PESTICIDE RESIDUES IN FOOD - 1981

    Sponsored jointly by FAO and WHO

    EVALUATIONS 1981

    Food and Agriculture Organization of the United Nations
    Rome

    FAO PLANT PRODUCTION AND PROTECTION PAPER 42

    pesticide residues in food:
    1981 evaluations

     the monographs

    data and recommendations
    of the joint meeting
    of the
    FAO panel of experts on pesticide residues
    in food and the environment
    and the
    WHO expert group on pesticide residues

    Geneva, 23 November-2 December 1981

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
    Rome 1982

    2, 4, 5 - T

    Explanation

         The 1979 Meeting felt minimal concern regarding food residues of
    2,4,5-T. Nevertheless it could not ignore the toxicological problems
    associated with TCDD and a high safety margin was utilized in
    estimating the temporary ADI of 0-0.003 mg/kg bw.*

         Although there are no new data available on 2,4,5-T, the
    following additional data have been received with respect to TCDD.

    DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

         Groups of 4 or 5 male Syrian golden hamsters (body weight
    62-94 g) were dosed orally or i.p. with 65 µg/kg bw, 98-99% pure
    (3H)-TCDD or (14C)TCDD. Tissue levels in 20 tissues (expressed
    as µg/g of tissue) following oral administration of (3H)-TCDD were
    highest in liver (4.03 ± 1.00% of administered dose), perirenal fat
    (2.93 ± 0.52%) and adrenal glands (1.56 ± 0.52%), 1 day after dosing.
    Twenty days after dosing, levels in liver, perirenal fat and adrenal
    glands were reduced to 0.86 ± 0.09, 0.32 ± 0.03, and 0.10 ± 0.01% of
    the administered dose, respectively. Tissue distribution is stated to
    be similar following oral and i.p. administration. Following a single
    i.p. administration of (3H)-TCDD, excretion appears to follow
    apparent first order kinetics. By day 35, 34.6 ± 5.4% and 50.0 ± 2.7%
    of the administered radioactivity was recovered in urine and faeces
    respectively. Total recovery of administered radioactivity from urine,
    faeces, liver and adipose tissue was 92.4 ± 12.3% during 35 days. The
    half-life for elimination of (3H)-TCDD administered orally was
    calculated to be 14.96 ± 2.33 days. Following i.p. administration, the
    half-life for (3H)-TCDD was 11.95 ± 1.95 days and for (14C)-TCDD,
    10.82 ± 2.35 days. Bile and urine samples examined 7 days post-
    treatment were shown to comprise, almost exclusively, TCDD
    metabolites. Liver and adipose tissue residues appeared to comprise
    unchanged TCDD (Olson  et al 1980).

         Two groups of 40 male Sprague-Dawley rats were intubated with
    50 µg (14C)-TCDD/kg bw in corn oil, or with unmodified corn oil.
    Twenty four hour urine and faecal samples were collected. Five
    rats/group were killed at 1, 3, 5, 7, 14 and 21 days. The remaining
    animals were killed at day 25 when half of the experimental group
    remaining had died. Faecal elimination accounted for 25% of the
    administered radioactivity within 72 h, and 52.3 ± 6.3% by 21 days.

    *  See Annex II for FAO and WHO documentation.

    Daily urinary excretion ranged from 0.1 to 0.2% of the administered
    dose/day over the first 12 days, and then increased to 0.25 to 0.43%
    by day 21. Total urinary excretion by day 21 comprised 4.54 ± 0.7% of
    the administered radioactivity. Liver tissue levels were 6 to 7 times
    higher than those of other tissues, being 8.39 ± 0.81% of the
    administered dose/g of tissue on day 1 post dosing. Rate of decrease
    was slow up to day 14, but a 50% decrease occurred between days 14 and
    21 post dosing. Radioactivity in the liver was concentrated in the
    microsomal fraction. Liver homogenates, 21 days post dosing, showed no
    change in protein or RNA concentrations, but a significant decrease in
    DNA concentrations/g of tissue. Microsomes from these liver
    homogenates showed decreased protein and increased phospholipid and
    cholesterol. Esterase, glucose-6-phosphate, and aromatic hydrolase
    activity was reduced. (14C)-TCDD half-life based on decrease in
    radioactivity in tissue with time, and on remaining body burden, was
    calculated to be 16.3 ± 2.3 and 21.3 ± 2.9 days (Allen  et al 1975).

