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PubMed2003

Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells.

There is growing evidence that vasculogenesis (progenitor cell-derived generation of new blood vessels) is required for the growth of some neoplastic diseases. Here we show that the administration of cyclophosphamide (CTX) at the maximum tolerable dose with 21-day breaks or at more frequent low-dose (metronomic) schedules have opposite effects on the mobilization and viability of circulating endothelial progenitors (CEPs) in immunodeficient mice bearing human lymphoma cells. Animals treated with the maximum tolerable dose CTX experienced a robust CEP mobilization a few days after the end of a cycle of drug administration, and tumors rapidly became drug resistant. Conversely, the administration of metronomic CTX was associated with a consistent decrease in CEP numbers and viability and with more durable inhibition of tumor growth. Our findings suggest that metronomic low-dose chemotherapy regimens are particularly promising for avoiding CEP mobilization and, hence, to potentially reduce vasculogenesis-dependent mechanisms of tumor growth.

Animals↗
PubMed1997

Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer.

PURPOSE: We conducted a phase I trial of the novel nucleoside analog, gemcitabine, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose and efficacy in this population. PATIENT AND METHODS: Eligibility requirements included stage III or IV NSCLC, performance status < or = 1, and no prior chemotherapy. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks every 4 weeks. We enrolled patients at doses that ranged from 1,000 to 2,800 mg/m2/wk (three patients per cohort). Responses were assessed after every two courses (8 weeks). RESULTS: We treated 33 chemotherapy-naive patients with stage III (n = 5) or IV (n = 28) NSCLC. Most had performance status 1, and 67% had adenocarcinoma. Eight of 32 assessable patients (25%) achieved a partial response. The projected median survival duration (all patients) is 49 weeks. The maximum-tolerated dose was 2,200 mg/m2/wk for 3 weeks every 4 weeks; dose-limiting toxicity was myelosuppression and reversible transaminase elevation. Other side effects were consistently mild. The maximum dose-intensity achieved with the first two cycles was 2,362 mg/m2/wk for 3 weeks every 4 weeks, which is a feasible phase II starting dose. CONCLUSION: This study estimates a phase II starting dose of gemcitabine in chemotherapy-naive patients to be 2,400 mg/m2/wk for 3 consecutive weeks every 4 weeks; this is much higher than that previously reported in heavily pretreated patients. Twenty-five percent of patients with advanced NSCLC achieved a partial response to gemcitabine. This significant activity in conjunction with a very favorable toxicity profile supports the further evaluation of gemcitabine in combination with other active agents.

Adult↗
PubMed1992

An examination of the association between maximum-tolerated dose and carcinogenicity in 326 long-term studies in rats and mice.

The association between rodent carcinogenicity and maximum-tolerated dose (MTD) was evaluated in 326 long-term carcinogenicity studies in mice and rats. Others investigating this association have focused primarily on positive studies, but our investigation considered all experimental outcomes. We found that chemicals with low MTDs were somewhat more likely to be rodent carcinogens than chemicals with high MTDs, but this association was limited primarily to gavage studies. Overall, the MTD was not a reliable predictor of whether or not a chemical would be a rodent carcinogen. Our investigation confirms that comparisons of carcinogenic potencies based only on positive studies may result in artifactually elevated estimates of the underlying association between chemical toxicity and rodent carcinogenicity and thus may also inflate the estimated interspecies correlation in carcinogenic response. Nevertheless, the results of our study are consistent with the frequently cited 75% concordance in carcinogenicity outcome between rats and mice. This concordance is quite high, particularly since 80% is approximately the maximum level of observable interspecies concordance achievable for a set of chemicals with relatively low carcinogenic potency, because of the variability in observed tumor responses that can induce false negative or false positive outcomes in either of the two species. Thus, the underlying qualitative interspecies correlation in carcinogenic response between rats and mice may be greater than is commonly recognized.

