Source: EPA, 1989.

+ = observed.

+/- = observed to limited extent, or +/- results.

0 = not observed.

Notes:

a. All human data assume a background level of 60 ppt TEQs in serum (lipid adjusted) in addition to the dioxin levels presented in the referenced papers. Dioxins are assumed to be distributed in the body lipid. Thus the concentration of dioxins in serum expressed as lipid adjusted are assumed to be equivalent to the concentration of dioxins in total body lipids. In addition, the average person is assumed to weigh 70 kg with 15% of the weight from body fat. Hence a person with background levels of 60 ppt TEQs in serum (lipid-adjusted levels) has a body burden of 9 ppt or 9 ng/kg. Although unpublished studies in our laboratory indicate that untreated 150-day-old mice also have background levels of dioxins and dibenzofurans of approximately 4 ng TEQ/kg, these values were not included in body-burden estimates for the effects seen in experimental animals.

b. The lower value, 45 ng/kg, is from a patient with chloracne who had the lowest reported serum dioxin level for any patient with chloracne (Ryan et al., 1990). In this patient adipose tissue levels at the time of exposure, and the development of chloracne, are estimated by the authors (Ryan et al., 1990) based on the patient's adipose tissue level of dioxins of 237 ppt and assuming a half-life of dioxin of 7.1 years. The higher of the two values is from Ryan et al., 1989 and represents the average body burden of dioxins in persons from Yu-Cheng who developed chloracne (Beck et al., 1989). Estimates of body burdens from the Yu-Cheng patients were determined by Ryan et al. in Beck et al. (1989).

c. Animal administered 1 µg/kg TCDD and it is assumed that essentially no TCDD was eliminated when the animal developed a chloracnegenic response. This is a LOEL dose; no lower doses were tested.

d. Assumes the same rate of elimination as the rat and that the animals weighs 2.5 kg throughout the experiment. This is a LOEL dose and no lower doses were tested.

e. Assumes a half-life of 11 days and an average weight of the animal at 25 grams. This is a LOEL dose, and no lower doses were administered.

f. According to the author (Lucier, 1991), in highly exposed patients from Yu-Cheng, there is a decrease in birth weights of children born from these patients compared to unexposed control populations. In addition, there is an association between placental levels of dioxins and alterations in placental epidermal growth factor receptor (EGFR) and CYP1A1. In addition, the author suggested that the changes in placental EGFR and CYP1A1 in these patients were maximal. Body burdens determined based on levels of 2,3,4,7,8-pentachlorodibenzofuran (TEF=0.1) and 1,2,3,4,7,8-hexachlorodibenzofuran in placenta tissue. Assumes placenta is 1% lipid (Beck et al., 1994) and that women have a fat content of 21% of body weight (Ganong, 1982). Also used these body burdens to estimate body burden of mothers of the children with decreased growth (Guo et al., 1994) and delayed developmental milestones (Rogan et al., 1988). All patients are from the Yu-Cheng rice oil poisoning.

g. Assumes pups exposed to an equal dose of TCDD as are the dams on a weight basis and that the pups do not eliminate any of the TCDD. For decreased body weight in pups 400 ng/kg is the LOEL, a dose of 64 ng/kg to the dam was the NOEL for this response. For decreased sperm count, the LOEL is 64 ng/kg, and no lower doses were tested.

h. Assumes a single first-order elimination rate constant and a half-life for the whole body elimination of 400 days (McNulty, 1985) and a gastrointestinal absorption of 86% (Rose et al., 1976). This is the LOEL from this study; no lower doses tested.

i. From Tritscher et al. (1992) and Maronpot et al. (1993). Liver levels measured in study at approximately 30 ppb. Liver and body weights were reported in 40. Assumes animal is 20% body fat by weight and that at this dose, the liver has four times the concentration of TCDD than adipose tissue. The body-burden calculation assumes that liver and fat account for 90% of the body burden in these animals. For tumor promotion, this is the LOEL in these animals. A NOEL for tumor promotion was observed at a dose of 35 ng/kg/d. For induction of CYP1A1 and downregulation of EGF-R, this body burden produces a maximal response.

