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A worksite study was conducted to examine whether a 15-min nap during a post-lunch rest period would affect subsequent alertness, performance, and nocturnal sleep in eight factory workers under a 3-week protocol. Subjects were asked to take the nap at 12:30 h on a reclining chair during the nap week, and to remain awake during the no-nap week. The order of these 2 weeks was counterbalanced between the subjects. During the third, follow-up week, each subject determined whether or not she/he would nap. Alertness on the job and nocturnal sleep were assessed using a sleep diary. Wrist activity was also recorded during sleep at night. Choice reaction time task (RT) was performed at 10:00 and 15:00 h every day of the nap week and every other day of the no-nap and follow-up weeks. Perceived alertness was significantly higher in the afternoon after nap than after no nap at the end of the week. Similar effects were observed during the follow-up week where almost half of the subjects napped. No significant differences between the three weeks were found for RT performance or nocturnal sleep. Workers' attitudes toward the nap were favourable. Although further intervention research is required, our results suggest that post-lunch napping may have the potential to promote daytime alertness at work. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate personal exposures of 27 workers to indium compounds as "total" dust and its "respirable" fraction in their breathing zones at 3 Japanese indium plants. Eight-hour time-weighted average (TWA) indium concentrations of personal exposure to dust collected in sampling periods of 6 h or longer were determined by ICP-MS. The arithmetic means of exposure concentrations were 0.095 mg indium (In)/m 3 , when sampled as total dust, and 0.059 mg In/m 3 , as respirable fraction. ACGIH's TLV-TWA of 0.1 mg In/m 3 for total particulate matter and Acceptable Exposure Concentration Limit (AECL) of 3×10 -4  mg In/m 3 for the respirable fraction notified by the Japanese Ministry of Health, Labour and Welfare were used to evaluate the exposure concentrations. Twenty-five out of 27 workers were exposed to indium concentrations lower than TLV-TWA, while all of the workers were exposed to the indium concentrations higher than AECL. We noted that there was a large discrepancy between the two occupational exposure limits referred to in this report, and these differences were attributed to the sampling strategies and health effects used as the prevention targets. Carcinogenicity of the respirable fraction of indium-containing particulates was considered in setting AECL, whereas it was not in ACGIH's TLV.

This study quantitatively assessed personal exposure of 86 workers to indium compounds as total dust at 11 Japanese indium plants. The personal exposures to indium concentrations in the breathing zone during an 8 h work-shift were determined by ICP-MS. The arithmetic mean indium concentration of all the workers was 0.098 mg Indium (In)/m 3 , with individual values ranging from 0.0001 to 1.421 mg In/m 3 . There were 11 workers whose exposure to indium concentrations exceeded the American Conference of Governmental Industrial Hygienists' Threshold Limit Value-Time Weighted Average (TLV-TWA) of 0.1 mg In/m 3 . Based on the condition TLV-TWA95 (upper 95th percentile of log-normal distribution), five indium plants were judged as "control measures required", while 3 other plants were evaluated as "control measures not required". Five workers belonging to the worst group were exposed to far higher indium concentrations than the TLV-TWA. Another group of 5 workers belonging to the best group was exposed to far lower indium concentrations than the TLV-TWA, and this was attributed to the stringent engineering control measures used at their workplaces. The quantitative assessment of occupational exposure to indium dust was influenced by different occupational exposure limit values without carcinogenicity and particle size-selectivity of indium particulates or "total" dust.

Objectives: This study aimed to assess workers' exposure to indium and its compounds in 55 indium-handling operations among 13 Japanese plants. The surveyed plants were selected from indium-manufacturing plants whose annual indium production exceeded 500 kg., Methods: The Control of Substances Hazardous to Health (COSHH) Essentials control banding toolkit, which contains simple scales for hazard levels, quantities in daily use, and "dustiness" characteristics, was used to assess generic risks of indium-handling operations. The operations were then classified into one of four Control Approaches (CAs)., Results: There were 35 indium-handling operations classified into CA4 (requires expert advice) and 16 grouped into CA3 (requires containment). There were three operations classified into CA2 (requires engineering controls) and only one into CA1 (requires good general ventilation (GV) and working practices). Of the 51 operations classified as CA4 and CA3, 36 were found to be improperly equipped with local exhaust ventilation, and the remaining 15 operations solely relied on GV practices. Respiratory protective equipment (RPE) used in the 13 indium plants was examined with reference to the recommendations of the COSHH Essentials and Japan's Technical Guidelines., Conclusions: Our findings suggest that stringent engineering control measures and respiratory protection from indium dust are needed to improve indium-handling operations. Our results show that the most common control approach for Japanese indium-handling operations is to require expert advice, including worker health checks for respiratory diseases and exposure measurement by air sampling.

