苯系混合物对小鼠仔代形态结构,行为发育及骨髓细胞DNA合成影响的研究

雌性小鼠孕6到15天时给予苯(100mg/m~3)、甲苯(1000mg/m~3)及二甲苯1000mg/m~3)混合吸入染毒,胎鼠生长发育、形态结构及骨骼发育未见明显异常;出生仔鼠生后3周体重增长明显低于对照组,雄住仔鼠四肢肌力及协调运动发育较对照组显著延迟,雌性仔鼠兴奋性显著高于对照组。提示孕鼠器官发生期给予苯系混合物染毒,其仔代末见结构异常,但出现一定程度的行为改变。     

间苯二酚毒性研究

大鼠经口LD50为745.3mg/kg,小鼠经口LD50为286.9mg/kg。蓄积系数大于5.3,属弱蓄积级。对皮肤、眼结膜有刺激作用,无致敏作用。大鼠亚急性吸入染毒,高浓度组(229.8mg/m~3)的平均体重、肺灌流液巨噬细胞存活率和溶菌酶含量都显著低于对照组,而低浓度组(37.1mg/m~3)除肺巨噬细胞存活率明显低于对照组外,其余指标无明显改变。据此认为,慢性阈浓度为37.1mg/m~3。     

三氧化二砷、黄磷、四氯化碳的急性肝脏毒作用的研究

大鼠每日分别经口染毒三氧化二砷（45mg/kg)、黄磷（3mg/kg)、四氯化碳（990mg/kg)，连续4日后，均出现肝脏病理改变，黄磷及四氯化碳组大鼠的血清GPT和GOT活性明显升高，但三氧化二砷组则无显著变化，三个染毒组大鼠的血清和肝微粒体过氧化脂质含量、血清IgM和补体C3含量均较对照组显著升高。     

吸入大气不同浓度飘尘和二氧化硫对大鼠肺损伤的研究

将大鼠置于上海居住区(飘尘0.293mg/m~3,SO_20.018mg/m~3)和相对清洁区(飘尘0.189mg/m~3,SO_20.012mg/m~3),吸入大气121天后,大鼠的生长状况、肺灌洗液中肺巨噬细胞、细胞分类计数、LDH、ACP、AKP、NA、ALB、肺羟脯氨酸、微核测定及病理组织均未见明显异常。     

GSTP1基因低表达与全氟辛烷磺酸致大鼠肝脏氧化损伤的关系研究

目的探讨GSTP1基因低表达与全氟辛烷磺酸(PFOS)暴露致大鼠肝脏氧化损伤的关系,及其在PFOS肝毒性中的作用。方法 40只健康雄性SD大鼠随机分为空白对照组和PDFOS 0.5、5.0、20 mg/kg·bw·d 3个剂量组,经口灌胃染毒90 d,1次/d。染毒期间观察动物的毒性反应,检测肝脏病理改变及超微结构变化;硫代巴比妥酸法检测脂质过氧化产物MDA含量及总抗氧化能力T-AOC活性;荧光定量PCR方法检测GSTP1基因mRNA表达情况。结果 0.5、5.0和20 mg/kg·bw·d剂量组染毒大鼠均出现体重下降、精神状态差和躁动易激惹等中毒体征,20 mg/kg·bw·d剂量组体重降低明显、肝脏系数增加(P0.01)。病理形态学发现各剂量组大鼠肝细胞不同程度的肿胀、胞浆空泡化及囊泡样脂滴沉积等毒性病理改变。与对照组比较,5.0和20 mg/kg·bw·d剂量组肝脏MDA含量显著升高(P0.01),伴随T-AOC活性降低。Real-time PCR结果显示,肝脏GSTP1基因mRNA表达水平在PFOS中、高剂量组呈现下降趋势,20 mg/kg·bw·d组下调明显(P0.05)。GSTP1 mRNA表达水平与MDA含量呈显著负相关(r=-0.307,P=0.028)。结论 PFOS暴露大鼠肝脏组织的GSTP1 mRNA表达水平下调。GSTP1基因转录抑制可能加剧肝脏氧化损伤发生发展,与PFOS的肝脏毒性有关。     

