[Living and experiencing with compensated respiratory insufficiency. From ventilator dependence under water].
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Adult↗
Biomedical subjects
I Brandt
Publications and source records attributed to I Brandt.
Metabolic activation of the food mutagen 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]indole (Trp-P-1) in endothelial cells of cytochrome P-450-induced mice.
3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a carcinogen which is metabolically activated by cytochrome P4501A. This microautoradiographic study showed that there was a highly selective solvent-resistant binding of radioactive substance in endothelial cells of the pulmonary and hepatic portal vascular system and of the vena cava and type 2 pneumocytes 1 day following i.p. or i.v. injection of [3H]Trp-P-1 (100 micrograms/kg) in NMRI mice treated with the cytochrome P4501A-inducing agent beta-naphthoflavone (BNF). In mice treated with indole-3-carbinol, a dietary cytochrome P4501A-inducing factor, a similar binding was observed in the liver but not in the lung. No binding in endothelial cells occurred in vehicle-treated control mice given injections of [3H]Trp-P-1. At incubation of tissues with [3H]Trp-P-1 (0.75 microM) there was also a selective binding of radioactive substance in endothelial cells of the lung and liver and in the vena cava from BNF-treated mice but not from vehicle-treated control mice. Ellipticine but not alpha-naphthoflavone inhibited the endothelial binding in BNF-treated mice exposed to [3H]Trp-P-1 in vivo or in vitro. No binding of radioactive substance occurred in hepatic central veins or in the aorta of BNF-treated mice exposed to [3H]Trp-P-1 in vivo or in vitro. Our data suggest an in situ metabolism of [3H]Trp-P-1 to a reactive species, catalyzed by an BNF-inducible P450 form, possibly 1A1, in endothelial cells. The results of this study and reported heterocyclic amine-induced tumors in the rodent vascular system suggest that endothelial cells are targets for food-derived mutagens.
Animals↗
Secondary combined resistance to the multidrug-resistance-reversing activity of cyclosporin A in the cell line F4-6RADR-CsA.
Multidrug-resistant tumor cells can be resensitized by combined application of the selecting cytostatic drug and a chemosensitizer, such as cyclosporin A (CsA) or a calcium channel blocker. Since clinical trials on the circumvention of multidrug resistance (MDR) with chemosensitizers report disparate results, we investigated whether tumor cells of the MDR phenotype can develop additional resistance to the cytostatic chemosensitizer combination. Thus, the Adriamycin(ADR)-selected, P-glycoprotein-positive MDR Friend leukemia cell line F4-6RADR was exposed to stepwise increased concentrations of CsA at a constant level of 0.05 microgram/ml ADR. The initial CsA concentration (plus 0.05 microgram/ml ADR) to inhibit cell growth of F4-6RADR cells by 50% (IC50) was 0.04 microgram/ml. By continuous incubation for more than 6 months, the IC50 for CsA (at constant ADR) was elevated to 3.6 micrograms/ml (90-fold), thus generating the variant F4-6RADR-CsA. The F4-6RADR-CsA cells were cross-resistant for cyclosporin H (CsH), a non-immunosuppressive derivative of CsA. As shown by immunocytochemistry as well as by the polymerase chain reaction and by Western blotting including densitometry, P-glycoprotein was preserved in the F4-6RADR-CsA variant and was expressed at a 4-fold higher level than in F4-6RADR cells. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis could detect no new proteins in F4-6RADR-CsA as compared to F4-6RADR. Interestingly, resistance of F4-6RADR-CsA cells remained reversible for the calcium antagonists verapamil and dihydropyridine B859-35 (dexniguldipine-HCl), indicating that CsA and these compounds interfere with the P glycoprotein function by different pharmacodynamic mechanisms. Transport studies with [14C]ADR, performed in the presence and absence of chemosensitizers, confirmed the good correlation of P-glycoprotein function with the pattern of resistance found in proliferation assays. Cellular accumulation of [3H]cyclosporin was reduced to 71% of that of the F4-6 controls in F4-6RADR-CsA cells, but remained at the level of controls in F4-6RADR cells. Results indicate that increased amounts of the P-glycoprotein--besides other, perhaps more important mechanisms that are as yet unknown--partially mediate CsA resistance in F4-6RADR-CsA cells. We have designated this new form of resistance "secondary combined resistance" (SCR). The results suggest that at least some clinical cases of insensitivity to chemosensitizers or of relapse after reversing therapy could be explained by SCR, and that resensitizing treatment of tumor patients should be based on the consideration of several chemosensitizers of different pharmacodynamics.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Nephrotoxicity and covalent binding of 1,1-dichloroethylene in buthionine sulphoximine-treated mice.