         Three groups of 10 male and 10 female Sprague-Dawley rats were
    fed diets containing 0, 7 or 20 ppb (14C)-TCDD for 42 days, followed
    by a 28-day withdrawal period. Two rats of each sex/group were
    sacrificed every 14 days. Total (14C)TCDD intakes from 7 ppb and
    20 ppb groups over 42 days were 21.8 and 61.1 µg/kg for males and
    21.6 and 53.2 ug/kg for females. Food intake was reduced during 0 to
    14 days in male groups receiving 7 ppb, and from 0 to 42 days in the
    male group receiving 20 ppb. In females, food intake was affected only
    in the 20 ppb group, where a reduction was apparent from 0 to 56 days.
    Reductions in body weight paralleled the reduced food intake. Liver
    weight ratio reductions were not directly related to TCDD intake, The
    response was greater at 7 ppb than at 20 ppb. However, during the
    withdrawal period, the 7 ppb group recovered normal liver weights,
    while those at 20 ppb remained elevated. (14C)-TCDD concentration in
    whole body (less liver) was 2 to 3 times higher in females than in
    males. This sex difference was lost with removal of fat, presumably
    because of the higher fat content of the female rat. (14C)-TCDD
    concentration was highest in liver and was directly proportional to
    (14C)-TCDD intake. Since data are reported for whole liver, and not
    for levels/g of tissue, it is difficult to compare male and female
    tissue concentration. However, 85% of retained (14C)-TCDD was in the
    male's liver, compared to 70% in the female's liver. Total retention
    was estimated to be about 10.5 times average daily intake. During
    withdrawal, the half-life of (14C)-TCDD in liver was 11 and 13 days
    for males and females respectively, and 21 and 17 days for the
    remaining body tissues (Fries & Marrow 1975).

         Male Spartan strain Sprague-Dawley rats were intubated with a
    single dose of 50 µg (14C)-TCDD/kg. About 30% of the administered 14C
    was eliminated in faeces in the first 48 h. Over the next 19 days,
    1-2% of the administered 14C was excreted per day, in faeces. At 21

    days, faecal excretion accounted for 53.2 ± 3.8% of the administered
    14C while urinary excretion accounted for 13,2 ± 1.3% and 3.2 ± 0.1%
    was detected in expired air. Excretion (based on calculated remaining
    body burden), excluding the first 48 h, when absorption effects
    occurred, followed apparent first order rate kinetics, the half-life
    being 17.4 ± 5.6 days. (14C)-TCDD residues occurred chiefly in liver
    and fat, liver values (as a percentage of dose) being 3.18, 4.49 and
    1.33% of the administered dose, on days 3, 7 and 21 post-dosing.
    Comparable figures for fat residues were 2.60, 3.22 and 0.43% (Piper
     et al 1973).

         Purified (3H)-TCDD (98.7% purity) was administered orally to
    female Sprague-Dawley derived rats, following cannulization (both
    directions) of the bile duct, at a dose of 20 µCi/rat. Bile was
    collected for 3 to 4 days post dosing. Bile radioactivity
    concentration remained constant at about 1% of the administered
    radioactivity. Liver tissue contained 8.5 to 12% of the administered
    3H. All but 2% of liver residues were extractable with
    dichloromethane, but only 1.5% of bile residues were extractable with
    this solvent. Since the 3H in non-extracted residue was dialysable,
    protein binding was excluded. Chelation of TCDD by bile elements was
    excluded by extraction of TCDD from bile incubated for several hours
    with added TCDD. Thin layer chromatography of extracts from liver gave
    an RF value corresponding to TCDD, while bile residues, following
    extraction after incubation with glucuronidase/arylsulphatase, showed
    compounds with much lower RF values. The results indicate TCDD is
    excreted into bile in a metabolized form - possibly as a water soluble
    conjugate (Poiger & Schlatter 1979).