Animals↗
PubMed1991

Estimation of maximum tolerated dose for long-term bioassays from acute lethal dose and structure by QSAR.

A quantitative structure-activity relationship (QSAR) model has been developed to estimate maximum tolerated doses (MTD) from structural features of chemicals and the corresponding oral acute lethal doses (LD50) as determined in male rats. The model is based on a set of 269 diverse chemicals which have been tested under the National Cancer Institute/National Toxicology Program (NCI/NTP) protocols. The rat oral LD50 value was the strongest predictor. Additionally, 22 structural descriptors comprising nine substructural MOLSTAC(c) keys, three molecular connectivity indices, and sigma charges on 10 molecular fragments were identified as endpoint predictors. The model explains 76% of the variance and is significant (F = 35.7) at p less than 0.0001 with a standard error of the estimate of 0.40 in the log (1/mol) units used in Hansch-type equations. Cross-validation showed that the difference between the average deleted residual square (0.179) and the model residual square (0.160) was not significant (t = 0.98).

Animals↗
PubMed2003

Predicting the maximum-tolerated dose of PNU-159548 (4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin) in humans using CFU-GM clonogenic assays and prospective validation.

A haematotoxicity model was proposed by Parchment in 1998 to predict the maximum-tolerated dose (MTD) in humans of myelosuppressive antitumour agents by combining data from in vitro clonogenic assays on haematopoietic progenitors and in vivo systemic exposure data in animals. A prospective validation of this model in humans was performed with PNU-159548, a novel agent showing selective dose-limiting myelosuppression in animals. PNU-159548 and its main metabolite, PNU-169884, were tested in vitro on murine, canine and human colony forming units-granulocyte macrophages (CFU-GM) and in vivo on mice and dogs. The IC(90x) ratios (IC(x)=concentration inhibiting x% of colony growth) for CFU-GM and drug plasma protein binding were used to adjust the target plasma concentrations versus time curve (AUC) and predict the human MTD. The predicted MTD was compared with values achieved in phase I studies. Canine CFU-GM were 6-fold more sensitive (P<0.01) and murine CFU-GM 1.7-fold less sensitive (P<0.05) to PNU-159548 treatment than the human progenitors. PNU-169884 behaved similarly to PNU-159548. The predicted MTDs in humans calculated from data in mice and dogs were 15 and 38 mg/m(2), respectively. Overall, 61 patients were treated in two phase I studies, at doses ranging from 1.0 to 16 mg/m(2). Thrombocytopenia was dose-limiting with a MTD of 14 and 16 mg/m(2) in heavily and minimally pretreated/non-pretreated patients, respectively. Adjusting animal MTD data by means of the CFU-GM ratio between species can predict the human MTD with a good quantitative accuracy. Inhibition of common haemopoietic progenitors by PNU-159548 induced neutropenia/thrombocytopenia in animals and thrombocytopenia in patients, probably due to the higher sensitivity to the compound observed in human colony forming units-megakaryocyte (CFU-MK).

Animals↗
PubMed1992

Subacute toxicity and maximum tolerable dose of sertaconazole in repeated administration studies.

28-Day oral and dermal subacute toxicity studies of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl) ethoxy-methyl] benzo [b] thiophene (sertaconazole, FI-7045, CAS 99592-32-2), were carried out. The oral studies included the evaluation of subacute toxicity in rat (dose levels of 50, 150 and 300 mg/kg) and maximum tolerable dose in repeated administration in ferrets (consecutive dose levels in accordance with a geometric progression of 50, 75, 112.5, 168 and 250 mg/kg), which were the animal species intended for chronic toxicity studies. The dermal studies included the evaluation of subacute toxicity in rats and rabbits (1 ml/kg of a 2% cream). The results, in general, have shown low toxic effects, which can be summarized as a slight non-significant hepatomegalia in the rat with increased gamma-GTP and alkaline phosphatase values and a high urinary pH value; no histopathological changes were observed. These effects are characteristic of azole derivatives and are therefore common to other antifungals with this chemical group.

