Fundamental and Applied Toxicology最新文献

{"title":"The Ototoxicity of Trichloroethylene: Extrapolation and Relevance of High-Concentration, Short-Duration Animal Exposure Data","authors":"K.M. Crofton ,&nbsp;X. Zhao","doi":"10.1006/faat.1997.2327","DOIUrl":"10.1006/faat.1997.2327","url":null,"abstract":"<div><p>Inhalation exposure to high concentrations of 1,1,2-trichloroethylene (TCE) has been shown to damage hearing in the mid-frequency range in the rat. The present study directly evaluated the adequacy of high-concentration, short-term exposures to TCE for predicting the neurotoxicity produced by longer duration exposures. Adult male Long–Evans rats (<em>n</em>= 10–12 per group) were exposed to TCE via inhalation (whole body) in 1-m³stainless steel flow-through chambers for 6 hr/day, 5 days/week. The following exposures were used: 1 day (4000–8000 ppm), 1 week (1000–4000 ppm), 4 weeks (800–3200 ppm), and 13 weeks (800–3200 ppm). Air-only exposed animals served as controls. Auditory thresholds were determined for a 16-kHz tone 3–5 weeks after exposure using reflex modification audiometry. Results replicated previous findings of a hearing loss at 16 kHz for all exposure durations. The dB15 concentrations (concentration that increases thresholds by 15 dB) for 16-kHz thresholds were 6218, 2992, 2592, and 2160 ppm for the 1-day, 1-week, 4-week and 13-week exposures, respectively. These data demonstrate that the ototoxicity of TCE was less than that predicted by a strict concentration × time relationship. These data also demonstrate that simple models of extrapolation (i.e.,<em>C × t = k</em>, Haber's Law) overestimate the potency of TCE when extrapolating from short-duration to longer-duration exposures. Furthermore, these data suggest that, relative to ambient or occupational exposures, the ototoxicity of TCE in the rat is a high-concentration effect.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"38 1","pages":"Pages 101-106"},"PeriodicalIF":0.0,"publicationDate":"1997-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2327","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20211250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changing Times Require Changing Behavior","authors":"Philip G. Watanabe (Founding Coeditor)","doi":"10.1006/faat.1997.2324","DOIUrl":"10.1006/faat.1997.2324","url":null,"abstract":"","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Page 101"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2324","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20186436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trichloroethylene-Induced Mouse Lung Tumors: Studies of the Mode of Action and Comparisons between Species","authors":"T. Green ,&nbsp;G.W. Mainwaring,&nbsp;J.R. Foster","doi":"10.1006/faat.1997.2312","DOIUrl":"10.1006/faat.1997.2312","url":null,"abstract":"<div><p>CD-1 mice exposed to 450 ppm trichloroethylene, 6 hr/day, 5 days/week, for 2 weeks showed a marked vacuolation of lung Clara cells after the first exposure of each week and a marked increase in cell division after the last exposure of each week. The damage seen in mouse lung Clara cells is caused by an accumulation of chloral resulting from high rates of metabolism of trichloroethylene but poor clearance of chloral to trichloroethanol and its glucuronide. The activity and distribution of the key metabolizing enzymes in this pathway have been compared in mouse, rat, and human lung. While mouse lung microsomal fractions were able to metabolize trichloroethylene to chloral at significant rates, the rate in rat lung was 23-fold lower and a rate could not be detected in human lung microsomes at all. Immunolocalization of cytochrome P450IIE1 in lung sections revealed high concentrations in mouse lung Clara cells with lesser amounts in type II cells. Lower levels of enzyme could be detected in Clara cells of rat lung, but not at all in human lung sections. Western blots of lung tissues from the three species and of mouse lung Clara cells were entirely consistent with these observations. Consequently, it is highly unlikely that humans exposed to trichloroethylene are at risk from the lung damage/cell proliferation mechanism that is believed to lead to the development of tumors in the mouse lung.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 125-130"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20187035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Testis Exposure Levels in the Insensitivity of Prepubertal Rats to Carbendazim-Induced Testicular Toxicity","authors":"Junghee Lim,&nbsp;Marion G. Miller","doi":"10.1006/faat.1997.2315","DOIUrl":"10.1006/faat.1997.2315","url":null,"abstract":"<div><p>Our recent studies have indicated that benomyl (BNL)-induced testicular toxicity is mediated by its major metabolite carbendazim (CBZ). The present study has used CBZ to investigate hypotheses that could explain prepubertal insensitivity to BNL. When CBZ (164 mg/kg intraperitoneally) was administered to postpubertal and prepubertal rats, it caused little