         Female Sprague-Dawley derived rats were dosed orally with 14.7 ng
    (3H)-TCDD in ethanol/rat. The percentage of the dose administered
    found in liver attained a maximum 24 h after dosing, being 36.7 ± 1.2%
    (based on results in 7 rats). Based on liver concentrations of
    (3H)-TCDD, comparisons were made between (3H)-TCDD uptake in 50%
    ethanol solution, in aqueous suspension of soil (37% w/w) following
    dry state contact between soil and dioxin for 10 to 15 h at room
    temperature, or over 8 days at 40°C with frequent moistening and
    drying, or in an aqueous suspension of activated carbon following 15
    to 20 h contact of carbon and dioxin in methanolic solution at room
    temperature. Percentages of the administered dose in the liver at 24 h
    were 24.1 ± 4.8% (17 rats) for 10-15 h soil contact specimen, 16 ± 2-2
    (10 rats) for 8-day contact soil specimen, and < 0,07% for
    activated carbon contact specimen. Similar experiments on dermal
    absorption, under standard occlusive dressings applied to hairless
    rats of the Naked ex Backcross and Holzman strains, resulted in
    14.8 ± 2.6 in liver, following application of 26 ng in methanol/rat of
    (3H)-TCDD, At the same exposure level, vaseline applied dermally
    resulted in 1.4 ± 0.4% of the administered dose in liver.

         Soil/water paste and activated carbon/water paste (with 10 to
    15 h dry contact between dioxin and adjunct) yielded < 0.05% of the
    administered dose in the liver. Doses of 350 ng/rat in polyethylene
    glycol, polyethylene glycol + 15% water, and soil/water paste, yielded
    9.3 ± 3.4%, 14.1 ± 4.9%, and 1.7 ± 0.5% of the administered dose in
    the liver, while 1300 nmg/rat of (3H)-TCDD in soil/water or activated
    carbon/water pastes gave 2.2 + 0.5% and > 0.05% of the administered
    dose in the liver. Acnegenic activity of TCDD on the rabbit ear was
    induced by soil/water paste containing dioxin levels approximately
    twice as great as the dioxin level required in acetone, vaseline, or
    polyethylene glycol vehicles. The dioxin dose in activated charcoal
    required to initiate acnegenic activity was at least 100 times the
    required dose in acetone (Poiger & Schlatter 1980.

         Three male and 3 female Sprague-Dawley rats were administered a
    single oral dose of 1 µg/kg/bw of 99% radiochemically pure (14C)-TCDD
    in a 1:25 acetone/corn oil solution. The rats were placed in
    individual metabolism cages, and daily urine, faeces and expired air
    samples were collected and analysed for 22 days. 14C was detected
    only in faeces. The dose remaining in the body as a function of time
    followed apparent first order kinetics. Rate constants were comparable
    for male and female rats. The body burden half-life was calculated to
    be 31 ± 6 days. At 22 days post-dosing, liver and fat contained
    comparable (14C)-TCDD concentrations (1.25 - 1.26% of the
    administered dose/g of tissue), with levels in thymus (0.09 ± 0.05%),
    kidney (0.06 ± 0.06%) and spleen (0.02 ± 0.01%) being lower (Rose
     et al 1976).

         Three further groups of 9 male and 9 female rats were treated
    orally with the same material 5 times weekly, at dose levels of 0.01,
    0.1, or 1.0 µg (14C)-TCDD/kg bw. Three males and 3 females/dose level
    were killed after 1, 3 and 7 weeks. The animals killed at 7 weeks were
    kept in metabolism cages, urine and faeces being collected daily.
    During the first 7 days, 24-h samples were analysed. Subsequently,
    samples collected Monday through Friday were pooled for analysis,
    while samples for Saturdays and Sundays were kept separate. Oral
    (14C)-TCDD at 1 µg/kg resulted in 3.1 ± 0.2% and 12.5 ± 5.1% of the
    cumulative administered dose being excreted in urine of male and
    female rats respectively. In both sexes, the amount excreted in urine
    increased with duration of exposure. At lower doses, urinary excretion
    was frequently below the level of detection, rendering comparisons
    between dose levels impossible. The pharmacokinetic constants were
    unaffected by dose at 0.1, or 1.0 µg/kg, or by sex. The overall rate
    constant for elimination corresponds to a half-life of 23.7 days.
    Calculations indicate that the rate constant of approach to steady
    state concentrations is independent of doses over the range from 0.1
    to 1.0 µg/kg. Steady state would be attained in approximately 13

    weeks. Whole body, liver, and fat all approach steady state at the
    same rate. In all cases, tissue accumulation follows apparent first
    order kinetics, although liver concentration is approximately 5 times
    as great as the concentration in fat. The material extracted from
    liver, analysed by combination gas chromatography-mass spectrometry
    and by gas chromatography, is predominantly TCDD (Rose  et al 1976).