j. Animals received a single dose and were sacrificed 24 hours later. Assumes no TCDD eliminated at this time. CYP1A1 induction determined by RT-PCR. This is the LOEL for this response; a NOEL from this study is 0.1 ng/kg.

k. Animals received 1.5 ng/kg/d, 5 d/wk for 13 wk. Animals sacrificed 3 days after last dose. Hepatic, dermal, and pulmonary EROD activity induced at this dose. Tissue levels measured in liver, skin, and fat. Assumes 100% of the body burden is in liver, skin, and fat. This is the LOEL from this study; no lower doses were tested.

l. Body burdens are estimated by Zinkl et al. (1973) for the increased accumulation of PCDD/PCDF in liver compared to adipose tissue.

m. Assumes a background TEQ of 60 ppt for dioxins, dibenzofurans, and PCBs. Also assumes a body weight of 70 kg with 15% body fat.

n. Data from DeVito and Birnbaum. TEQ for TCDD 1,2,3,7,8-PCDD; 2,3,7,8-TCDF; 1,2,3,7,8-PCDF; 2,3,4,7,8-PCDF; and OCDF in 150 day old female B6C3F1 mice. Chemicals were determined in liver, fat and skin of these animals. Assumes that 100% of the body burden is in liver, fat, and skin.

 

 

 

Notes:

a. Estimated highest body burden at time of last exposure. Calculations based on measured TCDD levels in serum (lipid adjusted) and assuming a first-order elimination kinetics and a half-life for elimination of 7.1 years. Also assumes a body weight of 70 kg and 22% body fat. Calculations for estimated serum concentrations at last time of exposure performed by authors (Fingerhut et al., 1991; Bertazzi et al., 1993).

b. Animals administered 100 µg/kg six times over a 4-week period. Assumes a half-life of 23.4 days and that animals are sacrificed at 10 months after the first dose. This is the LOEL; however, no other doses tested in this study.

c. Assumes a single first-order elimination rate constant and a half-life for the whole body elimination of 23.7 days (Rose et al., 1976) and a gastrointestinal tract absorption of 86% (Rose et al., 1976). This is the LOEL of the study; a dose of 10 ng/kg/d was also tested with no significant increase in tumors.

d. Body burden estimated from animals treated with 450 ng/kg/d for 90 days (DeVito and Birnbaum, unpublished results).

e. From Tritscher et al. (1992) and Maronpot et al. (1993). Liver levels measured in study at approximately 30 ppb. Liver and body weights were reported in White and Gasiewicz (1993). Assumes animal is 20% body fat by weight and that at this dose, the liver has four times the concentration of TCDD than adipose tissue. The body-burden calculation assumes that liver and fat account for 90% of the body burden in these animals. For tumor promotion, this is the LOEL in these animals. A NOEL for tumor promotion was observed at a dose of 35 ng/kg/d. For induction of CYP1A1 and downregulation of EGF-R, this body burden produces a maximal response.

f. Assumes an elimination rate of 11 days and a body weight of 20 grams.

g. From Egeland et al. (1994) in which workers with half-life extrapolated levels of TCDD of 496-1,860 ppt have a greater percentage of workers with low testosterone levels. Extrapolation performed by Egeland et al. (1994) assuming a half-life of 7.1 years. Also assumed that the background TEQ was 60 ppt so that the total serum TEQ was 496 ppt + 60 ppt = 556 ppt (lipid adjusted). Average worker was male weighing 70 kg with 15% body fat.

h. Animals received single exposure of 12.5 µg/kg (LOAEL) and sacrificed 7 days after dosing. Assumes a half-life of 23.4 days and body burden corrected for elimination. A dose of 6.25 µg/kg was tested and is the NOEL for this study.

i. From Ranch Hand study (Sweeney et al., 1992), assumes that high exposed group (>33 ppt) had a background of 60 TEQ ppt. Thus, this group had at least 93 TEQ ppt. Assumes average Ranch Hand patient was male weighing 70 kg with 15% body fat.

j. Same assumptions in note g except average serum level in affected workers is 640 ppt.

k. Guinea pigs received 0.03 µg TCDD/kg i.p. and sacrificed 24 hours after dose. Assumes that no TCDD was eliminated at this time. This is a LOEL; no other doses tested.