testicular damage in prepubertal rats, but in adult rats, sloughing of the seminiferous epithelium resulted. When the inhibitory effect of CBZ on prepubertal testicular microtubule assembly was compared with that on postpubertal assembly, the IC50 values were very similar. Pharmacokinetic studies revealed that blood levels of CBZ were comparable in the two age groups; however, higher levels of CBZ were found in the adult testes (210.52 nmol/g wet wt) in comparison with young testes (67.77 nmol/g wet wt). These data suggest that delivery to and/or retention of CBZ in the testis may play a role in the age-dependent differences in susceptibility to CBZ toxicity. When CBZ was administered intratesticularly to reach levels sufficient to cause damage, the young animals did show an increased incidence of vacuolization and detachment of the seminiferous epithelium; however, in contrast to the older animals, sloughing of the seminiferous epithelium was not observed in the prepubertal animals. Overall, the low levels of CBZ measured in the testes of prepubertal animals offer a partial explanation for the insensitivity of young animals to CBZ-induced testicular toxicity following intraperitoneal administration. A differential responsiveness between the two age groups is also likely, however, since prepubertal animals lack elongated spermatids and it is sloughing of this cell type that characterizes CBZ-induced testicular toxicity in the adult.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 158-167"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20187039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differences in Behavior among the Chlorides of Seven Rare Earth Elements Administered Intravenously to Rats","authors":"Yumiko Nakamura ,&nbsp;Yukari Tsumura ,&nbsp;Yasuhide Tonogai ,&nbsp;Tadashi Shibata ,&nbsp;Yoshio Ito","doi":"10.1006/faat.1997.2322","DOIUrl":"10.1006/faat.1997.2322","url":null,"abstract":"<div><p>Differences in behavior among the chlorides of seven rare earth elements (REEs)—yttrium (Y), cerium (Ce), and praseodymium (Pr) (light REEs); europium (Eu) and dysprosium (Dy) (medium REEs); ytterbium (Yb) and lutetium (Lu) (heavy REEs)—were investigated through intravenous administration of the REEs to rats. (1) Distributions of REEs and mineral concentrations in the organs on Day 1 were investigated at low and high doses (9–10 and 18–20 mg REE/kg, or 56–66 and 112–132 μmol REE/kg). More than 78% of the REEs administered was distributed into liver, bone, and spleen. High doses of Y, Eu, and Dy markedly increased the accumulation of REEs in spleen and lungs as well as the concentration of Ca in liver, spleen, and lungs. (2) The distribution patterns of REEs and changes in Ca concentrations in major organs over time were investigated by the administration of Pr, Eu, Dy, Yb (low dose), and Y (high dose). REEs disappeared from the blood within 1 day but were retained in the organs for a long time. The percentages of the doses of Y, Eu, Dy, and Yb found in the liver were highest at 8 hr to 2 days, then decreased gradually; hepatic Pr levels, however, remained high. Changes in Ca concentrations in liver, spleen, and lungs were in accordance with those of REEs. (3) Severe hepatotoxicity was observed after administration of Ce and Pr; fatty liver, jaundice, and elevated serum GOT and GPT levels were most prominent on Day 3. Therefore, we hypothesized that REE chlorides might be categorized into three groups according to their ionic radii (light REEs, Y and medium REEs, and heavy REEs) and from their behavior, i.e., distribution pattern, Ca-accumulating action, and hepatotoxicity.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 106-116"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20187033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Rapidin VitroAssay for Evaluation of Metabolism-Dependent Cytotoxicity of Antiepileptic Drugs on Isolated Human Lymphocytes","authors":"Ali R. Tabatabaei ,&nbsp;Robert L. Thies ,&nbsp;Kevin Farrell ,&nbsp;Frank S. Abbott","doi":"10.1006/faat.1997.2316","DOIUrl":"https://doi.org/10.1006/faat.1997.2316","url":null,"abstract":"<div><p><em>In vitro</em>assessment of human lymphocyte viability by trypan blue dye exclusion in the presence of an external metabolizing system (microsomes plus NADPH) has been shown to be a useful method in assessing predisposition to idiopathic toxicity in response to various anticonvulsant drugs. The trypan blue method, however, is labor intensive, is time consuming, is prone to human error, is not suitable for high-volume toxicity screening, and excludes autolysed cells. The objective of this study was to develop a rapid, high-capacity, objective, and easy<em>in vitro</em>cytotoxicity method for the detection of metabolism-dependent cytotoxicity of a test chemical. The<em>in vitro</em>system uses an external metabolizing system (rabbit microsomes) in conjunction with isolated human lymphocytes as the target cells. Cellular toxicity was determined by assessing plasma membrane integrity using a