Autoradiography of mice injected i.p. with 14C-labelled 1,1-dichloroethylene (vinylidene chloride, VDC) in C57B1/6 mice revealed a selective covalent binding of radioactivity in the proximal tubules, in the midzonal parts of the liver lobules and in the mucosa of the upper and lower respiratory tract. Since VDC is a renal carcinogen in male mice the effects of compounds modulating biotransformation and glutathione (GSH) levels on the renal covalent binding were examined following a single i.p. dose of 14C-VDC. Most pretreatments did not influence the level of binding but treatment with buthionine sulphoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase and glutathione (GSH)-depleting agent, increased the renal covalent binding of VDC three-fold. Histopathological examination of kidneys in BSO-pretreated male mice given single i.p. injections of subtoxic doses of VDC (25 and 50 mg/kg) showed necrosis in the proximal tubules (S1 and S2 segments) 24 h following administration. In mice given VDC only, no significant lesions in the kidneys were observed. The severe renal toxicity of VDC in BSO-pretreated mice is suggested to be related to metabolic activation of VDC in the proximal tubules, resulting in further GSH depletion and covalent binding.
Animals↗
Liver accumulation of 2,3,7,8-tetrachloro-[3H]dibenzofuran in mice: modulation by treatments with polychlorinated biphenyls.
The distribution of 2,3,7,8-tetrachloro-[3H]dibenzofuran ([3H]TCDF; 40 micrograms/kg) resembled that earlier reported for 2,3,7,8-tetrachlorodibenzo-p-dioxin, with a strong accumulation in the liver and a selective uptake in the nasal olfactory mucosa of adult and fetal mice. Pretreatments with a series of selected congeners of polychlorinated biphenyls (PCBs), i.e.. I (IUPAC)-77, I-105, I-118, I-126, I-153, I-156, I-169, and a commercial preparation, Aroclor 1254 (25-100 mg/kg body wt. i.p.), were found to modulate the hepatic uptake of [3H]TCDF (24 h post-3H-injection). At a short pretreatment time (4 h), non-ortho-chlorinated congeners decreased the uptake of [3H]TCDF equivalents in the liver (e.g., I-126 = 3,3',4,4',5-pentachlorobiphenyl: 34% of control), while several mono- and di-ortho PCB congeners and Aroclor 1254 increased the hepatic uptake of [3H]TCDF (e.g., I-156 = 2,3,3',4,4',5-hexachlorobiphenyl: 183% of control). At a longer pretreatment time (48 h), both a non-ortho (I-169 = 3,3',4,4',5,5'-hexachlorobiphenyl) and mono-ortho PCB congener(s) (e.g. I-156) markedly increased the hepatic 3H-uptake (190%), a probable effect of an induction of hepatic binding sites for TCDF. Ethoxyresorufin-O-deethylase activities, regarded to mirror the metabolic activity of cytochrome P-450 IA1 (CYP IA1), were strongly and time-dependently induced after I-169, but not after I-156, pretreatment (25 mg/kg). The initial liver concentrations of the two PCB congeners were similar and increased for I-169 but not for I-156 at later time points. In conclusion, the results show a selective uptake of [3H]TCDF in the mouse liver and nasal olfactory mucosa of both dam and fetus. The uptake of [3H]TCDF in the liver is influenced both by dose and pre-exposure with PCBs. The presence of a PCB-sensitive, but CYP IA1-independent, hepatic binding site for TCDF is suggested. Consequently, pharmacokinetic interactions with PCBs complicate the toxicity assessment of TCDF in complex mixtures.
Animals↗
Effects of glutathione-modulating agents on the covalent binding and toxicity of dichlobenil in the mouse olfactory mucosa.
