respiratory exposure pads, 95 samples of
    hand-rinse water, and 130 urine samples, collected during and
    following spraying, were analysed, which involved 35 different
    paraquat application situations. The exposure of field workers was
    found to range from about 0.40 mg/hour (dermal) to less than
    0.001 mg/hour (inhalation). As for individuals spraying yards or
    gardens, exposure ranged from 0.29 mg/hour (dermal) to less than
    0.001 mg/hour (inhalation). In almost all cases dermal exposure
    affected the hands. The respiratory paraquat values were generally
    below the sensitivity levels of the analytical method. No detectable
    paraquat concentrations were found in the urine samples (lower limit
    0.02 mg/litre). This study confirmed the general safety of paraquat
    under correct conditions of use (Staiff et al., 1975).

         The potential long-term hazard associated with the use of
    paraquat has been studied by comparing the health conditions of 27
    sprayers who had been exposed to paraquat for many months per year for
    an average of 5.3 years with those of 2 unexposed control groups
    consisting of 24 general workers and 23 factory workers. The workers
    were given full clinical examinations; lung, liver and kidney function
    tests were also carried out. There were a few skin lesions resulting
    from poor spraying techniques and 1 case of eye injury. There were no
    significant differences between exposed and control groups in any
    health parameters measured, which led the authors to suggest that the
    long-term use of paraquat is not associated with harmful effects on
    health (Howard et al., 1981).

         To evaluate the effects of protective equipment on occupational
    human exposure to paraquat, a paraquat formulation (240 g/litre)
    diluted 300 times by volume with water was sprayed for 2 hours on
    weedy ground. During the spraying operations, the concentrations of
    paraquat aerosol were 11 - 33 g/m3 air. The total dermal exposure
    was about 0.22 mg. No irritation of the eyes or the skin was reported.
    The urine of the workers who wore gauze masks contained significant
    amounts of paraquat 24 hours after spraying. The urine of the workers
    who had worn a high-performance mask did not contain detectable levels
    of paraquat. The authors discussed the need for protective equipment
    to decrease skin contact with paraquat and to avoid aerosol inhalation
    (Kawai & Yoshida, 1981).

         Quantitative estimates of dermal and respiratory exposure of 26
    plantation workers in Malaysia have shown a mean dermal dose of
    1.1 mg/kg b.w./hour. The highest individual total exposure was
    equivalent to 2.8 mg/kg b.w./hour; the mean respiratory exposure was
    0.24 - 0.97 g/paraquat/m3 air, which is 1% or less of a TLV of
    0.1 mg/m3 for respirable paraquat. Urine levels of paraquat were
    generally below 0.05 mg/litre (Chester & Woollen, 1982).

         A study was carried out on a group of 14 sprayers in Thailand
    using conventional high-volume knapsack sprayers and low-volume
    spinning-disc applicators with paraquat ion concentrations of
    1.5 g/litre and 20 g/litre, respectively. Irritation of unprotected
    skin was found, and this was severe (caustic burns on the feet) in
    workers using high spray conentrations and spinning-disc applicators.
    Urinary paraquat levels ranging from 0.73 - 10.2 mg/litre after 14
    days of spraying were detected in unprotected men using both
    concentrations, and there was evidence that urinary levels of paraquat
    increased as the trial progressed. No evidence of systemic toxicity
    was discovered among the sprayers undergoing clinical and radiographic
    examination 1 week after spraying ended. The author concluded that
    spray concentrations in hand-held equipment should not exceed 5 g
    paraquat ion/litre (Howard, 1982).

         After tomato spraying in the USA, the total body exposure to
    paraquat was determined to be 169 mg/hour. The use of enclosed tractor
    cabs or a high-clearance tractor reduced total body exposures to
    27 mg/hour or 18 mg/hour, respectively. The authors reported that the
    total body exposure of tractor sprayers working in 2 citrus locations
    was proportional to the tank concentrations (paraquat dilutions of
    0.7 g/litre and 1.1 g/litre were applied). Exposure levels of 13 and
    28 mg/hour were found for workers using the lower and high
    concentrations, respectively. In all situations studied, the
    respiratory exposure was consistently a small fraction (< 0.1%) of
    the total body exposure, which was primarily through the skin
    (Wojeck et al., 1983).