membrane-impermeant fluorescent nucleic acid dye (YO-PRO-1) and a multiwell plate scanner for fluorescence. Using this system, cells incubated with either acetaminophen (1500 μg/ml), carbamazepine (62.5 μ<span>m</span>), phenytoin (62.5 μ<span>m</span>), or phenobarbital (62.5 μ<span>m</span>) showed net increases in percentage cell death of 31 ± 5, 11 ± 4, 0 ± 3, and 2 ± 3, respectively. A metabolism-dependent concentration–response was observed for valproic acid-induced cytotoxicity, which approached a plateau at a concentration of 4000 μg/ml with a net percentage cell death of 31 ± 4. This technique resolves various technical difficulties inherent in viability determinations by the trypan blue exclusion method. The YO-PRO-1 method also may be useful in a clinical setting for the assessment of patients with a genetically determined susceptibility to certain drugs and for identifying the responsible drug in patients with idiopathic toxicity undergoing multiple-drug therapy.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 181-189"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137367218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytochrome P450-Mediated Metabolism and Nephrotoxicity ofN-(3,5-Dichlorophenyl)succinimide in Fischer 344 Rats","authors":"Alexander K. Nyarko ,&nbsp;Ginny L. Kellner-Weibel ,&nbsp;Peter J. Harvison","doi":"10.1006/faat.1997.2321","DOIUrl":"10.1006/faat.1997.2321","url":null,"abstract":"<div><p>The agricultural fungicide<em>N</em>-(3,5-dichlorophenyl)succinimide (NDPS) is nephrotoxic in rats. Previous studies have suggested that oxidative hepatic biotransformation is required for the induction of kidney damage. The experiments described in this paper were designed to further investigate the relationship between NDPS metabolism and nephrotoxicity using various modulators of cytochrome P450 activity. Male Fischer 344 rats were pretreated with the P450 inducers Aroclor 1254 (ARO), isoniazid (INH), 3-methylcholanthrene (3-MC), and phenobarbital (PB), or the P450 inhibitor 1-aminobenzotriazole (ABT). Control animals received vehicle only. NDPS metabolism was investigated using hepatocytes isolated from the various treatment groups. Separate experiments were also conducted to evaluate the effects of these pretreatments on NDPS-induced nephrotoxicity in rats. PB and ARO enhanced formation of the known nephrotoxic NDPS metabolites,<em>N</em>-(3,5-dichlorophenyl)-2-hydroxysuccinimide,<em>N</em>-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid, and<em>N</em>-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid, by the hepatocytes. In contrast, ABT inhibited formation of the nephrotoxic metabolites, whereas INH and 3-MC did not alter NDPS biotransformation. NDPS-induced renal damage was potentiated by pretreating the rats with PB or ARO and was attenuated by ABT. Compared with control animals, toxicity was unaffected by INH or 3-MC pretreatments. Thus, there was a correlation between pretreatments that induce P450-mediated NDPS metabolism and the effects that these compounds have on NDPS-induced nephrotoxicity. The data indicate that specific P450 isozymes metabolize NDPS to its hydroxylated products and suggest that these metabolites mediate the nephrotoxicity induced by NDPS.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 117-124"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20187034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of the Phosphorothioate Insecticide Fenitrothion on Mammalian Cytochrome P450-Dependent Metabolism of Estradiol","authors":"Conney W. Berger Jr.,&nbsp;Lester G. Sultatos","doi":"10.1006/faat.1997.2311","DOIUrl":"10.1006/faat.1997.2311","url":null,"abstract":"<div><p>Phosphorothioate insecticides, such as fenitrothion, are suicide substrates of cytochromes P450 (P450). These compounds undergo oxidative desulfuration by P450 resulting in the release and subsequent binding of atomic sulfur to the enzyme. Consequently, the P450-dependent metabolism of certain endogenous substrates could be inhibited by exposure to these insecticides. Formation of 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 16α-hydroxyestrone (16α-OHE1), and estriol in mammals occurs by P450-dependent hydroxylation of estradiol at various positions on the steroid nucleus. In the present study, pretreatment of male Swiss Webster mice with increasing doses of fenitrothion resulted in dose-dependent biphasic decreases in 2-OHE2 and 4-OHE2 production in mouse hepatic microsomes compared to control, with substantial decreases even at a dosage as low as 7 mg/kg. Fenitrothion pretreatment also resulted in dose-dependent biphasic increases in 16α-OHE1 and estriol production, along with substantial increases in estrone formation, probably as a result of shunting from the inhibition of 2- and 4-hydroxylation. These data suggest that exposure to fenitrothion might alter estradiol metabolism by inhibition of certain P450 isozymes.