Administration, Oral↗
PubMed1992

Decreased electrophilicity of chemicals carcinogenic only at the maximum tolerated dose.

While there was no significant difference between the actual or predicted mutagenicity and clastogenicity of a group of chemicals carcinogenic only at the maximum tolerated dose (MTD) and a group of chemicals carcinogenic below the MTD, as a group, the chemicals carcinogenic below the MTD exhibited a significantly decreased LUMO (Lowest Unoccupied Molecular Orbital) energy, indicative of increased electrophilicity (i.e. DNA reactivity). These findings suggest that chemicals carcinogenic only at the MTD either require increased doses of "weak" electrophiles to be carcinogenic or that they may act by a "non-genotoxic" mechanism.

Animals↗
PubMed2000

Amphotericin B preparations: a maximum tolerated dose in severe invasive fungal infections?

Availability of lipid formulations of amphotericin B has opened up the possibility of treating invasive fungal infections in immunocompromised patients with high doses of this antifungal agent. Evidence is emerging to suggest that lipid formulations may have heightened efficacy compared to conventional amphotericin B. The issue of optimal dosage has been a neglected area. This article reviews published data accrued from clinical, open-label, salvage, and other studies, and finds little support that the use of high doses of lipid formulations are more efficacious than lower doses. The response rates for invasive fungal infection from most studies are predictably around 56%, irrespective of the lipid formulation and dose used. Animal models provide evidence that low doses of a lipid formulation are as successful in reducing fungal dissemination and in prolonging survival as higher doses, although concomitant tissue fungal eradication is not as effectively achieved by the lower doses (survival-mycologic eradication dissociation). Kinetic studies performed in the clinically relevant setting of critically ill patients give further support to the use of low doses, since levels of liposomal amphotericin B at all dosages between 1 and 4 mg/kg/day are similar and above maximum inhibitory concentrations for commonly encountered fungi. There has only been one prospective randomised study designed with the primary end-point of comparing two dosages of an amphotericin B lipid formulation on clinical response and survival. That European Organization for Research and Treatment of Cancer (EORTC) study concluded that liposomal amphotericin B given at 1 mg was as efficacious as 4 mg/kg/day in treating neutropenic patients with invasive pulmonary aspergillosis. There are a multitude of unanswered questions concerning dosing, and their answers are confounded by difficulties in performing clinical trials and the multiplicity of factors other than antifungal chemotherapy that influence outcome. Maximum tolerated dose studies using existing lipid formulations, or perhaps with the newer formulations such as pegylated immunoliposomal amphotericin B, could be performed to shed light on this difficult area.

Amphotericin B↗
PubMed1991

An appreciation of the maximum tolerated dose: an inadequately precise decision point in designing a carcinogenesis bioassay?

Cancers arise in specific tissues. One difficulty with the present definitions of the Maximum Tolerated Dose (MTD), as they pertain to the rodent cancer bioassay, is that they base MTD on relatively crude parameters associated with the well-being of the entire animal rather than with the lack of specific tissue toxicity. Additional factors that could be included in the MTD definition, or could be separately determined, are addressed. Many of these factors refer to toxic behavior in one or a few tissues and, if used in setting the MTD, may mask more relevant events occurring at higher dose levels in other tissues. Reducing the MTD to a level that fails to take into account pesticide or drug-related toxicity may lead to the loss of relevant information in the bioassay. It is concluded, therefore, that there are two possible approaches to a more appropriate use of the MTD. The highest dose of the test agent (MTD) may be chosen (i) to lie below the thresholds of carcinogenicity-related non-genotoxic toxicity or (ii) the present high level MTD may continue to be used and tumors that arise may be classified as being irrelvant to humans at some or all exposure levels. The latter approach is to be preferred. It has the potential to avoid missing high level effects of the test agent that may be relevant to the human population.