Twenty-four hours following injection of a single dose of the herbicide dichlobenil (2,6-dichlorobenzonitrile) in C57Bl/6 mice a steep dose-response curve for the histopathological toxicity in the olfactory mucosa was observed. Four hours following injection of a toxic dose of [ring-14C]dichlobenil (12 mg/kg) the covalent binding in the olfactory mucosa was 26 times higher than that in the liver. A dose-dependent decrease of nonprotein sulfhydryls (mainly glutathione, GSH) in the olfactory mucosa was observed 2.5 hr following injection of dichlobenil (6, 12, 25 mg/kg). The synthetic GSH precursor N-acetyl-L-cysteine decreased both the dichlobenil-induced toxicity and the covalent binding, whereas N-acetyl-D-cysteine had no effect. No protective effects of the cyanide antidotes nitrite, thiosulfate, or superoxide dismutase on the dichlobenil-induced toxicity were observed. In mice given the GSH-depleting agent phorone and a subtoxic dose of dichlobenil (6 mg/kg), an extensive toxicity and an increased covalent binding in the olfactory mucosa were demonstrated. Autoradiography showed no change in the distribution of covalent [14C]dichlobenil binding to nontarget tissues of phorone-treated mice. In conclusion, the results demonstrate a relationship between the degrees of covalent binding, GSH depletion, and toxicity of dichlobenil in the olfactory mucosa. Hence, the level of GSH appears to be of importance for the dichlobenil-induced toxicity in the olfactory mucosa.
Acetylcysteine↗
Tissue-binding and toxicity of compounds structurally related to the herbicide dichlobenil in the mouse olfactory mucosa.
The herbicides dichlobenil (2,6-dichlorobenzonitrile), chlorthiamid (2,6-dichlorothiobenzamide) and their environmental degradation product 2,6-dichlorobenzamide are irreversibly bound and toxic to the olfactory mucosa following single injections in mice (Brandt et al., Toxicology and Applied Pharmacology 1990, 103, 491-501; Brittebo et al., Fundamental and Applied Toxicology 1991, 17, 92-102). In the present study, autoradiography showed an irreversible binding of radioactivity in the olfactory mucosa (preferentially in the Bowman's glands) in C57Bl/6 mice treated with the 14C-labelled analogues [14C]2,6-difluorobenzonitrile ([14C]DFBN) and [14C]2,6-difluorobenzamide ([14C]DFBA). Therefore the toxicity of DFBN, DFBA and of some structurally related compounds including benzonitrile (BN) and the herbicides bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and ioxynil (3,5-diiodo-4-hydroxybenzonitrile) in the mouse olfactory mucosa was examined. No histopathological changes in the olfactory mucosa or in the liver were observed following a single ip dose of any of these compounds [0.145 mmol/kg (all compounds); 0.58 mmol/kg (DFBN, DFBA and BN)]. Also in mice treated with the glutathione-depleting agent phorone, none of these compounds induced any histopathological changes in the olfactory mucosa. The covalent binding of [14C]DFBN in the olfactory mucosa was 16 times lower than an equimolar toxic dose of [14C]dichlobenil, suggesting a low rate of metabolic activation of DFBN in the olfactory mucosa or a low reactivity of the DFBN metabolites formed. The results of this study thus show that single doses of DFBN, DFBA, BN, IX and BX, compounds structurally related to the potent olfactory toxicant dichlobenil, do not elicit acute toxicity in the olfactory mucosa of mice.
Animals↗
Adrenocortical toxicity of 3-methylsulphonyl-DDE; 3: Studies in fetal and suckling mice.
Irreversible binding and toxicity of the DDT metabolite 3-methylsulphonyl-DDE (MeSO2-DDE) were examined in fetuses and suckling pups following administration to pregnant or lactating C57Bl mice. Tape-section autoradiography showed a high and tissue-specific accumulation and binding of MeSO2-DDE-14C-derived radioactivity in the late gestational fetal adrenal cortex. According to microautoradiography an irreversibly bound residue was confined to the zona fasciculata. Similarly, there was a high concentration of irreversibly bound 14C-labelled material in the adrenal zona fasciculata of suckling pups. Intraperitoneal injection of MeSO2-DDE-14C to lactating mice resulted in higher concentrations of radioactivity in the liver and stomach contents (milk) of the suckling pups than in the maternal liver. This treatment also resulted in a higher level of radioactivity in the adrenals of the pups than in the maternal adrenals, both at a subtoxic and at a toxic dose. Histopathologic examination of adrenals from suckling pups revealed extensive vacuolation and necrosis of the zona fasciculata 2 days following a single dose of MeSO2-DDE (25 mg/kg) to the dam. In the fetal adrenal zona fasciculata, slight degenerative changes were observed following a maternal dose of 50 mg/kg. In conclusion, the study shows that MeSO2-DDE is a highly tissue-specific toxicant to the fetal and postnatal adrenal zona fasciculata in mice. Based on the present data and on previous results in adult mice, we propose that a tissue-specific activation to a reactive metabolite in the fetal and postnatal adrenal cortex is mediated by cytochrome P-450 (11 beta).