Workplace air concentrations of formaldehyde (FA) in medical facilities where FA and FA-treated organs were stored and handled were measured before and during working hours and assessed by the official method specified by Work Environment Measurement Law. Sixty-percent of the total facilities examined were judged as inappropriately controlled work environment. The concentrations of FA before working hours by spot sampling were found to exceed 0.1 ppm in some facilities, and tended to increase with increasing volume of containers storing FA and FA-treated materials. Regression analysis revealed that logarithmic concentrations of FA during working hours by the Law-specified analytical method were highly correlated with those before working hours by spot sampling, suggesting the importance for appropriate storing methods of FA and FA-treated materials. The concentrations of FA during working hours are considered to be lowered by effective ventilation of FA-contaminated workplace air and appropriate storage of FA and FA-treated materials in plastic containers in the medical facilities. In particular, such improvement by a local exhaust ventilation system and tightly-sealed containment of FA-treated material were urgently needed for the dissecting room where FA-treated cadavers were prepared and handled for a gross anatomy course in a medical school.

Certain attitudes toward suicide may be a risk factor for suicide among the bereaved. To explore this possibility, we examined the relationship between attitudes toward suicide and family history of suicide. We focused on two specific attitudes indicating resignation in a survey: #1 "When a person chooses to die by suicide, the suicide is inevitable" (i.e., inevitability belief); and #2 "A suicide cannot be stopped by any person, because suicide is unpreventable" (i.e., unpreventable belief). The data of 5117 fully completed questionnaires were analyzed. Logistic regression analysis revealed that the two attitudes of resignation were significantly associated with a family history of suicide. The adjusted odds ratio for #1 was 1.39 (95% CI, 1.07-1.79) for individuals having experienced suicide by a family member or relative, while that for #2 was 1.57 (95% CI, 1.27-1.95) for experiencing a suicide by a family member or relative and 1.25 (95% CI, 1.05-1.49) for experiencing a suicide by a friend, business associate, partner or other. These two attitudes of resignation toward suicide were significantly associated with a family history of suicide. These attitudes might increase suicide risk among the bereaved.

Objectives: We aimed to assess the exposure of offset printing workers to hazardous substances in the rinsing processes of small-sized companies using a control banding method., Methods: We obtained half-year amounts of hazardous substances purchased through a questionnaire survey and the hazardous information from the safety data sheets (SDSs) and related literature., Results: The amount of petroleum kerosine and carbon hydride markedly increased in 2013 compared with that in 2010. In contrast, the amount of dichloromethane (DCM) decreased in 2013, and 1,2-dichloropropane (DCP) was not used in either 2010 or 2013. Mineral oil and xylene were allocated to Hazard Group D and judged to require Control Approach 3. In addition to DCM with Global Harmonization System's carcinogenic category 1, mildly treated mineral oil and solvent naphtha, allocated into Hazard Group E, are carcinogenic to humans and were judged to require Control Approach 4. There are two limitations of the control banding assessment: first, only limited and scarce hazard information could be obtained from SDSs, and second, safe-sided judgment for control technology for industrial hygiene., Conclusion: Small-sized enterprises are encouraged to implement control banding assessment for hazardous substances and to access expert advice available from Regional Industrial Health Centers. Easy access to appropriate expert advice is important to compensate for the limited and scarce hazard information and safe-sided judgment for control technology for Control Approaches 3 and 4.

Objectives: Feeling ashamed for seeking help when distressed is known to be a critical factor promoting suicidal behaviors. The objective of this study was to examine the relationship between suicidal ideation and psychosocial factors, including worries or anxieties, having a person to confide in, feeling ashamed for seeking help when distressed, and K6 score., Methods: Fourteen out of 77 municipalities from Nagano Prefecture participated in this questionnaire survey. Participants of both sexes over 20 years of age were randomly selected according to age distribution in each municipality. Association between suicidal ideation and sociodemographic and psychosocial factors, including "feeling ashamed for seeking help", were determined by multiple logistic regression analysis., Results: Among a total of 11,100 participants, 7394 (66.6%) returned the questionnaire. 2147 participants responded properly to essential study parameters and were submitted to the final analyses. The adjusted odds ratio of suicidal ideation was 2.09 (95% CI 1.49-2.94) among participants feeling ashamed for seeking help, compared to those not feeling ashamed. Although the rate of "no person to confide in" was 4.4%, participants who responded with "no person to confide in" had significantly increased odds ratio of suicidal ideation compared with those who responded with "having a person to confide in" (OR 1.97, 95% CI 1.12-3.47)., Conclusions: Our findings suggest a need for tailored intervention targeting individuals at risk by gatekeepers to encourage individuals at risk to overcome feeling ashamed for seeking help and to cultivate an appropriate person to confide in.