二乙氧基乙醇对大鼠脂、糖代谢的影响

目的探讨2-乙氧基乙醇(EE)染毒对大鼠某些脂代谢指标和血糖的影响及其可能机制.方法选取雄性Wistar大鼠,随机分为4组对照组、EE 200、400和800 mg/kg组.每天灌胃染毒1次,每周6次,持续6周.分别于每周后,将各组动物随机处死5只,对血液及肝脏中的脂代谢指标进行测定.结果从第3周开始,EE染毒大鼠血清甘油三酯(TG)含量(889.6±70.2)mg/L显著高于对照组(632.0±88.2)mg/L,血清极低密度脂蛋白(VLDL)含量(177.9±14.0)mg/L显著高于对照组(126.4±17.2)mg/L;肝脏脂肪酸β-氧化速度从第3周开始显著低于对照组;肝脏TG含量仅在染毒第5和6周,中、高剂量组显著高于对照组;血清含量从第4周开始,仅中或高剂量组显著降低;血清总胆固醇(TC)、高密度脂蛋白(HDL)和低密度脂蛋白(LDL)含量未发生显著性改变.结论EE长期染毒可对大鼠脂、糖代谢造成一定影响.     

三甲基氯化锡染毒致小鼠过氧化损伤分析北大核心CSCD

目的分析三甲基氯化锡(TMT)低剂量染毒小鼠血清、肝脏和脑的氧化损伤情况方法将56只雄性昆明种小鼠分为7组,每组8只。2个实验组分别腹腔注射TMT 1.0和2.15 mg/kg,对照组给予无菌生理盐水,在染毒后24h处死,测定血清、肝脏和脑组织中的SOD和MDA水平;另外2个实验组腹腔注射TMT 2.15 mg/kg,2个对照组给予无菌生理盐水,分别于染毒后3和7 d处死,测定血清、肝脏和脑中的SOD和MDA水平。结果 2.15 mg/kg TMT染毒组动物在20 h后开始出现神经毒性症状,2.15 mg/kg TMT组动物染毒后24h,血清、肝脏和脑组织中MDA水平较对照组明显增加,肝脏SOD明显下降(P<0.01或P<0.05),1.0 mg/kg TMT染毒后24 h,血清和脑组织中MDA较对照组明显增加(P<0.01或P<0.05),2.15 mg/kg TMT染毒后3 d肝脏、脑组织SOD较对照组明显下降(P<0.01),染毒7 d,血清MDA增高,肝脏SOD水平明显下降(P<0.05)。结论给予小鼠低剂量TMT染毒小鼠24 h后,血清、肝脏和脑组织均会造成一定程度的过氧化损伤,而在染毒后3和7 d肝脏和脑中SOD会发生损耗,而小鼠过氧化损伤程度进一步缓解。     

三甲基氯化锡染毒致小鼠过氧化损伤分析

目的分析三甲基氯化锡(TMT)低剂量染毒小鼠血清、肝脏和脑的氧化损伤情况方法将56只雄性昆明种小鼠分为7组,每组8只。2个实验组分别腹腔注射TMT 1.0和2.15 mg/kg,对照组给予无菌生理盐水,在染毒后24h处死,测定血清、肝脏和脑组织中的SOD和MDA水平;另外2个实验组腹腔注射TMT 2.15 mg/kg,2个对照组给予无菌生理盐水,分别于染毒后3和7 d处死,测定血清、肝脏和脑中的SOD和MDA水平。结果 2.15 mg/kg TMT染毒组动物在20 h后开始出现神经毒性症状,2.15 mg/kg TMT组动物染毒后24h,血清、肝脏和脑组织中MDA水平较对照组明显增加,肝脏SOD明显下降(P0.01或P0.05),1.0 mg/kg TMT染毒后24 h,血清和脑组织中MDA较对照组明显增加(P0.01或P0.05),2.15 mg/kg TMT染毒后3 d肝脏、脑组织SOD较对照组明显下降(P0.01),染毒7 d,血清MDA增高,肝脏SOD水平明显下降(P0.05)。结论给予小鼠低剂量TMT染毒小鼠24 h后,血清、肝脏和脑组织均会造成一定程度的过氧化损伤,而在染毒后3和7 d肝脏和脑中SOD会发生损耗,而小鼠过氧化损伤程度进一步缓解。     

