Diliberto J J, Akubue P I, Luebke R W, Birnbaum L S
Environmental Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Toxicol Appl Pharmacol. 1995 Feb;130(2):197-208. doi: 10.1006/taap.1995.1025.
Tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to be dose-dependent in rats. However, no reported studies in mice have demonstrated dose- and time-dependent distribution of TCDD and the potential sensitivities of target tissues to enzyme induction. The objectives of this study were to determine in mice the effects of dose (0, 0.1, 1, or 10 micrograms [3H]TCDD/kg) and time (7, 14, 21, and 35 days posttreatment) on tissue distribution (18 tissues) and enzyme induction (CYP1A1 in liver, skin, and lung and CYP1A2 in liver). Distribution of TCDD-derived radioactivity in all tissues was dose- and time-dependent with nonlinear distribution. Liver-to-adipose tissue concentration ratios range from 0.6 to 3.1 (low to high dose at Day 7) demonstrating a dose-dependent shift in the disposition of TCDD. In contrast to liver, relative concentrations of percentage dose/g and percentage dose/total tissue decreased with increasing doses in all other tissues. At Day 7 and lowest dose, all tissues contained < 3% dose/g except for thyroid, adrenals, skin, liver, and adipose tissue which had 3, 6, 6, 15, and 24% dose/g, respectively. Induction of EROD activity, a marker for CYP1A1, was dose-dependent in liver, lung, and skin but did not parallel tissue concentrations of TCDD. At the highest dose, fold induction of EROD activity was two times greater in lung than liver, while the concentration in liver was 100 times greater than that in lung. Fold inductions of EROD activity in liver and skin were similar but the concentration was 20 times greater in liver than that in skin. Induction of hepatic acetanilide-4-hydroxylase (ACOH) activity, a CYP1A2 marker, was dose-dependent. Results of the present study demonstrated dose and time dependency in tissue distribution and induction of CYP1A1 and CYP1A2 as well as tissue sensitivities for enzyme induction in the female B6C3F1 mouse. These results provide important considerations for high- to low-dose extrapolations in risk assessments and use of sensitive markers of enzyme induction as surrogates for estimating exposure and in predicting risk.
2,3,7,8-四氯二苯并对二恶英（TCDD）在大鼠体内的组织分布已显示出剂量依赖性。然而，在小鼠中尚未有研究报道TCDD的剂量和时间依赖性分布以及靶组织对酶诱导的潜在敏感性。本研究的目的是确定在小鼠中剂量（0、0.1、1或10微克[³H]TCDD/千克）和时间（处理后7、14、21和35天）对组织分布（18种组织）和酶诱导（肝脏、皮肤和肺中的CYP1A1以及肝脏中的CYP1A2）的影响。TCDD衍生放射性在所有组织中的分布呈剂量和时间依赖性，且分布是非线性的。肝脏与脂肪组织的浓度比范围为0.6至3.1（第7天从低剂量到高剂量），表明TCDD的处置存在剂量依赖性变化。与肝脏相反，在所有其他组织中，每克组织的剂量百分比和总组织剂量百分比的相对浓度随剂量增加而降低。在第7天和最低剂量时，除甲状腺、肾上腺、皮肤、肝脏和脂肪组织分别含有3%、6%、6%、15%和24%的每克剂量外，所有组织每克组织所含剂量均<3%。作为CYP1A1标志物的EROD活性诱导在肝脏、肺和皮肤中呈剂量依赖性，但与TCDD的组织浓度不平行。在最高剂量时，肺中EROD活性的诱导倍数比肝脏大两倍，而肝脏中的浓度比肺中的浓度大100倍。肝脏和皮肤中EROD活性的诱导倍数相似，但肝脏中的浓度比皮肤中的浓度大20倍。作为CYP1A2标志物的肝脏乙酰苯胺-4-羟化酶（ACOH）活性诱导呈剂量依赖性。本研究结果表明，在雌性B6C3F1小鼠中，组织分布以及CYP1A1和CYP1A2的诱导存在剂量和时间依赖性，以及组织对酶诱导的敏感性。这些结果为风险评估中的高剂量到低剂量外推以及使用酶诱导的敏感标志物作为估计暴露和预测风险的替代物提供了重要考虑因素。