         Groups comprising 5 male Sprague-Dawley rats, 4 male infant
    (2-4 months) Rhesus monkeys, and 3 adult female Rhesus monkeys were
    injected i.p. with 400 µg (3H)-TCDD/kg bw, in corn oil. Faecal and
    urine samples were collected daily, from individual animals, for 7
    days, after which the animals were killed and tissues were subjected
    to radioactivity analyses and microscopic examination. Seven-day
    cumulative 3H excretion, as a percentage of administered
    radioactivity, in faeces and urine was 3.75 ± 0.91% and 1.06 ± 0.25%
    for adult monkeys, 1.26 ± 0.34% and 1.96 ± 0.42% for infant monkeys,
    and 4.96 ± 0.3% and 0.51 ± 0.05% for rats. (The high level for urinary
    excretion in infant monkeys is possibly attributable to difficulties
    in urinofaecal separation, according to the authors.) The tissue
    concentration of tissue expressed as a percentage of administered 3H
    differed markedly among species. The concentrations of 3H in rat
    liver were approximately 35 times, in rat brain 18 times, in rat
    kidney 6 times, in rat lung 7 times, in rat spleen 3 times, and in rat
    adipose tissue 7 times as great as the concentrations/g of tissue in
    infant monkeys. The disparity was slightly greater when compared to
    adult monkeys. However, skin concentration/g of tissue in infant
    monkeys exceeded levels in rat skin by a factor of 2. In adult monkey
    skin, the concentration/g of tissue was one fifth that in rat skin.
    Based on concentration of administered dose/organ, rat liver residue
    levels exceeded adult and infant monkey liver residue levels by
    factors of approximately 4 and 10. However, total residues in infant
    and adult monkey muscle exceeded total rat muscle residues 9 and 2
    fold, respectively, while skin residue levels exceeded those in rat 5
    and 3 fold (Van Miller  et al 1976).

         Seven beef cattle were fed 24 ppt TCDD in complete rations for 28
    days. Five additional animals served as controls. On day 29, 3 treated
    and 3 control calves were killed for tissue analysis. Fat biopsies
    were taken from surviving animals during a 36-week withdrawal period.
    Survivors were sacrificed at 50 weeks after termination of dosing.
    Feed intake and body weight were unaffected by dosing. TCDD was
    detected in muscle (2 ppt), kidney (6 to 8 ppt), liver (7 to 10 ppt)
    and fat (66 to 95 ppt) after 28 days exposure. The levels in muscle
    appear to be proportional to the fat content. A computer programme
    based on fat TCDD levels from biopsies indicates a dissipation half-
    life estimated at 16.5 ± 1.4 weeks (Jensen  et al 1981).

    TOXICOLOGICAL STUDIES

    Acute toxicity

         Following single oral or i.p. doses of 650 µg (3H) on
    (14C)-TCDD/kg bw, Syrian Golden hamsters exhibited thymic atrophy.
    Orally doses animals frequently showed hyperplasia, necrosis, and
    haemorrhages of the mucosal epithelium of the ileum (Olson  et al 
    1980).

         Male Sprague-Dawley rats treated orally with 50 µg (14C)-TCDD/kg
    bw, in corn oil showed loss of body weight and hair, the severity of
    which increased with increasing time after dosing. Thymic atrophy was
    noted (characterized by the small number of cortical thymocytes) from
    day 1 to day 25 post dosing. At day 21 post dosing, haemoglobin,
    haematocrit, white cell serum lipids, serum cholesterol, serum
    triglycerides, serum protein, and serum albumin/globulin ratio were
    within normal limits. Absolute and relative liver weights were
    increased; liver histopathology showed increased smooth endoplastic
    reticulum and increased lipid droplet content of the cells (Allen
     et al 1975).