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 150-157"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20187038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Methimazole, an FMO Substrate and Competitive Inhibitor, on the Neurotoxicity of 3,3′-Iminodipropionitrile in Male Rats","authors":"C.G. Nace ,&nbsp;M.B. Genter ,&nbsp;L.M. Sayre ,&nbsp;K.M. Crofton","doi":"10.1006/faat.1997.2307","DOIUrl":"10.1006/faat.1997.2307","url":null,"abstract":"<div><p>This study was designed to examine the role of flavin-containing monooxygenase (FMO) on the auditory and vestibular neurotoxicity of 3,3′-iminodipropionitrile (IDPN) using the FMO substrate and competitive inhibitor methimazole (MMI). Specifically, the purpose was to block the FMO-mediated conversion of IDPN to the putative neurotoxic metabolite<em>N</em>-hydroxy3,3′-iminodipropionitrile (HOIDPN). In three separate experiments, adult male Long–Evans hooded rats were administered (ip) saline (vehicle), MMI, IDPN, or HOIDPN individually, or a combination of IDPN and MMI or HOIDPN and MMI. Animals were observed daily for signs of the ECC syndrome (excitation with choreiform and circling movements) for 10 days. One to 2 weeks after exposure, a battery of behavioral tests was used to examine vestibular and auditory function. MMI completely blocked the neurotoxicity associated with a 600 mg/kg dose of IDPN and partially blocked the effects of a 1000 mg/kg dose of IDPN. In contrast, MMI failed to block, and instead increased, the neurotoxicity associated with HOIDPN. These data suggest that FMO-mediated metabolism of IDPN is necessary for the generation of a metabolite responsible for the vestibular and auditory neurotoxicities.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 131-140"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2307","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20187036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dichloromethane Metabolism to Formaldehyde and Reaction of Formaldehyde with Nucleic Acids in Hepatocytes of Rodents and Humans with and without GlutathioneS-TransferaseT1andM1Genes","authors":"Mercedes Casanova ,&nbsp;Douglas A. Bell ,&nbsp;Henry d'A. Heck","doi":"10.1006/faat.1997.2313","DOIUrl":"https://doi.org/10.1006/faat.1997.2313","url":null,"abstract":"<div><p>Metabolism of dichloromethane (DCM) to formaldehyde (HCHO) via a glutathione<em>S</em>-transferase (GST) pathway is thought to be required for its carcinogenic effects in B6C3F₁mice. In humans, this reaction is catalyzed primarily by the protein product of the gene<em>GSTT1,</em>a member of the Theta class of GST, and perhaps to a small extent by the protein product of the gene<em>GSTM1.</em>Humans are polymorphic with respect to both genes. Since HCHO may bind to both DNA and RNA forming DNA–protein crosslinks (DPX) and RNA–formaldehyde adducts (RFA), respectively, these products were determined in isolated hepatocytes from B6C3F₁mice, F344 rats, Syrian golden hamsters, and humans to compare species with respect to the production of HCHO from DCM and its reaction with nucleic acids. Only mouse hepatocytes formed detectable amounts of DPX, the quantities of which corresponded well with quantities of DPX formed in the livers of mice exposed to DCM<em>in vivo</em>[Casanova, M., Conolly, R. B., and Heck, H. d'A. (1996).<em>Fundam. Appl. Toxicol.</em><strong>31,</strong>103–116]. Hepatocytes from all rodent species and from humans with functional<em>GSTT1</em>and<em>GSTM1</em>genes formed RFA. No RFA were detected in human cells lacking these genes. Yields of RFA in hepatocytes of mice were 4-fold higher than in those of rats, 7-fold higher than in those of humans, and 14-fold higher than in those of hamsters. The RFA:DPX ratio in mouse hepatocytes incubated with DCM was approximately 9.0 ± 1.4, but it was 1.1 ± 0.3 when HCHO was added directly to the medium, indicating that HCHO generated internally from DCM is not equivalent to that added externally to cells and that it may occupy separate pools. DPX were not detected in human hepatocytes even at concentrations equivalent to an<em>in vivo</em>exposure of 10,000 ppm; however, the possibility that very small amounts of DPX were produced from DCM cannot be excluded, since HCHO was formed in human cells. Maximal amounts of DPX_liverthat might be formed in humans were predicted from the amounts in mice and the relative amounts of RFA in hepatocytes of both species. With predicted DPX_liveras the dosimeter, the unit risk, the upper 95% confidence limit on the cancer risk, and the margin of exposure were calculated at several concentrations using the linearized multistage and benchmark dose methods. Since the actual delivered dose is smaller than that predicted, the results suggest that DCM poses at most a very low risk of liver cancer to humans.</p></div>","PeriodicalId":100557,"journal":{"name":"Fundamental and Applied Toxicology","volume":"37 2","pages":"Pages 168-180"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1006/faat.1997.2313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"137367608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}