This cross-sectional study was intended to examine health effects of 678 male workers employed during an 8-yr period from 2000 to 2007 at 36 municipal and private waste incineration plants in Japan. Blood samples were obtained for analysis of concentrations of dioxins including coplanar polychlorinated biphenyls (coplanar PCBs) and evaluation of health effects. Health effects including diabetes were surveyed via a physician's interview or clinical data from blood samples. There was a certain difference in serum concentrations of polychlorinated dibenzofurans (PCDFs) between the incinerator workers and Japanese general population, although no differences in the concentrations of total dioxins or polychlorinated dibenzo-p-dioxins (PCDDs) were found between the two groups. A few positive correlations between serum levels of PCDDs and PCDFs and the results of laboratory and physiological tests were found, but coplanar PCBs showed significant relations with 14 parameters of the tests. The background serum levels of PCDDs, PCDFs and total dioxins were significantly associated with the prevalence of diabetes. No essential differences in serum concentrations of total dioxins and in prevalence of diabetes between our subjects and the general population suggested that the incinerator workers were marginally exposed to dioxins in the workplace without any recognizable adverse health effects.

The aim of this study was to clarify patterns of serum concentrations of dioxins in the employees of a waste incineration plant and to estimate elimination rates and half-lives of serum dioxin isomers, and the maximum serum concentrations of dioxin isomers at the time of plant shutdown. Sixteen subjects participating 3 times or more in annual health examinations during an 8-yr period from 2000 to 2007 were recruited for this study. Serum concentrations of dioxins expressed as TEQ/g lipid decreased gradually after plant shutdown with the highest decrease observed in polychlorinated dibenzofurans (PCDFs) followed by polychlorinated deibenzo-p-dioxins (PCDDs) and then coplanar PCBs. The serum toxic equivalency (TEQ) concentrations of PCDF and PCDD congeners in the employees were higher than those in the general population survey by the Ministry of the Environment, Japan, whereas the serum concentrations of coplanar PCBs were similar to those in the general population. The estimated half-lives and elimination rates of PCDDs and PCDFs in the highly exposed workers increased compared with the moderately exposed workers. The estimated geometric mean serum concentrations of PCDDs, PCDFs and total dioxins at the time of plant shutdown were 35, 53 and 107 pg TEQ/g lipid, respectively.

We evaluated total body burden of N,N-dimethylformamide (DMF) taken through the lung and skin by personal exposure of workers to DMF and urinalysis of N-methylformamide (NMF) and N-acetyl-S(N-methylcarbamoyl)-cysteine (AMCC). A total of 270 workers were engaged in four different jobs in a workplace distant from main production lines emanating high levels of DMF. They were not required to wear any personal protective equipment including respirators or gloves. We found that log-transformed urinary levels of NMF and AMCC increased with an increase in log-transformed concentrations of exposure to DMF. Urinary levels of NMF and AMCC were significantly higher in the summer than the winter, although there was no significant seasonal difference in the concentrations of exposure to DMF. Our findings suggested that the increased urinary levels of NMF and AMCC in the summer resulted in increased skin absorption of DMF due to an increased amount of DMF absorbed by the moisturized skin under humid and hot conditions. Seasonal changes in the relative internal exposure index confirmed the present finding of enhanced summertime skin absorption of DMF. AMCC is thought to be a useful biomarker for assessments of cumulative exposure to DMF over a workweek and for evaluations of workers' health effects.