         Adult (3 females) and infant (4 males, 2-4 months old) Rhesus
    monkeys, and 5 adult male Sprague-Dawley rats were dosed once i.p.
    with 400 µg (3H)-TCDD/kg bw in corn oil. All animals were killed 7
    days post dosing. Body weight loss as a percentage of original weight
    was 10.8 ± 3.8, 20.7 ± 1.7 and 10.6 ± 5.3% for mature monkeys, infant
    monkeys and rats, respectively. Gross pathological examinations
    revealed thymic atrophy in rats. Light microscopy showed 2 or 3 adult
    monkeys with hypertrophied centrilobular hepatocytes, and small
    eosinophilic cells in the periportal areas of the liver. All rats
    showed moderate fatty infiltration of the liver. In all animals,
    smooth endoplasmic reticulum proliferation and development of isolated
    membraneous concentric arrays were noted, as well as increased
    vacuolation of liver Kupfer cells (Van Miller  et al 1976).

    Special studies on reproduction - 2,4,5-T

         Four groups of 4 to 6-week old Sprague-Dawley rats were fed diets
    containing purified 2,4,5-T (less than 0.03 ppb TCDD) to give 0 (16
    males and 32 females), 3 (10 males and 20 females), 10 (10 males and
    20 females) or 30 (16 males and 32 females) mg 2,4,5-T/kg bw/day.
    Dosing was continuous throughout the experiment, commencing 90 days
    prior to F0 matings and continuing through F1a, F2a, F3a and F3b
    litters. Pairing comprising 2 exposures of females for 6 days to
    different males, with a 6-day interval between pairings. F1 and F2
    generation pairings were initiated at 130 days of age. No compound-
    related effects were noted with respect to pre-mating parental body
    weights, food intake, appearance or behaviour. Time between first
    co-habitation and parturition were comparable to control values for

    all generations and litters, as were autopsy findings and light
    microscopy findings on 4 to 6 weanlings/sex/dose level from each
    generation on liver, kidney and thymus. Litter size was not reduced
    significantly in any generation at any dose level, but it was
    increased at 3 mg/kg/day in offspring of the F1 parents. Fertility
    was reduced in all test groups of the second F2 parental pairing, the
    reduction being significant only at 10 mg/kg bw/day p=0.05. The
    percentage of live/dead pups at birth was statistically significantly
    reduced in the F1 generation at 3 and 30 mg/kg bw/day, and in the F2
    generation at 30 mg/kg bw/day. However, percentage changes in
    live/dead pups were within normal limits for Sprague-Dawley rats (92%
    in all generations). Post-natal survival to 21 days was statistically
    significantly reduced in F1 generation litters at 10 and 30 mg/kg
    bw/day, and in F3a litters at 30 mg/kg bw/day. In F3b litters,
    survival was poor in all groups, including controls. In this
    generation, the post-natal survival was significantly increased, as
    was the survival in the F1 generation at 3 mg/kg bw/day. In the
    latter litter, sex ratio differed from controls in favour of females
    (40:60). Weanling relative kidney weights were comparable to controls
    in all generations. Relative liver weights were statistically
    significantly increase at 30 mg/kg bw/day in F2 litter males and
    females, F3a males, and F3b males and females. Statistically
    significant thymus weight decreases were seen only in F3b males at
    30 mg/kg bw/day (Smith  et al 1981).