         Two groups of workers exposed to paraquat formulations were
    examined. The first group of 18 workers, in England, consisted of
    subjects exposed to dust and liquid paraquat formulations during a
    37.5-hour working week, the mean length of exposure being 5 years. The
    second group also consisted of 18 males, from Malaysia, exposed to
    liquid concentrate formulations during a 42-hour working week, the
    mean length of exposure being 2.3 years. Partly protective clothing
    was worn. However, in Malaysia, no gloves, rubber aprons, or goggles
    were used. The medical records and the dermatological examinations
    revealed acute skin rashes, nail damage, epistaxis, blepharitis, and
    delayed wound healing in 12 - 66% of these workers. Delayed caustic
    effects were often found among the Malaysian formulation workers,
    where low levels of safety and hygiene were apparent. Clinical
    examination did not reveal any evidence of chronic contact dermatitis,
    hyperkeratosis, or eczematous lesions (Howard, 1979).

         Some studies designed to estimate dermal and inhalation exposure
    to paraquat are summarized in Table 7. From the data reported it can
    be seen that:

    (a)  the main route of exposure of agricultural workers to
         paraquat is via the skin; respiratory exposure is
         negligible.

    (b)  The worst case of exposure (of those examined) was via
         knapsack spraying).

         From 1956 - 1973, no deaths attributable to paraquat were
    registered among agricultural workers in the USA, but in 1974 4 fatal
    cases were associated with this herbicide. However, it is not clear
    whether they were accidental, suicidal, or occupational (Hayes &
    Vaughan, 1977).

         Fitzgerald et al. (1978a) summarized the clinical findings and
    pathological details concerning 13 accidents involving paraquat among
    agricultural workers, 6 of which were fatal. In 5 of these cases,
    swallowing was involved. Of the 6 fatalities studied, 3 swallowed

    Gramoxone (a 20% solution of paraquat dichloride in water) after
    sucking the outlet of a sprayer. In 1 non-fatal case, the man had
    sucked out a nozzle containing diluted paraquat, while in another case
    the man who had blown into the jet, to clear it, escaped with only
    minor signs of poisoning. The use of a leaking sprayer by another
    worker with severe extensive dermatitis probably resulted in fatal
    absorption of paraquat through the damaged skin.

        Table 7.  Comparison of dermal and inhalation exposure to paraquat resulting from
              various methods of application1.
                                                                                              

                               Dermal             Respiratory
    Method of application      exposure           exposure                Reference
                               (mg/hour)          (mg/hour)
                                                                                              

    Hand-held knapsack         66                 (0.45 - 1.3)  10-3     Chester & Woollen,
                               (12.1 - 169.8)                             1982

    Vehicle mounted            0.4                (0 - 2)  10-3          Staiff et al., 1975
                               (0.1 - 3.4)

    Aerial                                                                Chester & Ward, 1981
      Flagman                  0.1 - 2.4          (0 - 47)  10-3
      Pilot                    0.5 - 0.1          (0 - 0.6)  10-3
      Mixer/loader             0.18               (1.3 - 1.5)  10-3
                                                                                              

    1   From WHO, 1984
    
         Several other cases of fatal poisoning resulting from dermal
    absorption of paraquat have been reported. Jaros (1978) has described
    how the use of concentrated solutions of paraquat (50 g/litre instead
    of 5 g/litre), with an old leaking knapsack sprayer, resulted in
    paraquat contamination of the neck, back, and legs of a worker. After
    4 hours of work, the worker complained of a burning sensation on the
    neck and scrotum. On admission to a hospital 6 days later, cough and
    respiratory difficulties were recorded. Three days later the patient
    died of renal and respiratory failure.