Animals↗
PubMed2003

Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics.

In a previous study of prevalidation, a standard operating procedure (SOP) for two independent in vitro tests (human and mouse) had been developed, to evaluate the potential hematotoxicity of xenobiotics from their direct and the adverse effects on granulocyte-macrophages (CFU-GM). A predictive model to calculate the human maximum tolerated dose (MTD) was set up, by adjusting a mouse-derived MTD for the differential interspecies sensitivity. In this paper, we describe an international blind trial designed to apply this model to the clinical neutropenia, by testing 20 drugs, including 14 antineoplastics (Cytosar-U, 5-Fluorouracil, Myleran, Thioguanine, Fludarabine, Bleomycin, Methotrexate, Gemcitabine, Carmustine, Etoposide, Teniposide, Cytoxan, Taxol, Adriamycin); two antivirals (Retrovir, Zovirax,); three drugs for other therapeutic indications (Cyclosporin, Thorazine, Indocin); and one pesticide (Lindane). The results confirmed that the SOP developed generates reproducible IC90 values with both human and murine GM-CFU. For 10 drugs (Adriamycin, Bleomycin, Etoposide, Fludarabine, 5-Fluorouracil, Myleran, Taxol, Teniposide, Thioguanine, and Thorazine), IC90 values were found within the range of the actual drug doses tested (defined as the actual IC90). For the other 10 drugs (Carmustine, Cyclosporin, Cytosar-U, Cytoxan, Gemcitabine, Indocin, Lindane, Methotrexate, Retrovir, and Zovirax) extrapolation on the regression curve out of the range of the actual doses tested was required to derive IC90 values (extrapolated IC90). The model correctly predicted the human MTD for 10 drugs out of 10 that had "actual IC90 values" and 7 drugs out of 10 for those having only an extrapolated IC90. Two of the incorrect predictions (Gemcitabine and Zovirax) were within 6-fold of the correct MTD, instead of the 4-fold range required by the model, whereas the prediction with Cytosar-U was approximately 10-fold in error. A possible explanation for the failure in the prediction of these three drugs, which are pyrimidine analogs, is discussed. We concluded that our model correctly predicted the human MTD for 20 drugs out of 23, since the other three drugs (Topotecan, PZA, and Flavopiridol) were tested in the prevalidation study. The high percentage of predicitivity (87%), as well as the reproducibility of the SOP testing, confirm that the model can be considered scientifically validated in this study, suggesting promising applications to other areas of research in developing validated hematotoxicological in vitro methods.

Acute Disease↗
PubMed2003

Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease.

Hydroxyurea improves hematologic parameters for children with sickle cell disease (SCD), but its long-term efficacy at maximum tolerated dose (MTD) has not been determined. Between 1995 and 2002, hydroxyurea therapy was initiated for 122 pediatric patients with SCD including 106 with homozygous sickle cell anemia (HbSS), 7 with sickle hemoglobin C (HbSC), 7 with sickle/beta-thalassemia (HbS/ beta-thalassemia [6 HbS/beta0, 1 HbS/beta+]), and 2 with sickle hemoglobin OArab (HbS/OArab). Median age at initiation of therapy was 11.1 years. Hydroxyurea was escalated to MTD, with an average dose of 25.4 +/- 5.4 mg/kg per day; the average duration of hydroxyurea therapy has been 45 +/- 24 months (range, 6-101 months). Hydroxyurea was discontinued for 15 (12%) children with poor compliance. Mild transient neutropenia occurred, but no hepatic or renal toxicity was noted. Hydroxyurea therapy led to significant increases in hemoglobin level, mean corpuscular volume, and fetal hemoglobin (HbF) level, whereas significant decreases occurred in reticulocyte, white blood cell, and platelet counts and serum bilirubin levels. Children with variant SCD genotypes also had hematologic responses to hydroxyurea. HbF induction has been sustained for up to 8 years without adverse effects on growth or increased numbers of acquired DNA mutations. Long-term hydroxyurea therapy at MTD is well tolerated by pediatric patients with SCD and has sustained hematologic efficacy with apparent long-term safety.

