The in vivo biotransformation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat

Ramsey, John C.; Hefner, Jochen; Karbowski, R.J.; Braun, Werner; Gehring, P.J.

doi:10.1016/0041-008x(82)90377-5

Cited by 36 publications

(9 citation statements)

References 8 publications

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“…Moreover, the HPLC analysis showed that in both strains, the bulk of the label in the liver was linked to the parent compound, which is also in agreement with previous findings (Rose et al 1976). Although reactive metabolites of TCDD were found in one study on mice (Guenthner et al 1979), it is now generally believed that TCDD toxicity is due to the parent substance and not to its metabolites (Mason & Safe 1986;Weber et al 1982;Ramsey et al 1982;Beatty et al 1978). The levels of radioactivity in the liver were much the same in the two strains, even at 50 pg/kg of TCDD (autoradiographic data) which is a dose lethal to L-E but sublethal to H/W rats .…”

Section: Discussionsupporting

confidence: 86%

Tissue Distribution, Metabolism, and Excretion of ¹⁴C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Strain^a

Pohjanvirta

Vartiainen

Uusi-Rauva

et al. 1990

Pharmacology & Toxicology

110

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A comparative study was carried out in the most TCDD-resistant [Han/Wistar (H/W), LD50 greater than 3000 micrograms/kg] and the most TCDD-susceptible [Long-Evans (L-E), LD50 about 10 micrograms/kg] rat strain to assess the significance of kinetic factors in TCDD toxicity. Young adult males of both strains were administered 5 micrograms/kg (1.9 microCi/kg) 14C-TCDD intraperitoneally. Four rats per strain were killed at 4 hr, 1, 4, 8, 16, and 32 days after exposure. A total of 22 tissues along with blood and serum were sampled for liquid scintillation counting. From half of the animals, daily urine and faeces were also analyzed. In addition, 3 rats per strain were given 50 micrograms/kg (19 microCi/kg) 14C-TCDD and prepared for whole-body autoradiography after 1, 4 or 8 days. The livers of two rats per strain killed at 4 hr, 4 or 16 days, and the excreta from two rats of both strains collected on days 1-4, 5-8, 13-16, and 29-32 after exposure were analyzed for metabolites of TCDD by high pressure liquid chromatography. The label was mainly excreted in faeces as metabolites of TCDD, and the half-life of elimination was 20.8 (L-E) or 21.9 (H/W) days. A very similar overall distribution pattern was observed in both strains irrespective of dose, and the liver was the major site of accumulation. Practically all liver 14C-activity was found as the parent compound. Moderate strain-related differences were observed in the thyroid, thymus, prostate, adrenals, and brown and white fat, where lower values were recorded in H/W rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 86%

Tissue Distribution, Metabolism, and Excretion of ¹⁴C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Strain^a

Pohjanvirta

Vartiainen

Uusi-Rauva

et al. 1990

Pharmacology & Toxicology

110

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“…Biotransformation of TCDD is regarded as a detoxification process (Beatty et al., ; Ramsey et al., ; Weber et al., ; Mason and Safe, ), and TCDD toxicity is ascribed to the unchanged parent compound. As TCDD‐inducible CYPs appear to be involved in the biotransformation step, TCDD may generally be able to induce its own metabolism at high doses (Neal et al., ; Poiger and Buser et al., ; Poiger and Schlatter, ; Wroblewski and Olson, , ; Leung et al., ; Shinkyo et al., ; Inui et al., ).…”

Section: Assessmentmentioning

confidence: 99%

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

Knutsen¹,

Alexander²,

Barregård³

et al. 2018

EFS2

137

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The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL‐PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre‐ and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005‐TEQ/g fat in blood sampled at age 9 years based on PCDD/F‐TEQs. No association was observed when including DL‐PCB‐TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F‐TEQ only was on average 2.4‐ and 2.7‐fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL‐PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.

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“…Although metabolic transformation occurred very slowly, TCDD has been shown to be metabolized in vim and in vitro (30,31). The binding and subsequent slow metabolism of TCDD by cytochrome P-450d therefore remains a possibility, although we were never able to obtain evidence for metabolism by cytochrome P-450d in these experiments.…”

Section: Discussionmentioning

confidence: 68%

TCDD (2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin) is a tight binding inhibitor of cytochrome p‐450D

Voorman

Aust

1989

J. Biochem. Toxicol.

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Based on data indicating that compounds which induce cytochrome P-450d also bind to the enzyme [R. Voorman and S. D. Aust (1987). Toxicol. Appl. Pharmacol. 90, 69-78], we investigated the inhibition of cytochrome P-450d-dependent estradiol 2-hydroxylase by (2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD), using ligand-free cytochrome P-450d from isosafrole-treated rats. Since maximum inhibition of estradiol 2-hydroxylase occurred at TCDD concentrations comparable to the concentration of enzyme (50 nM), a modified form of steady-state kinetic analysis was used. Using I50 = Et/2 + Ki where Et = total enzyme concentration), we showed that TCDD inhibited cytochrome P-450d-dependent estradiol 2-hydroxylase activity with Ki equal to 8 nM. Association of TCDD with P-450d occurred within 2 min of inhibitor addition. Therefore, TCDD can be considered a tight binding inhibitor of cytochrome P-450d.

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The in vivo biotransformation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat

Cited by 36 publications

References 8 publications

Tissue Distribution, Metabolism, and Excretion of ¹⁴C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Strain^a

Tissue Distribution, Metabolism, and Excretion of ¹⁴C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Strain^a

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

TCDD (2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin) is a tight binding inhibitor of cytochrome p‐450D

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The in vivo biotransformation of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat

Cited by 36 publications

References 8 publications

Tissue Distribution, Metabolism, and Excretion of 14C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Straina

Tissue Distribution, Metabolism, and Excretion of 14C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Straina

Risk for animal and human health related to the presence of dioxins and dioxin‐like PCBs in feed and food

TCDD (2, 3, 7, 8‐tetrachlorodibenzo‐p‐dioxin) is a tight binding inhibitor of cytochrome p‐450D

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Tissue Distribution, Metabolism, and Excretion of ¹⁴C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Strain^a

Tissue Distribution, Metabolism, and Excretion of ¹⁴C‐TCDD in a TCDD‐Susceptible and a TCDD‐Resistant Rat Strain^a