         Severe skin damage, followed by death due to respiratory
    insufficiency, occurred in a woman 8 weeks after initial contact with
    paraquat. The toxic dermatitis started with scratches on the arms and
    legs from the branches of fruit trees. The patient had often failed to
    wear protective clothing or to shower after spraying. During the 4

    weeks preceding her first admission to the hospital, she developed
    ulcers and respiratory complaints combined with anorexia. Damaged and
    broken skin was thus exposed to paraquat. A chest X-ray and needle
    biopsy of the lung revealed pulmonary lesions. Seventeen days after
    discharge from hospital, without a specific diagnosis, she was
    re-admitted, and died 2 weeks later with progressive lung, hepatic,
    and renal dysfunction (Newhouse et al., 1978).

         The clinical and pathomorphological investigation of a patient
    who died of hypoxia after repeated dermal exposure to paraquat
    (28 g/litre) and diquat (29 g/litre) in a water-oil dilution has been
    described recently. The worker had used a leaking sprayer. A
    characteristic ulcer developed at the site of paraquat contact. There
    was also lung damage (Levin et al., 1979).

         Another reported fatal case of dermal poisoning with paraquat
    occurred after prolonged contact with a concentrated formulation
    following spillage from a bottle in the back trouser pocket
    (Waight & Wheather, 1979).

         Wohlfahrt (1982) discussed the factors related to severe paraquat
    poisoning due to dermal absorption in tropical agriculture. Three
    fatal incidents followed skin contamination; 1 victim used paraquat to
    treat scabies infestation, and 1 used it to treat lice. In all cases,
    the skin was blistered and ulcerated. The patients died of progressive
    respiratory failure 4 - 7 days after the accidents. In 1 of these
    cases, the presence of mouth and throat ulceration strongly suggested
    that ingestion might also have occurred (Davies, 1982).

         Local skin and nail effects of paraquat have been reviewed by WHO
    (1984). Brief contact with liquid formulations, as well as repeated
    exposure to dilute solutions, produced skin irritation, desquamation,
    and, finally, necrosis at the site of contact (Ongom et al., 1974;
    Binns, 1976; Newhouse et al., 1978; Waight & Wheather, 1979;
    Levin et al., 1979, Horiuchi et al., 1980). Harmful dermal effects
    have been reported among sprayers who worked without protective
    clothes and with naked feet (Howard, 1982). The blistering and
    ulceration of the skin were due to excessive contact and inadequate
    hygiene. Horiuchi and Ando (1980) carried out patch testing on 60
    patients with contact dermatitis due to Gramoxone. In 8 patients
    (13.3%) positive allergic reactions were established. In another
    survey with 52 persons, a positive photo-patch response was reported
    in 11 patients. Nail damage may also occur after frequent exposure to
    paraquat concentrations during the formulation of the herbicide or the
    preparation of the working dilution (Howard, 1979).

         There have been some reports (Malone et al., 1971; Mircev,
    1976; Bismuth et al., 1982) of adverse effects as a result of
    inhalation exposure to paraquat. However, inhalation of droplets in
    normal paraquat spraying does not appear to represent a significant
    health hazard (Howard, 1980), and the effects of occupational
    inhalation have usually been limited to nose bleeds and nasal and
    throat irritation (Swan, 1969; Howard, 1979).

         Ocular damage may result from splashes of concentrated paraquat
    that come into contact with the eye. Apart from irritation of the eye
    and blepharitis, a week later more serious ocular damage may occur,
    such as destruction of the bulbar and tarsal conjunctiva and of the
    corneal epithelium. Anterior uveitis, conjunctival necrosis,
    progressive keratitis with gross corneal opacity, and decreased visual
    acuity may also occur (WHO, 1984).

         It has been noted that when the recommended dilution rates were
    correctly used, systemic effects of oral, inhalation, or dermal
    exposure to paraquat have not been observed. Skin and eye irritation
    have occurred only when protective measures were disregarded
    (WHO, 1984).

         In a volunteer study the percutaneous absorption of
    14C-paraquat through the legs, hands, and forearms of 6 human
    subjects was studied. The total dose absorbed in 5 days after a single
    application of 0.64 mg paraquat dichloride was very low (0.3%) at all
    sites of application (Wester et al., 1984).