Adolescent↗
PubMed1996

Establishing the maximum tolerated dose of lesopitron in patients with generalized anxiety disorder: a bridging study.

Lesopitron, a 5-hydroxytryptamine 1A agonist, is a new potential anxiolytic of the azapirone class. It has greater potency in animal models of anxiety than buspirone, gepirone, or ipsapirone, and it lacks the antidopaminergic effects associated with buspirone. Lesopitron has been tolerated at single doses up to 50 mg and repeated dosages of 45 mg/day in healthy volunteers. Forty-two patients with generalized anxiety disorder (GAD) were enrolled in this double-blind bridging study to determine the safety and tolerability of fixed doses of lesopitron (20, 25, 30, 40, 45, 50, and 60 mg two times a day) over a 6 1/2-day inpatient administration period. Each of the seven panels included six patients (four drug/two placebo). One patient in the 25-mg, two-times-a-day panel voluntarily withdrew because of increased anxiety symptoms. One patient experienced severe orthostatic hypotension at 60 mg two times a day, and moderate to severe adverse events (dizziness, lightheadedness, nausea, headache) occurred in two other patients at this dosage. The most commonly reported adverse events in all the panels were headache, dizziness, and nausea. Lesopitron is rapidly absorbed in patients, having a time to maximum concentration (Tmax) ranging from 0.5 to 1 hour, and its elimination half-life ranged from 1.1 to 5.6 hours. Peak plasma concentrations showed high interindividual variability for lesopitron, but increased linearly with dose for the main metabolite, 5-hydroxylesopitron. We defined the maximum tolerated dose in GAD patients as 50 mg two times a day, twice as high as the highest dose tested in healthy volunteers.

Adolescent↗
PubMed1993

Structural relationships between mutagenicity, maximum tolerated dose, and carcinogenicity in rodents.

The CASE structure-activity relational system was applied to a study of the structural bases of toxicity as expressed in the maximum tolerated dose (MTD) of a group of chemicals for which rodent carcinogenicity and mutagenicity data were also available. All of the results were obtained under the aegis of the U.S. National Toxicology Program. The analyses revealed that there was a structural basis for the MTD in mice and in rats and that these overlapped considerably. There was also some overlap between structural determinants of the MTD and of carcinogenicity in rodents but there was also a significant "antagonism" between such fragments; i.e., fragments associated with high toxicity (low MTD) were associated with lack of carcinogenicity and vice versa. The highest overlaps observed were between the structural determinant for a low MTD (i.e., high toxicity) and mutagenicity in Salmonella.

Animals↗
PubMed2006

Biological standardization and maximum tolerated dose estimation of an Alternaria alternata allergenic extract.

BACKGROUND: The manufacture of allergenic extracts from the mold Alternaria alternata is influenced by factors such as strain variability, allergenic origin, culturing conditions and extraction process, which affect the reproducibility of the preparations intended for diagnostic and therapeutic use. OBJECTIVES: To select the most adequate antigenic source of A. alternata extracts and determine its maximum tolerated dose (MTD) to be used in a subsequent immunotherapy efficacy clinical trial. METHODS: Twenty-one patients monosensitized to A. alternata were involved in a biological standardization process of A. alternata extracts. Four different mold strains were cultured and used to produce extracts by three different methods, each incorporating proteins from different origins: culture filtrate, buffer extractable fraction and cellular antigens. The selected extract, characterized as in-house reference (IHR) preparation was used in a MTD finding immunotherapy study. Serum IgE, IgG, IgG1 and IgG4 specific of complete extract and purified natural and recombinant forms of Alt a 1 were determined by different EIA methods. RESULTS: Culture filtrate extract containing the allergens secreted to the spent medium was shown to be the most adequate option for establishing an IHR preparation for A. alternata extract manufacturing. A maximum dose of 1670 UBE, equivalent to 0.1 microg Alt a 1, was determined as MTD for immunotherapy. One year of administration of such a dose at monthly intervals elicited pronounced immunological changes with statistically significant decreases in IgE and increases in IgG4, both estimated with whole extract or purified Alt a 1. CONCLUSION: A high quality natural A. alternata extract has been developed and preliminarily tested to define its MTD for subsequent determination of the optimal dose in an immunotherapy efficacy clinical trial.

