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
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1975 distribution, excretion and biological effects of
( 14C)-tetrachlorodibenzo-p-dioxin in rats. Food and
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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,
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