    Special studies on reproduction - TCDD

         Four groups of 7-week old Sprague-Dawley rats were fed diets
    containing 99% purity TCDD to give dose levels of 0 (16 males and 32
    females), 0.001 (10 males and 20 females), 0.01 (10 males and 20
    females) or 0.1 (16 males and 32 females) µg TCDD/kg bw/day, for 90
    days prior to pairing. Pairing of F0 animals to give the F1a litters
    was conducted by pairing 1 male and 2 females for 15 days. In
    subsequent pairings, 1 male to 1 female, paired for 2 periods of 6
    days (different males) with a 6-day rest between pairings, were
    utilized. F0 parents were remated to give F1b litters 33 days after
    parturition of the last F1a litter. F1b pairings (and subsequent
    pairings) were conducted at 130 days of age. F2 offspring provided
    the parents for the F3 litters (one breeding/generation). In the F0
    generation, body weight, food intake and appearance remained
    comparable in all groups during the pre-pairing period. The 0.1 µg/kg
    bw/day dosage level was abandoned after the F1 matings, but the 3
    male and 2 female pups (from 1 litter) surviving at this dose level
    showed normal body weight gain, food intake and appearance. At
    0.01 µg/kg bw/day, body weight was reduced in both sexes of F1 and
    F2 generations (accompanied by a trend to reduced food intake);
    fertility was reduced in F1 and F2 generations; time between initial
    cohabitation and parturition was increased in F1 and F2 generations;
    litter size was reduced in F2 and F3 litters; percentage of
    stillbirths was increased in F2 and F3 litters; post-natal survival

    was reduced in F1a and F2 litters., and post-natal litter weights
    were reduced in F2 litters on day 1 and F3 litters on day 14. Female
    weanling body weights were also reduced in F3 litters. No consistent
    adverse reproductive effects were noted at 0.001 µg/kg bw/day. Gross
    necropsy of 21-day old pups indicated a significant increase in the
    incidence of slightly dilated renal pelves in F1 generation receiving
    0.001 µg/kg bw/day. This was not seen in other generations or at
    0.01 µg/kg bw/day. The 3 surviving male rats from the 0.1 µg/kg bw/day
    dose all showed dilated renal pelves when sacrificed as adults.
    Organ/bw ratios in weanlings were not obtained for F2 litters at
    0.01 µg/kg bw/day. Available data at this dose level show a trend to
    thymus weight reduction in F1b offspring and a statistically
    significant reduction in F3 offspring. Liver weight ratios in females
    were increased at 0.01 µg/kg bw/day in the F3 offspring. Light
    microscopy of 4 to 6 rats/sex/dose level did not show any compound-
    related effects on liver, kidney or thymus (Murray  et al 1979).

         A cross-mating study using the few survivors of the F1 litters
    (3 males and 2 females) dosed at 0.1 µg/kg bw/day and maintained at
    that exposure level for 12 months, indicated that male fertility was
    unaffected, and the low fertility index was attributed, at least in
    part, to the high incidence of resportions, especially late
    resorptions (Murray  et al 1979).

    Observations in humans

         The report based on field studies performed in Oregon by the
    American Government (US Environmental Protection Agency 1979)
    purporting to show a correlation between incidences of miscarriages
    and aerial spraying of 2,4,5-T, but lacking in supporting data on
    cause and effect, has been refuted by various authorities (Wagner
     et al 1979; Kilpatrick  et al 1980; Tschirley  et al 1979). As it
    is not accepted as being a valid study, it is not reported here.

         In extensive investigations of 13 cases in which 2,4,5-T may have
    resulted in adverse health effects in humans, no evidence could be
    found by UK authorities confirming an exposure/effect relationship
    (Kilpatrick  et al 1980).

         Other investigations quoted by Kilpatrick  et al (1980) include:
    a study by the New Zealand Department of Health in 1977 concerning a
    high incidence of neural tube defects in 3 areas of North Island. The
    Department concluded it could give "a very high assurance of safety in
    normal use" of 2,4,5-T herbicides. Other quoted studies in Victoria
    and Queensland, Australia, failed to yield any evidence of birth
    defect induction owing to 2,4,5-T in the environment.

         The Scientific Dispute Resolution Conference on 2,4,5-T (Schirley
     et al 1979) also concluded that the New Zealand and Victoria,
    Australia data failed to show any evidence of 2,4,5-T induced human

    malformations. They also indicated a Swedish National Board of Health
    and Welfare Report (1977), which reported that 10 women with infants
    suffering neural tube defects, in Varmland Country, were not exposed
    to 2,4,5-T.

         The use of 2,4,5-T in Hungary increased 30 fold between 1968 and
    1977, current use being 660 tons active ingredient per annum. Thomas
    (1980) has evaluated the national registers of compulsory notification
    of malformations between birth and 1 year of age. There are no changes
    in incidence trends with respect to stillbirths, anencephaly, spina
    bifida, cleft palate, cleft lip or cystic kidney.