全氟辛烷磺酸对SD大鼠肝毒性及其肝脏细胞色素P450 mRNA表达的影响

目的研究全氟辛烷磺酸盐(PFOS)染毒SD大鼠后,其对大鼠肝脏毒性及细胞色素P450(CYP450)亚型mRNA表达的影响。方法 40只SD雄性大鼠,随机分为5组:4个PFOS染毒组,染毒剂量分别为0.5、1.0、3.0和10.0mg/(kg.d),1个对照组。连续灌胃染毒28 d后,分析血清生化指标和观察肝脏病理变化,并检测肝脏CYP450各亚型mRNA的表达水平。结果与对照组相比,大鼠染毒PFOS 28 d后,各染毒组大鼠的体重明显降低,10.0 mg/kg染毒组大鼠的肝脏重量显著增加。各染毒组大鼠的血清谷丙转氨酶、胆汁酸等水平显著升高,三酰甘油、总胆固醇含量降低。病理检查发现,各染毒组大鼠的肝脏细胞出现浊肿、变性,甚至坏死。此外,3.0和10.0 mg/kg组大鼠肝脏的CYP1A2mRNA水平降低,而CYP17A1 mRNA水平升高。各染毒组CYP2B1 mRNA水平均升高,呈剂量效应关系。结论 PFOS的肝毒性呈剂量效应关系,并对CYP450的各个亚型有不同影响。     

二硫化碳对妊娠母鼠及胎鼠肝混合功能氧化酶活性影响的研究

研究表明,未经苯巴比妥钠处理的妊娠母鼠,腹腔注射染毒组胎肝细胞色素P-450、细胞色素b_5和蛋白质含量均明显低于对照组。125和11mg/m~3吸入染毒组胎肝细胞色素P-450和蛋白质含量也明显低于对照组。但细胞色素b_5仅125mg/m~3染毒组低于对照组。腹腔注射CS_2染毒时,妊娠母鼠和胎鼠肝NADPH-细胞色素C-还原酶均显著高于对照组。     

Effect of polybrominated biphenyls, beta-naphthoflavone and phenobarbital on arylhydrocarbon hydroxylase activities and chloroform-induced nephrotoxicity and hepatotoxicity in male C57BL/6J and DBA/2J mice

Administration of chloroform (CHCl3) to male C57/6J (C57) and DBA/2J (DBA) mice produced dose-dependent hepatic and renal damage. Hepatic arylhydrocarbon hydroxylase (AHH) activity was higher in C57 than DBA mice; in kidney, AHH activity was higher in DBA than in C57 mice. CHCl3 caused the same degree of liver damage in both strains of mice; however, nephrotoxicity of CHCl3 was greater in DBA than in C57 mice. Pretreatment of C57 and DBA mice with phenobarbital (PB) markedly increased hepatic AHH activity and hepatotoxicity of CHCl3 in both strains but did not affect renal AHH or nephrotoxicity of CHCl3. Similarly, beta-naphthoflavone (BNF) enhanced AHH activity and CHCl3 hepatotoxicity in C57 mice, but had little effect on nephrotoxicity. BNF did not affect hepatic AHH nor CHCl3-induced hepatic injury in male DBA mice. Pretreatment with polybrominated biphenyl (PBB) enhanced AHH activity in liver and CHCl3 hepatotoxicity in both strains. After PBB, nephrotoxicity of CHCl3 and renal AHH activity were increased in C57 mice whereas PBB did not alter nephrotoxicity or renal AHH in DBA mice. These results suggest that CHCl3-nephrotoxicity is independent of hepatotoxicity.     

Correlation of a specific mitochondrial phospholipid-phosgene adduct with chloroform acute toxicity

The dose and time dependence of formation of a specific adduct between mitochondrial phospholipid and phosgene have been determined in the liver of Sprague-Dawley (SD) rats as well as in the liver and kidney of B6C3F1 mice after dosing with chloroform. Rats were induced with phenobarbital or non-induced. Determination of tissue glutathione (GSH) and of serum markers of hepatotoxicity and nephrotoxicity was also carried out. With dose-dependence experiments, a strong correlation between the formation of the specific phospholipid adduct, GSH depletion and organ toxicity could be evidenced in all the organs studied. With non-induced SD rats, no such effects could be induced up to a dose of 740 mg/kg. Time-course studies with B6C3F1 mice indicated that the specific adduct formation took place at very early times after chloroform dosing and was concurrent with GSH depletion. The adduct formed during even transient GSH depletion (residual level: 30% of control) and persisted after restoration of GSH levels. Following a chloroform dose at the hepatotoxicity threshold (150 mg/kg), the elimination of the adduct in the liver occurred within 24 h and correlated with the recovery of ALT, which was slightly increased (12 times) after treatment. Following a moderately nephrotoxic dose (60 mg/kg), the renal adduct persisted longer than 48 h, when a 100% increase in blood urea nitrogen and a 40% increase in serum creatinine indicated the onset of organ damage. The formation of the adduct in the liver mitochondria of B6C3F1 mice was associated with the decrease of phosphatidyl-ethanolamine (PE), in line with previous results in rat liver indicating that the adduct results from the reaction of phosgene with PE. The adduct levels implicated the reaction of phosgene with about 50% PE molecules in the liver mitochondrial membrane of phenobarbital-induced SD rats and of about 10% PE molecules of the inner mitochondrial membrane of the liver of B6C3F1 mice. The association of this adduct with the toxic effects of chloroform makes it a very good candidate as the primary critical alteration in the sequence of events leading to cell death caused by chloroform.     

