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- (AGP:1970/M/12/1) T, 2,4,5- (Pesticide residues in food: 1979 evaluations)