Adolescent↗
PubMed1999

Maximum tolerated dose and large tumor radioimmunotherapy studies of 64Cu-labeled monoclonal antibody 1A3 in a colon cancer model.

The purpose of this study was 2-fold: to determine the maximum tolerated dose (MTD) of 64Cu-bromoacetamidobenzyl- 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT)-2-iminothiolane (2IT)-monoclonal antibody (MAb) 1A3 in hamsters, and second, to determine the therapeutic efficacy of 64Cu-BAT-2IT-MAb 1A3 at various dose levels in hamsters with large (600 mg), 7-day-old GW39 human colorectal carcinoma tumors. In the MTD studies, non-tumor-bearing hamsters were injected with varying amounts of Cu-64-BAT-2IT MAb 1A3 (>10 mCi) normalized to mCi injected/kg of hamster body weight. Results indicated that the MTD was 150 mCi of Cu-64/kg of body weight. Hamsters receiving higher doses (170-190 mCi/kg) lost greater than 20% of their body weight, and all died between 8 and 13 days (n = 3). All hamsters receiving doses < or = 150 mCi/kg (120-150 mCi; n = 13) survived to the experimental end point (6 weeks) with an overall gain in weight. WBC and platelet counts were depressed in all animals 7 days after treatment but returned to normal values in the survivors by 2 weeks. For larger tumor therapy studies, 40% (8 of 20) of hamsters receiving a single dose of 7.0 mCi and 62.5% (5 of 8) of hamsters receiving 15 mCi of Cu-64-BAT-2IT-MAb 1A3 remained tumor free 4 months after treatment. In dose fractionation studies, hamsters received two 3.5 mCi doses separated by 24 or 48 h with 44% (4 of 9) and 25% (2 of 8) survival, respectively. In every large tumor experimental group, 100% of animals experienced tumor growth inhibition compared to saline control animals. Together, the MTD and the large tumor therapy studies confirm that 64Cu-labeled agents are excellent candidates for radioimmunotherapy trials.

Animals↗
PubMed2004

Maximum tolerable dose of red pepper decreases fat intake independently of spicy sensation in the mouth.

Dietary red pepper suppresses energy intake and modifies macronutrient intake. We have investigated whether a stimulus in the mouth and the sensation of spiciness are necessary for red pepper-induced changes in energy and macronutrient intake in human volunteers. In a preliminary test, sixteen Japanese male volunteers tasted samples of a soup with graded doses of red pepper in order to define a moderate and a maximum tolerable (strong) dose of red pepper. On the day of the experiment, a standardised breakfast was given to the volunteers. At lunchtime, the subjects ingested one of four experimental soups containing either a placebo, a moderate or a strong dose of red pepper plus placebo capsules, or a placebo soup plus capsules delivering a strong dose of red pepper. The rest of the meal was given ad libitum to all subjects. The amount of food, protein and carbohydrate ingested was similar for all conditions. Energy and fat intake were similar after the ingestion of the moderate soup compared with placebo. However, the strong soup significantly lowered fat intake compared with placebo (P=0.043), and ingestion of strong capsules also tended to suppress it (P=0.080). Moreover, energy intake after strong soup and capsules tended to be lower than placebo (P=0.089 and 0.076, respectively). The present results indicate that the maximum tolerable dose is necessary to have a suppressive effect of red pepper on fat intake. The main site of the action of red pepper is not in the mouth.