         Nelson  et al (1979) performed a retrospective study on the
    possible relationship between cleft palate incidence in Arkansas and
    agricultural use of 2,4 5-T. No correlation could be detected.

         Twenty-one living, and 31 deceased male patients with soft-cell
    sarcomas, ranging from 21 to 80 years of age, were compared with 4
    matched controls for each case. Controls selected were residents of
    the same municipality as the patient at the time of hospital
    admission. Controls for the living cases were of a comparable age. For
    deceased cases, controls were of a comparable age, sex, year of death
    and residence. Age comparability was accepted as valid within ± 5
    years. Exposure to phenoxy-acetic acids, or chlorophenols, exceeding a
    duration of 1 day, at least 5 years prior to tumour diagnosis was
    determined by patient/or next of kin recall, supported where possible
    by questionnaires to employers. Of the cases, 36.5% indicated that
    there had been exposure to phenoxy-acetic acids or to chlorophenols;
    12/19 of the cases were exposed to phenoxy-acetic acids only. The
    matching controls to these twelve cases were, in one of the four
    matched controls, exposed to similar acids in 5 of the cases and to
    chlorophenols in one case.

         Data from employers pertaining to exposure was uncertain and
    "difficult to evaluate". Thus, the conclusions were based on patient
    recall, over periods commencing 5 years previously or on recall of
    next of kin over similar time periods.

         On this basis, 19/52 cases were exposed, compared with 19/206
    controls. A subdivision of the case data into living and dead showed
    a calculated risk of 9.9 for living patients, compared to 3.8 for
    deceased patients, and 5.7 for the combined groups, as compared to
    "matched" controls. The authors indicate that it is not possible to
    evaluate separately the effects of chlorophenoxyacetic acids, or of
    chlorophenols, because of the potential for contamination with such
    materials as chlorinated dioxins, dibenzofurans etc., and carriers
    such as diesel oils. Data on exposure to other pesticides were not
    considered, although most cases were from rural areas (Hardell and
    Sandstrom 1979).

    EVALUATION

    COMMENTS

         The 1979 Meeting of the JMPR expressed minimal concern with
    respect to residues of 2,4,5-T in food, but indicated that studies on
    the bioaccumulation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in
    mammalian tissues were required. Concerns were also expressed about
    TCDD levels in technical 2 4,5-T. Both of these concerns have been
    answered, and the Meeting has therefore established an ADI for
    technical 2,4,5-T containing no more than 0.01 mg/kg TCDD.

         Work on information indicated as being desirable by the 1979 JMPR
    included any available epidemiological studies. The Meeting considered
    a number of such studies, which were negative or had been of limited
    informational value. A study described in the 1979 monograph (Hardell
    and Sandstrom 1979) does not apply to 2,4,5-T containing less than
    0.01 mg/kg TCDD. Data gathering by telephone survey of individuals
    occupationally exposed to 2,4,5-T was not considered by the Meeting to
    be a suitable method of studying epidemiology.

         No data were submitted regarding interaction between 2,4,5-T and
    TCDD with respect to carcinogenicity. It was noted however, that no
    carcinogenic potential had been observed in long-term rat studies
    using 2,4,5-T containing 0.05 mg/kg TCDD, a level of TCDD considerably
    exceeding the 0.01 ppm level required by the proposed ADI.

    Level causing no toxicological effect

         Rat : Dietary administration of 3 mg/kg bw/day.

    Estimate of acceptable daily intake for man

         0 - 0.03 mg 2,4,5-T (containing not more than 0.01 mg TCDD/kg)
    per kg bw.

    FURTHER WORK OR INFORMATION

    Desirable

    Observations in humans.

    REFERENCES

    Allen, J.R., Van Miller, J.P. and Norback, D.H. Tissue
    1975      distribution, excretion and biological effects of
              ( 14C)-tetrachlorodibenzo-p-dioxin in rats. Food and
              Cosmetics Toxicology, 13: 501.505.

    Fries, G.F. and Marrow, G.S. Retention and excretion of 2,3,7,8-
    1975      tetrachlorodibenzo-p-dioxin by rats. Journal of Agricultural
              and Food Chemistry, 23: 265-269.