Acute Chloroform Ingestion Successfully Treated with Intravenously Administered N-acetylcysteine

Chloroform, a halogenated hydrocarbon, causes central nervous system depression, cardiac arrhythmias, and hepatotoxicity. We describe a case of chloroform ingestion with a confirmatory serum level and resultant hepatotoxicity successfully treated with intravenously administered N-acetylcysteine (NAC). A 19-year-old man attempting suicide ingested approximately 75 mL of chloroform. He was unresponsive and intubated upon arrival. Intravenously administered NAC was started after initial stabilization was complete. His vital signs were normal. Admission laboratory values revealed normal serum electrolytes, AST, ALT, PT, BUN, creatinine, and bilirubin. Serum ethanol level was 15 mg/dL, and aspirin and acetaminophen were undetectable. The patient was extubated but developed liver function abnormalities with a peak AST of 224 IU/L, ALT of 583 IU/L, and bilirubin level reaching 16.3 mg/dL. NAC was continued through hospital day 6. Serum chloroform level obtained on admission was 91 μg/mL. The patient was discharged to psychiatry without known sequelae and normal liver function tests. The average serum chloroform level in fatal cases of inhalational chloroform poisoning was 64 μg/mL, significantly lower than our patient. The toxicity is believed to be similar in both inhalation and ingestion routes of exposure, with mortality predominantly resulting from anoxia secondary to central nervous system depression. Hepatocellular toxicity is thought to result from free radical-induced oxidative damage. Previous reports describe survival after treatment with orally administered NAC, we report the first use of intravenously administered NAC for chloroform ingestion. Acute oral ingestion of chloroform is extremely rare. Our case illustrates that with appropriate supportive care, patients can recover from chloroform ingestion, and intravenously administered NAC may be of benefit in such cases.     

Methoxsalen decreases the metabolic activation and prevents the hepatotoxicity and nephrotoxicity of chloroform in mice

The effects of methoxsalen, a potent inhibitor of cytochrome P-450, on the hepatotoxicity and nephrotoxicity of chloroform have been determined in mice. Hepatic and renal monooxygenase activities and the in vitro covalent binding of chloroform metabolites to hepatic and renal microsomal proteins were decreased by 20-70% in microsomes from mice killed 2 hr after the administration of methoxsalen (250 mumol.kg-1ip) alone. Administration of methoxsalen (250 mumol.kg-1ip), 30 min before [14C]chloroform (1 ml.kg-1ip), did not modify blood levels of [14C]chloroform (and metabolites) but decreased the in vivo covalent binding of [14C]chloroform metabolites to hepatic and renal proteins 4 hr after the administration of [14C]chloroform. This pretreatment markedly decreased serum glutamic pyruvic transaminase activity, blood urea nitrogen, glucosuria, liver and kidney lesions, and mortality 24 hr after the administration of chloroform (0.125-1.5 ml.kg-1ip). Other cytochrome P-450 inhibitors (SKF 525-A or piperonyl butoxide), given at the same molar dose (250 mumol.kg-1ip), exerted no protective effect. Pretreatment with methoxsalen appears to decrease the metabolic activation of chloroform and essentially prevents its hepatotoxicity and nephrotoxicity in mice. Methoxsalen may have use as a tool to determine the role of metabolic activation by cytochrome P-450 in the hepatotoxicity and nephrotoxicity of drugs and chemicals.     

Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage

The potential protective role of aminoguanidine (AG), gadolinium chloride (GdCl(3)) and oleanolic acid (OA) in acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity was investigated in rats. Pretreatment of rats with AG (50mg/kg) orally, GdCl(3) (10mg/kg) intramuscularly or OA (25mg/kg) intramuscularly protected markedly against hepatotoxicity and nephrotoxicity induced by an acute oral toxic dose of APAP (2.5g/kg) as assessed by biochemical measurements and by histopathological examination. None of AG-, GdCl(3)- or OA-pretreated animals died by the acute toxic dose of APAP. Concomitantly, pretreatment of rats with these agents suppressed the profound elevation of nitric oxide (NO) production and obvious reduction of intracellular reduced glutathione (GSH) levels in liver and kidney induced by the acute toxic dose of APAP. Similarly, daily treatment of rats with a smaller dose of AG (10mg/kg), GdCl(3) (3mg/kg) or OA (5mg/kg) concurrently with a smaller toxic dose of APAP (750mg/kg) for 1 week protected against APAP-induced hepatotoxicity and nephrotoxicity. This treatment also completely prevented APAP-induced mortality and markedly inhibited APAP-induced NO overproduction as well as hepatic and renal intracellular GSH levels reduction. These results provide evidence that inhibition of NO overproduction and consequently maintenance of intracellular GSH levels may play a pivotal role in the protective effects of AG, GdCl(3) and OA against APAP-induced hepatic and renal damages.     

女性艾滋病患者接受奈韦拉平抗病毒治疗方案致肝毒性的临床观察

目的探讨女性艾滋病患者在CD4+T淋巴细胞计数≥250个/μl时使用奈韦拉平(NVP)抗病毒治疗方案是否会增加肝毒性。方法选取女性艾滋患者158例,其中CD4+T淋巴细胞计数≥250个/μl者86例设为高CD4+组,CD4+T淋巴细胞计数<250个/μl者72例设为低CD4+组。分别于治疗前、治疗后1个月、2个月、3个月、6个月、9个月、12个月检测肝功能、血常规、CD4+T淋巴细胞等,分析2组患者3个月内的肝功能变化,并观察2组肝损害程度。结果低CD4+组治疗后(1个月、2个月、3个月)ALT水平均高于治疗前,差异均有统计学意义(P<0.05);高CD4+组患者治疗后(1个月、2个月)ALT水平均高于治疗前,差异均有统计学意义(P<0.05)。2组患者治疗后(1个月、2个月、3个月)TBIL水平均高于治疗前,差异均有统计学意义(P<0.05)。2组治疗后肝损害程度明显增加(P<0.05),且2组治疗后比较差异无统计学意义(P>0.05)。结论高效抗逆转录病毒治疗中奈韦拉平发生肝毒性较常见,女性艾滋病患者CD4+T淋巴细胞计数≥250个/μl时使用含有奈韦拉平的治疗方案未增加肝毒性。     

The potential protective role of alpha-lipoic acid against acetaminophen-induced hepatic and renal damage

The potential protective role of alpha-lipoic acid (alpha-LA) in acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity was investigated in rats. Pretreatment of rats with alpha-LA (100mg/kg) orally protected markedly against hepatotoxicity and nephrotoxicity induced by an acute oral toxic dose of APAP (2.5 g/kg) as assessed by biochemical measurements and by histopathological examination. None of alpha-LA pretreated animals died by the acute toxic dose of APAP. Concomitantly, APAP-induced profound elevation of nitric oxide (NO) production and oxidative stress, as evidenced by increasing of lipid peroxidation level, reducing of glutathione peroxidase (GSH-Px) activity and depleting of intracellular reduced glutathione (GSH) level in liver and kidney, were suppressed by pretreatment with alpha-LA. Similarly, daily treatment of rats with a smaller dose of alpha-LA (25mg/kg) concurrently with a smaller toxic dose of APAP (750 mg/kg) for 1 week protected against APAP-induced hepatotoxicity and nephrotoxicity. This treatment also completely prevented APAP-induced mortality and markedly inhibited APAP-induced NO overproduction and oxidative stress in hepatic and renal tissues. These results provide evidence that inhibition of NO overproduction and maintenance of intracellular antioxidant status may play a pivotal role in the protective effects of alpha-LA against APAP-induced hepatic and renal damage.     