Adult↗
PubMed1997

Inhibitory effects of fluorinated pyrimidines, 5'-DFUR, UFT and T-506, in a model of hepatic metastasis of mouse colon 26 adenocarcinoma-assessment of inhibitory activity and adverse reactions at the maximum tolerated dose.

The effects of fluorinated pyrimidines, 5'-DFUR, UFT and T-506, on a mouse model of hepatic metastasis were assessed in regard to inhibitory activity and adverse reactions at the maximum tolerated dose. The model was prepared by injecting the mouse colonic cancer cell line, colon 26, into the portal vein of CDF1 mice. At the treatment regimens employed for 5'-DFUR (1.0 mmol/kg/day, p.o., daily from days 1 to 7), UFT (0.1 mmol/kg/day, p.o., daily from days 1 to 7), and T-506 (0.074 mmol/kg/day, i.v., days 1, 4, 7, and 10), complete inhibition of hepatic metastasis was obtained in six out of seven mice (85.7%) with 5'-DFUR, and in five out of six mice (83.3%) with T-506. Significant inhibition of hepatic metastasis was not achieved with UFT (3/7, 42.9%). 5'-DFUR and T-506 showed the highest rate of inhibition of hepatic metastasis, suggesting that these drugs would be effective for the prophylactic treatment of metastatic disease. 5'-DFUR and UFT exhibited mild adverse reactions such as loss of body weight.

Adenocarcinoma↗
PubMed1997

Pulmonary carcinogenicity of inhaled particles and the maximum tolerated dose.

Chronic inhalation bioassays in rodents are used to assess pulmonary carcinogenicity for purposes of hazard identification and potentially for risk characterization. The influence of high experimental doses on tumor development has been recognized for some time and has led to the concept of maximum tolerated dose (MTD) for dose selection, with the highest dose being at the MTD. Exposure at the MTD should ensure that the animals are sufficiently challenged while at the same time the animal's normal longevity is not altered from effects other than carcinogenicity. A characteristic of exposure-dose-response relationships for chronically inhaled particles is that lung tumors are significantly increased only at high exposure levels, and that lung tumors are seen in rats only but not in mice or hamsters. This lung tumor response in rats is thought to be secondary to persistent alveolar inflammation, indicating that the MTD may have been exceeded. Thus, mechanisms of toxicity and carcinogenicity may be dose dependent and may not operate at lower doses that humans normally experience. Despite awareness of this problem, carcinogenicity bioassays that evaluate particulate compounds in rodents have not always been designed with the MTD concept in mind. This is due to several problems associated with determining an appropriate MTD for particle inhalation studies. One requirement for the MTD is that some toxicity should be observed. However, it is difficult to define what degree of toxic response is indicative of the MTD. For particle inhalation studies, various noncancer end points in addition to mortality and body weight gain have been considered as indicators of the MTD, i.e., pulmonary inflammation, increased epithelial cell proliferation, increased lung weight, impairment of particle clearance function, and significant histopathological findings at the end of a subchronic study. However, there is no general agreement about quantification of these end points to define the MTD. To determine whether pulmonary responses are indicative of the MTD, we suggest defining an MTD based on results of a multidose subchronic and chronic inhalation study with a known human particulate carcinogen, e.g., asbestos or crystalline silica. Quantification of effects in such a study using the noncancer end points listed above would identify a dose level without significant signs of toxicity at the end of the subchronic study. If this dose level still results in significant lung tumor incidence at the end of the chronic study. We will have a sound basis for characterizing the MTD and justifying its use in future particle inhalation studies. Also, a better understanding of cellular and molecular mechanisms of particle-induced lung tumors is needed to support the MTD concept.

Air Pollutants↗