         A large number of cases of accidental or suicidal poisoning have
    been reported since 1966, the earlier cases being mostly accidental
    which apparently resulted from the habit of decanting the liquid
    formulations into small unmarked or incorrectly labelled containers
    such as beer, wine, or soft-drink bottles. An increasing ratio of
    suicidal to accidental poisonings has been noted in recent years
    (Fitzgerald et al., 1978b; Bramley & Hart, 1983). This change from
    accidental to suicidal poisoning was considered to be reflected by
    enhanced percentages of fatal cases, shorter survival times, and
    higher tissue and body fluid levels (WHO, 1984). The vast majority of
    cases of paraquat poisoning have been due to ingestion. A few cases of
    fatal or non-fatal poisonings have been reported following either skin
    contamination (McDonagh & Martin, 1970; Kimura et al., 1980) or skin
    application in order to kill body lice (Ongom et al., 1974;
    Binns, 1976). Symptoms of poisoning depend on the dose absorbed.

         It is difficult to estimate the dose absorbed from case histories
    since in many cases the patients spat out part of the paraquat
    concentrate or vomited profusely after swallowing the herbicide. Some
    patients have survived after apparently ingesting 10 - 20 g paraquat,
    whereas some died after taking as little as 2.5 g paraquat. The

    probability of survival after paraquat poisoning can be predicted from
    plasma paraquat concentration at a given time after ingestion
    (Proudfoot et al., 1979; Hart et al., 1984). The minimum lethal
    dose of paraquat for human beings has been estimated to be about
    35 mg/kg b.w. (Pederson et al., 1981; Bismuth et al., 1982). The
    common factor of most, if not all, cases of paraquat poisoning is
    damage to the lung. Cases of fatal paraquat poisoning have been
    divided into 2 broad categories:

         a)   Cases of acute fulminant poisoning due to massive amounts of
              paraquat absorbed, resulting in death within 1 to 5 days
              from ingestion. Death is due to multi-organ failure
              associated with damage to the lungs, kidneys, liver, brain,
              and adrenals.

         b)   Cases of poisoning due to ingestion or absorption of smaller
              doses of paraquat resulting in death 6 to several days
              later. In these cases death is due primarily to lung and
              kidney damage.

    COMMENTS

         A small amount of paraquat is rapidly absorbed by the gut of
    rats, guinea pigs, dogs, monkeys, and man, most of the oral dose being
    excreted as unchanged paraquat. Following administration by different
    routes to animals, paraquat is rapidly distributed in most tissues,
    the highest concentrations being found in the lungs and kidneys. The
    compound accumulates slowly in the lung owing to uptake by an
    energy-dependent process which is also responsible for the uptake of
    putrescine. Saturation kinetics for the uptake of paraquat by the lung
    have been shown to be similar in rats and man. Excretion of absorbed
    paraquat is biphasic, owing to lung accumulation, and occurs largely
    in the urine as unchanged paraquat, but also to a limited extent in
    the bile. Biotransformation of absorbed paraquat is, in general,
    remarkably poor in all species studied (rats, guinea pigs, dogs, hens,
    pigs, goats, and sheep) although there is some controversy as to the
    possibility and extent of its metabolism by the gut microflora.
    Metabolism occurs via demethylation (monomethyl dipyridone ion) or
    oxidation (paraquat pyridone ion and paraquat dipyridone ion).

         The mechanism of paraquat toxicity has been investigated
    extensively, but it has not yet been elucidated completely. The
    available evidence indicates that paraquat toxicity is due to the
    ability of the compound to undergo redox cycling in biological
    systems, resulting in the production of superoxide anion radicals and
    in the oxidation of cellular NADPH. These effects may lead to the
    formation of other highly toxic oxygen species and to depletion of
    important defense mechanisms, both events which are potentially
    capable of switching on further pathological processes, resulting in
    damage to Type I and Type II pneumocytes.