Adrenal Cortex↗
Enrichment of metabolites in the cerebrospinal fluid of cod (Gadus morhua) following oral administration of hexachlorobenzene and 2,4',5-trichlorobiphenyl.
The disposition of 14C-labelled hexachlorobenzene (HCB) and 2,4',5-trichlorobiphenyl (triCB) was studied in cod (Gadus morhua) and rainbow trout (Oncorhynchus mykiss). For both compounds tape section autoradiography revealed substantial amounts of radiolabelled material in the central nervous system (CNS) of cod, whereas only traces of radioactivity were observed in the CNS of rainbow trout. Furthermore, an enrichment of radiolabelled compound in the cerebrospinal fluid (CSF) was observed in the cod, whereas no radioactivity could be detected in the CSF of rainbow trout. According to autoradiography, the CNS of cod dosed with HCB contained the parent compound, whereas the major part of radioactivity in CSF was due to HCB metabolites. Thin-layer chromatography of extracts from cod dosed with triCB showed the presence of parent compound in the CNS, whereas part of the radioactivity in the CSF was due to triCB metabolites. The activities of cytochrome P-450 and UDP-glucuronosyltransferase in the CNS of cod and rainbow trout were determined in microsomal and mitochondrial fractions. Both species expressed activities which were in the same order of magnitude as those reported for the corresponding fractions from rat brain. Incubation of triCB with cod brain mitochondria and microsomes resulted in the formation of two polar metabolites. It is suggested that cod may be more vulnerable than rainbow trout regarding neurotoxicological effects of HCB, triCB and related environmental pollutants.
Administration, Oral↗
Tissue distribution of the food mutagen MeIQx in control and BNF-treated mice.
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Animals↗
Metabolic activation of halogenated hydrocarbons in the conjunctival epithelium and excretory ducts of the intraorbital lacrimal gland in mice.
Autoradiographic studies were performed to determine the localization of irreversibly bound radioactivity in the eyes and accessory structures of mice exposed to 14C-labelled organic solvents in vivo or in vitro. A selective localization of bound radioactivity was observed in the conjunctival epithelium of mice given i.v. injections of 1,2-dibromoethane, chloroform, carbon tetrachloride or bromobenzene. Similar results were observed after instillation of chloroform or carbon tetrachloride in the conjunctival sac and after incubation of eyelids with the labelled compounds in vitro. A high level of irreversibly bound radioactivity was also observed in the excretory ducts of the intraorbital lacrimal glands of mice exposed to 1,2-dibromoethane in vivo and in vitro. After incubation of 14C-labelled 1,2-dibromoethane or chloroform with homogenates prepared from rat conjunctiva, the presence of irreversibly protein-bound radioactivity was detected. The results indicate that the conjunctival epithelium can metabolically activate halogenated organic solvents into products that bind to the tissue. The significance of a metabolic activation of chemicals in the pathogenesis of chemically induced lesions in the conjunctiva merits further attention.
Animals↗
Adrenocortical toxicity of 3-methylsulfonyl-DDE in mice. II. Mitochondrial changes following ecologically relevant doses.
Transmission electron microscopy was used to characterize early ultrastructural lesions in the adrenal zona fasciculata of female C57BL mice given a single ip injection of the adrenocorticolytic DDT-metabolite 3-methylsulfonyl-DDE (MeSO2-DDE). Following 3 mg/kg, mitochondrial changes were observed 6 hr after dosing. At 12 and 24 hr the mitochondrial changes were conspicuous, with disorganization and disappearance of central cristae. At doses of 6, 12, and 25 mg/kg body wt initial (6 hr) mitochondrial vacuolization was observed, followed by disappearance of mitochondria (6-12 mg/kg) or cellular necrosis (25 mg/kg). The metabolic activation and binding of MeSO2-[14C]DDE in adrenal homogenates were determined in vitro. The irreversible binding of MeSO2-[14C]DDE to the mitochondria-containing adrenal S-9 pellet fraction was 50 times higher than that to the postmitochondrial S-12 supernatant fraction. The apparent Km was 2.1 microM and the apparent Vmax was 104 pmol/mg protein/30 min for the binding of MeSO2-[14C]DDE to S-0.3 supernatants. The irreversible protein binding was inhibited by metyrapone (Ki = 1 microM) and 11-deoxycorticosterone (Ki = 3 microM). In conclusion, the adrenal metabolic activation of MeSO2-DDE is suggested to be mediated by a mitochondrial cytochrome P450 form, presumably P450 (11 beta). A primary mitochondrial lesion develops and subsequently leads to degeneration and necrosis of the zona fasciculata.