l. Animals were treated with 0.1 µg/kg/day for 30 days and assumes half-life of TCDD in the rat is 23.4 days.

m. Assumes a background TEQ of 60 ppt for dioxins, dibenzofurans, and PCBs. Also assumes a body weight of 70 kg with 15% body fat.

n. Data from DeVito and Birnbaum (1994). TEQ for TCDD, 1,2,3,7,8-PCDD; 2,3,7,8-TCDF; 1,2,3,7,8-PCDF; 2,3,4,7,8-PCDF; and OCDF in 150-day-old female B6C3F1 mice. Chemicals were determined in liver, fat, and skin of these animals. Assumes that 100% of the body burden is in liver, fat, and skin.

Notes:

a. Assumes a single first-order elimination rate constant and a half-life for the whole body elimination of 400 days (McNulty, 1985) and a gastrointestinal absorption of 86% (Rose et al., 1976). This is the LOEL from this study; no lower doses tested.

b. Assuming a single first-order elimination rate constant and a half-life of 6-8 wks. Body burdens calculated by authors (Neubert et al., 1992).

c. Body burden determined in these animals (Diliberto et al., submitted). Approximately 70% of the body burden remains at 7 days after dosing. This is the LOEL from this study. A dose of 5 ng/kg was also tested in this study with no effect (NOEL).

d. Assumes pups exposed to an equal dose of TCDD as are the dams on a weight basis and that the pups do not eliminate any of the TCDD. For decreased body weight in pups 400 ng/kg is the LOEL, a dose of 64 ng/kg to the dam was the NOEL for this response. For decreased sperm count, the LOEL is 64 ng/kg, and no lower doses were tested.

e. Assumes a background TEQ of 60 ppt for dioxins, dibenzofurans, and PCBs. Also assumes a body weight of 70 kg with 15% body fat.

f. Data from DeVito and Birnbaum (1994). TEQ for TCDD, 1,2,3,7,8-PCDD; 2,3,7,8-TCDF; 1,2,3,7,8-PCDF; 2,3,4,7,8-PCDF; and OCDF in 150-day-old female B6C3F1 mice. Chemicals were determined in liver, fat, and skin of these animals. Assumes that 100% of the body burden is in liver, fat, and skin.

Notes:

a. Using gel retardation assay, Probst et al. (1993) compared the ability of the Ah receptor isolated from either murine or human cell lines to bind to a dioxin response element (DRE). The authors used only one concentration of TCDD for either cell type, 2 nM for murine cells and 10 nM for human cells.

b. White and Gasiewicz (1993) compared the ability of Ah receptors isolated from either murine or human cell lines to bind to a DRE found in the human estrogen receptor (ER) structural gene. Concentration values are binding affinities to this DRE.

c. Splenic lymphocytes from C57Bl/6 mice and peripheral blood lymphocytes were isolated, cultured, and exposed to TCDD. EROD activity, a marker for CYP1A1, was determined following TCDD exposure. Data presented are EC₅₀.

d. Abbott and Birnbaum (1991) compared the cytotoxic effects of TCDD on organ culture of human, mouse, and rat embryonic palatal shelves. Embryonic palates from human mouse and rat were grown in the same organ culture system and exposed to TCDD. Cytotoxicity was detected using transmission electron microscopy. Concentrations are the lowest observable effect level.

e. Neubert et al. (1991) isolated lymphocytes from human and primates and determined lymphocyte subsets following antigen stimulation in cells treated with TCDD. The concentration is the level at which the authors describe a consistent effect on lymphocyte subsets in this system.

f. Thymocytes were isolated from either human or murine sources and cocultured with a human thymic epithelium culture (human thymocytes) or with murine thymic epithelium (murine thymocytes). The incorporation of tritiated thymidine was determined in cells treated with TCDD following antigen stimulation. Data presented are LOEL for both cell lines.

g. Human tonsilar lymphocytes and murine splenic lymphocytes were used to isolate B cells. Human and murine B cells were grown under identical conditions and exposed to TCDD. Proliferation and IgM secretion were determined in response to different concentrations of TCDD ranging from 0.3 to 30 nM. Values presented are LOELs from Wood et al. (1993).