    Hardell, L. and Sandstrom A. Case-control study: Soft tissue sarcomas
    1979      and exposure to phenoxyacetic acids or chlorophenols.
              British Journal of Cancer, 39: 711-717.

    Jensen, D.J., Hummel, R.A., Mahle, N.H., Kocher, C.W. and Higgins,
    1981      H.S. A residue study on beef cattle consuming 2,3,7,8-
              tetrachlorodibenzo-p-dioxin. Journal of Agricultural and
              Food Chemistry, 29: 265-268.

    Kilpatrick, R. et al. Further review of the safety for use in the
    1980      U.K. of the herbicide 2,4,5-T. Advisory Committee on
              Pesticides. U.K. December.

    Murray, F.J., Smith, F.A., Nitschke, K.D., Humiston, C.G. Kociba,
    1979      R.J. and Schwetz, B.A. Three-generation reproduction study
              of rats given 2,3 7,8-tetrachlorodibenzo-p-dioxin (TCDD) in
              the diet. Toxicology and Applied Pharmacology, 50: 241-252.

    Nelson, C.J., Holson, J.F., Green, H. G. and Gaylor, D.W.
    1979      Retrospective study of the relationship between agricultural
              use of 2,4,5-T and cleft palate occurrence in Arkansas.
              Teratology, 19: 377-384.

    Olson, J.R., Gasiewiez, T.A. and Neal R.A. Tissue distribution,
    1980      excretion and metabolism of 2,3,7,8-tetrachlordibenzo-p-
              dioxin (TCDD) in the Golden Syrian hamster. Toxicology and
              Applied Pharmacology, 56: 78-85.

    Piper, W.N., Rose, J.Q. and Gehring, P.J. Excretion and tissue
    1973      distribution of 2,3,7,8 tetrachlorodibenzo-p-dioxin in the
              rat. Environmental Health Perspectives Sept. 241-244.

    Poiger, H. and Schlatter, Ch. Biological degradation of TCDD in rats.
    1979      Nature, 281:706-707.

    Poiger, H. and Schlatter, Ch. Influence of solvents and adsorbents on
    1980      dermal and intestinal absorption of TCDD. Food and Cosmetics
              Toxicology 18: 477-481.

    Rose, J.Q., Ramsey, J.C., Wentzler, T.H., Hummel, R.A. and Gehring,
    1977      P.J. The fate of 2,3,7,8-tetrachlorodibenzo-p-dioxin
              following single and repeated oral doses to the rat.
              Toxicology and Applied Pharmacology, 36: 209-226.

    Smith, F.A., Murray, F.J., John, J.A., Nitschke, K.D., Kociba, R.J.
    1981      and Schwetz, B.A. Three-generation reproduction study of
              rats ingesting 2,4,5-trichlorophenoxyacetic acid in the
              diet. Food and Cosmetics Toxicology, 19: 41-45.

    Thomas, H.F. 2,4,5-T use and congenital malformation rates in Hungary.
    1980      Lancet, 2 (8187): 214-215.

    Tschirley, F.H.  et al. Scientific dispute resolution conference on
    1979      2,4,5-T. Sponsored and published by The American Farm Bureau
              Federation, August.

    U.S. Environmental Protection Agency. Report of assessment of a field
    1979      investigation of six-year spontaneous abortion rates in
              three Oregon areas in relation to forest 2,4,5-T spray
              practices. February.

    Van Miller, J.P., Marlar, R.J. and Allen, J.R. Tissue distribution and
    1976      excretion of tritiated tetrachlorodibenzo-p-dioxin in non-
              human primates and rats. Food and Cosmetics Toxicology,
              14: 31-34.

    Wagner, S.L., Witt, J.M., Norris, L.A., Higgins, J.E., Agresti, A. and
    1979      Ortiz, M., Jr. A scientific critique of the EPA Alsea II
              study and report. Environmental Health Sciences Center,
              Oregon State University, October 25th.
    See Also:
       Toxicological Abbreviations
       T, 2,4,5- (PDS)
       T, 2,4,5- (AGP:1970/M/12/1)
       T, 2,4,5- (Pesticide residues in food: 1979 evaluations)