Adrenal Cortex↗
Toxicity of 2,6-dichlorothiobenzamide (chlorthiamid) and 2,6-dichlorobenzamide in the olfactory nasal mucosa of mice.
The toxic effects of the herbicide chlorthiamid (2,6-dichlorothiobenzamide) and its major environmental metabolite 2,6-dichlorobenzamide (DCBA) were examined in the nasal passages of C57Bl mice following single ip injections. Chlorthiamid (12.25, and 50 mg/kg) induced an extensive destruction of the olfactory region, similar to that previously observed with the analogue dichlobenil (2,6-dichlorobenzonitrile). Necrosis of Bowman's glands was evident first, whereas degeneration and necrosis of the olfactory neuroepithelium developed less rapidly. The lesions were most severe in the dorsomedial region of the nasal cavity. At longer post-treatment intervals, the olfactory epithelium was replaced by a respiratory-like epithelium, and there was fibrosis of the lamina propria. DCBA was also toxic to the olfactory region (100 mg/kg), inducing necrosis of the Bowman's glands and the neuroepithelium in the dorsomedial region of the nasal cavity. No lesions were observed in other parts of the nasal cavity or in the liver after administration of chlorthiamid or DCBA. Chlorthiamid (IC50 = 51 microM), but not DCBA, inhibited the covalent binding of 14C-labeled dichlobenil in the olfactory mucosa in vitro. It is proposed that the toxic effects of chlorthiamid and dichlobenil in the olfactory mucosa are mediated by common or closely related metabolites.
Animals↗
[Significance of age correction in premature infants].
Age correction for prematurity is still discussed controversially, however it is now recommended in most studies; the main argument of its opponents is that by an age correction the developmental quotients become inadequately high, i.e. overcorrection, and by this a retardation can be overlooked. For the same reason some authors recommend a partial age correction. According to the results of the Bonn longitudinal study a complete age correction is necessary at least in the first two years because of the very rapid development. By this an overdiagnosis of a retardation is avoided and herewith unnecessary trouble for the family.
Birth Weight↗
Activation and toxicity of bromobenzene in nasal tissue in mice.
Autoradiography of mice injected i.v. with bromobenzene-14C (BB; 25 mumol/kg body wt) revealed a high concentration of non-volatile metabolites in the olfactory mucosa and in the glands around the maxillary sinuses. As determined with solvent-extracted tissue sections, there was a high level of irreversibly bound metabolites in the Bowman's glands in the olfactory mucosa, while the level of bound metabolites was low in the glands around the maxillary sinuses. Histopathological examination of the nose region of mice given a single i.p. dose of unlabelled BB (greater than or equal to 4.8 mmol/kg body wt) revealed degeneration and necrosis of the glands of Bowman. Degenerative changes in the olfactory epithelium were also observed. Moreover, focal degeneration and necrosis were found in the lateral nasal glands (greater than or equal to 4.8 mmol/kg body wt). Cyst-like dilatation of acini was observed in the lateral nasal glands and in the maxillary glands located around the maxillary sinus. Incubation of BB (26 microM) with a homogenate prepared from the olfactory mucosa revealed an irreversible binding, which clearly exceeded that of the liver. It is suggested that BB is activated in situ to a cytotoxic metabolite that reacts with the glands of Bowman. The specific toxicity observed in the lateral nasal glands correlated with a high concentration of non-volatile but extractable metabolites in these glands.
Animals↗
Irreversible binding and toxicity of the herbicide dichlobenil (2,6-dichlorobenzonitrile) in the olfactory mucosa of mice.