         Two teratogenicity studies, 1 in mice and 1 in rats, showed
    paraquat to be non-teratogenic at doses up to 10 mg/kg b.w./day.
    Slight maternal toxicity was observed in mice and high maternal
    toxicity and some fetal toxicity were observed in rats at 5 and
    10 mg/kg b.w./day paraquat ion. In a teratology sub-group in a
    3-generation reproduction study in rats, paraquat was not teratogenic,
    but delays in ossification were found at all 3 dose levels tested
    (72, 145, and 290 ppm paraquat cation).

         In previous in vitro studies both positive and negative results
    were obtained, with mutagenicity usually associated with high
    cytotoxicity. Recent studies have shown paraquat to be non-mutagenic,
    both in the presence and absence of metabolic activation, when tested
    by the Ames test, mouse micronucleus test, unscheduled DNA synthesis
    assay, rec-assay, and host-mediated assay. A mouse lymphoma cell test
    was inconclusive. The herbicide was clastogenic to human lymphocytes
    in vitro at cytotoxic doses and induced sister chromatid exchange in
    Chinese hamster lung fibroblasts.

         In 2 rat 3-generation reproduction studies paraquat had no
    effects on the reproductive performance or development of the
    reproductive organs of rats. In 1 of these studies a reduction of
    lactation index was observed at 290 ppm paraquat cation.

         The acute oral toxicity of paraquat is higher in guinea pigs,
    monkeys, cattle, and man than in rats and birds. Confidence limits of
    LD50 values are small. There are no significant differences between
    the 2 sexes in the oral, s.c., or i.p. LD50 values of paraquat in
    rats or mice. Paraquat induces characteristic dose-related fibrotic
    changes in the lungs of mice, rats, dogs, and monkeys, but not in
    rabbits, guinea pigs, or hamsters. The acute pulmonary toxicity of
    paraquat in rats and man is biphasic. In the early, destructive phase,
    the alveolar epithelial cells are extensively damaged. Death may occur
    within a few days due to pulmonary oedema. In the later, proliferative
    phase, fibroblasts and collagen accumulate in the lungs of surviving
    animals and humans, possibly resulting in fibrosis.

         In a short-term study in mice, treatment-related lung, body
    weight, and organ-weight changes were found. Another short-term study
    in rats indicated that paraquat was responsible for lung lesions and
    other minor changes. In a short-term study in dogs using 3
    animals/sex/group, paraquat-dependent lung and kidney lesions were
    observed.

         In a 1-year feeding study in dogs, paraquat caused lung changes
    at the 2 highest dietary levels; the no-effect level in this study was
    15 ppm (as paraquat cation), equal to 0.45 mg/kg b.w./day in males and
    0.48 mg/kg b.w./day in females.

         In 2 long-term feeding studies, 1 in mice and 1 in rats,
    haematological and blood biochemical changes were observed in both
    species. These changes have not been reported previously and were
    considered to be of little toxicological significance.

         A lifetime feeding study in mice showed no oncogenic potential
    for paraquat, although a slightly higher incidence of lung tumours was
    noted in animals of the high-dose group dying between 79 and 98 weeks
    of treatment when compared with control mice. Based on renal lesions
    observed in males, the no-effect level in this study was 12.5 ppm
    (as paraquat cation), equal to 1.4 mg/kg b.w./day.

         A long-term feeding study in F344 rats indicated that paraquat
    administration for 104 weeks at 217 ppm was responsible for a
    significant increase in the incidence of pulmonary adenomas in
    females. This incidence (8.7%) was significantly higher than that
    observed in historical control animals of the same laboratory (2.2%).
    Paraquat was also cataractogenic in both male and female rats. Based
    on the lung and eye changes the no-effect level in this study was
    22 ppm (as paraquat cation), equal to 0.77 mg/kg b.w./day.

         In another long-term study in F344 rats paraquat induced
    proliferative benign lung lesions in females in the high-dose group,
    which were considered neoplastic by 1 pathologist and non-neoplastic
    by 2 others (the total incidence of pulmonary adenoma in females
    ranged from 0/70 to 8/70). The reasons for the discrepancy were
    unclear, owing to the lack in most cases of adequately detailed
    histopathological descriptions of the lung lesions. The historical
    incidence of lung adenoma in control female F344 rats in the
    laboratory in which the study was conducted was reported to be 1.1%,
    and the incidences reported in the literature are 1.4% for females and
    1.9% or 0% for males. The results of these studies indicate a weak,
    organ-specific, sex-related potential of paraquat to produce benign
    proliferative changes in the lungs of female F344 rats.