Mechanism of chloroform nephrotoxicity : I. Time course of chloroform toxicity in male and female mice

Chloroform (CHCl3) nephrotoxicity in male mice could be detected as early as 2 hr after CHCl3 administration (250 microliter/kg, sc) as decreased ability of renal cortical slices to accumulate p-aminohippurate (PAH) and tetraethylammonium (TEA). The decrease was preceded and paralleled by a reduction of renal cortical nonprotein sulfhydryl (NPSH) concentration, an index of tissue reduced glutathione concentration. Histologic alterations were not observed until NPSH concentrations and PAH and TEA accumulation had reached the nadir, 5 hr after CHCl3 administration. Female mice exhibited no evidence of nephrotoxicity to CHCl3 even when the dose was increased to 1000 microliter/kg or when pretreated with diethyl maleate to reduce renal cortical NPSH concentrations prior to CHCl3 injection. The extent of hepatotoxicity was similar in male and female mice and decreases of hepatic NPSH concentrations also were detected by 1.5 hr after CHCl3 administration. The rapid response of the kidney to CHCl3 toxicity in male mice and the similarity of liver toxicity in both sexes suggests that nephrotoxicity occurs independently of hepatotoxicity. Furthermore, the ability to detect these early changes in vivo following CHCl3 administration may permit the development of an in vitro model to evaluate the mechanism of CHCl3 nephrotoxicity.     

Chloroform inhalation exposure conditions necessary to initiate liver toxicity in female B6C3F1 mice.

Chloroform is a nongenotoxic-cytotoxic carcinogen in rodent liver and kidney, including the female B6C3F1 mouse liver. Because tumors are secondary to events associated with cytolethality and regenerative cell proliferation, these end points are valid surrogates for tumor formation in cancer risk assessments. The purpose of the experiments presented here was to more clearly define the combinations of atmospheric concentration and duration of exposure necessary to induce cytolethality and regenerative cell proliferation in the sensitive female B6C3F1 mouse liver. Female B6C3F1 mice were exposed to chloroform by inhalation for 7 consecutive days using atmospheres of 10, 30, or 90 ppm and selected exposure times of 2, 6, 12, or 18 h/day. Bromodeoxyuridine (BrdU) was given the last 3.5 days via an implanted osmotic pump to label cells in S-phase. Labeled hepatocytes were visualized immunohistochemically, and the labeling index (LI) was determined as the percentage of cells in S-phase. LI was a more sensitive indicator of cellular damage than histopathological examination and is the more conservative end point for use in risk assessments. Significant concentration and exposure time related increases in LI were observed at 30 and 90 ppm but not at any 10-ppm exposure. These data defined an empirical relationship for the combinations of airborne exposure concentration and duration needed to induce cytolethality. These results suggest that concentrations of about 10 ppm or below will not induce hepatotoxicity in these mice regardless of exposure duration. Thus, the rate of production of toxic metabolites and the subsequent rate of cellular damage produced by a continual exposure of approximately 10 ppm chloroform are less than the maximum rates at which hepatocytes can detoxify those metabolites and repair any induced cellular damage. A physiologically based pharmacokinetic (PBPK) dosimetry model was used to compare anticipated responses in mice and humans and predicted that chloroform concentrations of approximately an order of magnitude greater than 10 ppm would be required to induce human liver toxicity. Thus, no safety factor to account for species to species extrapolation should be required in formulating a chloroform inhalation cancer risk assessment based on the dose x time inhalation data presented here.     

Acute nephrotoxicity of 1,1-dichloroethylene in the rat after inhalation exposure

A renal toxicity of 4 h inhalation exposure to 1,1-dichloroethylene (vinylidene chloride; VDC) was studied in male Sprague-Dawley rats. Kidney wt./body wt. ratios, serum urea nitrogen and creatinine levels were significantly increased 24 h after exposure to 250 ppm or more of VDC. Histopathologic examination by light microscopy of hematoxylin and eosin (H&E)-stained sections revealed severe tubular necrosis with calcium deposits at the higher exposure concentrations. Specific staining for calcium oxalate was negative, indicating that biotransformation of VDC to oxalate is probably not responsible for its nephrotoxicity. Pretreatment with polychlorinated biphenyl (PCB) induced the level of renal cytochrome P-450. Phenobarbital (PBT) pretreatment did not alter the renal P-450 level, but both PCB and PBT pretreatments antagonized VDC nephrotoxicity. These pretreatments have also been reported to antagonize VDC-induced hepatotoxicity. In summary, inhalation of VDC is nephrotoxic in the rat; the mechanism of nephrotoxicity does not involve calcium oxalate formation, and the magnitude of nephrotoxicity does not correlate directly with the total amount of renal cytochrome P-450.