Following a single ip injection (12, 25, 50 mg/kg) of the herbicide dichlobenil (2,6-dichlorobenzonitrile) into C57Bl mice or Sprague-Dawley rats, an extensive destruction of the glands of Bowman and in the neuroepithelium of the olfactory region was observed. In mice, necrosis of the Bowman's glands was evident 8 hr after the lowest dose (12 mg/kg). Degeneration and/or necrosis of the neuroepithelium developed less rapidly but appeared at all doses examined. The mucosal lesions were most severe in the dorsal meatus and in the medial aspects of the ethmoturbinates. Three to seven days after dosing, the olfactory region was covered by an attenuated surface epithelium or by a respiratory-like epithelium. Seven to twenty days after dosing, there was fibrosis of the olfactory region. Partial regeneration of the olfactory epithelium and scattered intact Bowman's glands were observed after 20 days. Autoradiograms of mice given a single iv injection of 14C-labeled dichlobenil showed a high irreversible binding of radioactivity in Bowman's glands, whereas the binding in the olfactory epithelium was insignificant. In mice pretreated with metyrapone the binding decreased markedly, indicating that the reactive metabolite was formed by a cytochrome P450-dependent mechanism. The metyrapone treatment also resulted in a decreased or completely inhibited toxicity of dichlobenil to the olfactory mucosa. Hence, the tissue-specific toxicity of dichlobenil seems to be mediated by a reactive, tissue-binding metabolite. We propose that dichlobenil induces a primary lesion in the glands of Bowman, resulting from the pronounced binding of a metabolite in these glands. The toxicity to the olfactory neuroepithelium may be secondary to the destruction of the glands of Bowman.
Animals↗
Effects of dietary and intraperitoneally administered beta-naphthoflavone on mutagenicity and tissue distribution of Trp-P-1 in the rat.
The effect of dietary beta-naphthoflavone (BNF) on tissue retention of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) was studied in the rat. Female rats, 3 weeks old, were fed a BNF-containing diet for 3 days before being dosed orally or i.v. with 14C-labelled Trp-P-1. The rats were killed at 4, 24 or 48 h after dosage and subjected to tape-section autoradiography. The tissue localization of Trp-P-1-derived radioactivity was compared to that observed in untreated rats and in rats given BNF i.p. Ethoxyresorufin-O-deethylase (EROD) activity and mutagenicity of Trp-P-1 in the Ames test, using S9 prepared from forestomach, glandular stomach, small intestine, liver and lung, were used as in vitro assays to measure the degree of cytochrome P450IA1 and/or P450IA2 induction. Dietary BNF treatment caused a 30- to 40-fold increase in EROD activity in the small intestine, but only a 2-fold increase in the liver and the lung. These inter-organ differences were not observed after i.p. administration of BNF. The increase in mutagenicity of Trp-P-1 in the Ames test could be correlated to the increase in EROD activity. The autoradiographic data showed that the route of administration of BNF as well as of Trp-P-1 were important for the tissue localization of Trp-P-1. Dietary BNF treatment caused a pronounced retention of Trp-P-1-derived radioactivity in the epithelia of the small intestine, forestomach, oesophagus and the oral cavity, regardless of the administration route of Trp-P-1; a similar though less pronounced epithelial retention was observed after i.p. injection of BNF. A clear-cut boundary of accumulated radioactivity between the forestomach and the glandular stomach where the levels were almost non-detectable was observed in rats fed the BNF-containing diet. It is concluded that dietary inducers may be important determinants of metabolism and tissue distribution of toxic compounds.
Animals↗
Interactions of xenobiotics in the respiratory tract following non-inhalation routes of exposure.
Compounds of highly variable structure may induce toxic effects and tumours in the respiratory tract following peroral or parenteral administration in experimental animals. Such compounds are used in industrial processes or may be present in the food as contaminants or pesticide residues. This review gives examples of selective metabolism and toxicity of chemicals in different segments of the respiratory tract. Many of these compounds require metabolic activation to exert toxicity. Accordingly, the susceptibility of the respiratory tract to the effects of such agents may be influenced by other compounds modulating the activity of activating xenobiotic metabolizing enzymes. Dietary factors may alter the susceptibility to experimental lung carcinogenesis also via other mechanisms. As concluded from experimental data, the human lung may be exposed to a wide array of potentially toxic compounds present in the diet or the environment. Such exposures may constitute confounding factors in low-risk lung cancer epidemiology.
Animals↗