         The following observations were considered by the Joint Meeting:

         a)   paraquat was shown to be non-mutagenic in most in vitro
              and, apparently, all in vivo tests;

         b)   the lung is the target organ for both acute and chronic
              paraquat toxicity in rats;

         c)   only female F344 rats, but not male F344 rats, developed
              treatment-related benign neoplastic lesions;

         d)   proliferative changes were observed in rats and not in mice;
              and

         e)   paraquat selectively interferes with the uptake of
              polyamines by pneumocytes.

         Polyamines are endogenous substrates playing an important role in
    cell division and growth. These observations suggest that the
    potential of paraquat to induce lung cell proliferation may be
    modulated by species-, sex-, and organ-dependent factors, such as
    hormonal activity, cell growth, defense and repair mechanisms, etc. No
    lung changes were observed at 24 ppm in any of the dose groups, and
    significant increases in the incidence of lung adenocarcinomas were
    not observed in any of the treated groups when compared to controls in
    these studies.

         Observations in man, including reports on accidental or suicidal
    poisonings, confirm the type of acute and subacute toxicity observed
    in some experimental animals. Death occurred after oral and, in some
    cases, dermal absorption of high doses of paraquat. The organs
    primarily involved are the lung and kidney and, to a lower extent, the

    intestinal tract, liver, pancreas, adrenals, and CNS. The minimal
    lethal dose of paraquat in man is estimated to be about 35 mg/kg b.w.
    Skin, nail, and eye lesions were found in subjects with prolonged
    occupational exposure to paraquat. Significant paraquat concentrations
    (up to 10 mg/1) were detected in the urine of workers using high spray
    concentrations, but not in protected workers. The use of protective
    measures has proved to be effective in preventing lesions due to skin
    contact.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mice:     13 ppm (as paraquat cation), corresponding to 17 ppm
                   (as paraquat dichloride) in the diet, equal to
                   1.9 mg/kg b.w./day for males and 38 ppm (as paraquat
                   cation, corresponding to 52 ppm (as paraquat
                   dichloride), equal to 5.9 mg/kg b.w./day for females.

         Rats:     a) 22 ppm (as paraquat cation), corresponding to 30 ppm
                   (as paraquat dichloride) in the diet, equal to
                   1.1 mg/kg b.w./day for males and 1.2 mg/kg b.w./day for
                   females (cataract).

                   b) 25 ppm (as paraquat cation), corresponding to 35 ppm
                   (as paraquat dichloride) in the diet, equal to
                   1.4 mg/kg b.w./day for males and 1.7 mg/kg b.w./day for
                   females (proliferative lung changes).

         Dogs:     15 ppm (as paraquat cation), corresponding to 20 ppm
                   (as paraquat dichloride) in the diet, equal to
                   0.62 mg/kg b.w./day for males and 0.66 mg/kg b.w./day
                   for females.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.004 mg/kg b.w. as paraquat cation (0 - 0.006 mg/kg b.w.
    expressed as paraquat dichloride).

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         1.   Further observations in humans.

         2.   Studies on the mechanism of paraquat-induced proliferative
              lung changes.

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    See Also:
       Toxicological Abbreviations
       Paraquat (HSG 51, 1991)
       Paraquat (PIM 399)
       Paraquat (JMPR Evaluations 2003 Part II Toxicological)
       Paraquat (AGP:1970/M/12/1)
       Paraquat (WHO Pesticide Residues Series 2)
       Paraquat (Pesticide residues in food: 1976 evaluations)
       Paraquat (Pesticide residues in food: 1978 evaluations)
       Paraquat (Pesticide residues in food: 1981 evaluations)
       Paraquat (Pesticide residues in food: 1982 evaluations)