Objective: We evaluated the percutaneous absorption of N,N-dimethylformamide (DMF) in DMF-exposed workers in the summer and winter by assessing their urinary levels of DMF metabolites., Methods: Breathing-zone concentrations of DMF and workers' urinary levels of N-methylformamide (NMF) and N-acetyl-S-(N-methylcarbamoyl)-cysteine (AMCC) were simultaneously measured in the summer and winter in 193 male workers wearing a respirator and chemical protective gloves., Results: The mean breathing-zone concentrations of DMF in both seasons were below the occupational exposure limit of 10 ppm. Although there was no significant seasonal difference in the breathing-zone concentrations of DMF, workers' urinary levels of NMF and AMCC were significantly higher in the summer than in the winter. Log-transformed urinary levels of the metabolites were significantly correlated with log-transformed breathing-zone concentrations of DMF in the summer, whereas no significant correlation between AMCC and DMF was found in the winter. The urinary levels of AMCC were dispersed more widely than those of NMF, suggesting that urinary AMCC reflected the cumulative exposure to DMF over a workweek., Conclusions: Percutaneous absorption was the principal route of exposure to DMF for the respirator-wearing workers. Increased urinary levels of NMF and AMCC in the summer were attributed to increased percutaneous absorption of DMF resulting from the increased amount of water-soluble DMF absorbed by sweaty skin caused by the increased summertime room temperature and humidity.

Objectives: Suspended indium dust in an indium-recycling plant was quantified, in order to improve the work environment and to reduce workers' exposure to the dust., Methods: Assessment of indium dust in the workplace air by multipoint area sampling and personal breathing zone sampling was conducted twice in 2004 and 2008., Results: In 2004, all recycling processes except for purity analysis were classified into control class III according to the 2004 Notification. Two out of 5 workers were exposed to total dust with indium concentrations exceeding the ACGIH's TLV-TWA of 0.1 mg In/m(3). In 2008, the indium-contaminated workplace air was improved by local exhaust ventilation systems installed in some processes, resulting in control class I. According to the 2010 Technical Guideline, however, all the processes were classified into stage II or III, indicating that the first assessment value or Measurement B-based concentrations exceeded the acceptable exposure concentration limit of 0.0003 mg In/m(3) of respirabe dust. Exposure of almost all the workers to indium dust was below the TLV-TWA., Conclusions: The first field survey showed that almost all workplaces were classified into control class III, and that some workers were exposed to dust with indium concentrations exceeding the TLV-TWA. It was found in the second survey that workplace air contamination was improved by the local exhaust ventilation system, but was not reduced sufficiently to a level that meets the new Guideline.

Objectives: Two- and 13-week inhalation toxicities of indium-tin oxide (ITO) and indium oxide (IO) were characterized for risk assessments of workers exposed to ITO., Methods: F344 rats of both sexes were exposed by inhalation to ITO or IO aerosol for 6 h/day, 5 day/wk for 2 wk at 0, 0.1, 1, 10 or 100 mg/m(3) or 13 wk at 0, 0.1 or 1 mg/m(3). An aerosol generator and inhalation exposure system was constructed., Results: Blood and lung contents of indium were elevated in a dose-related manner in the ITO- and IO-exposed rats. ITO and IO particles were deposited in the lung, mediastinal lymph node and nasal-associated lymphoid tissue. Exposures to ITO and IO induced alveolar proteinosis, infiltrations of alveolar macrophages and inflammatory cells and alveolar epithelial hyperplasia in addition to increased lung weight. ITO affected the lung more severely than IO did. Fibrosis of alveolar wall developed and some of these lesions worsened at the end of the 26-week post-exposure period., Conclusions: Persistent pulmonary lesions including alveolar proteinosis and macrophage infiltration occurred after 2- and 13-week inhalation exposures of rats to ITO and IO. Fibrosis of alveolar wall developed later. These lesions occurred after ITO exposure at the same concentration as the current occupational exposure limit in the USA and at blood indium levels below the biological exposure index in Japan for indium.

Objectives: Carcinogenicity and chronic toxicity of indium-tin oxide (ITO) were examined by inhalation exposure of rats and mice to ITO aerosol., Methods: Fifty mice of both sexes were exposed to ITO at 0 (control), 0.01, 0.03 or 0.1 mg/m(3) for 6 h/day, 5 day/wk for 104 wk, and 50 rats of both sexes were exposed to 0, 0.01 or 0.03 mg/m(3) ITO for the same time period. The repeated exposure of 50 rats of both sexes to 0.1 mg/m(3) ITO was discontinued at the 26th wk, followed by clean air exposure for the remaining 78 wk., Results: In rats, incidences of bronchiolo-alveolar adenomas and carcinomas, bronchiolo-alveolar hyperplasia, alveolar wall fibrosis and thickened pleural wall, alveolar proteinosis and infiltrations of alveolar macrophages and inflammatory cells were significantly increased. Combined incidences of malignant lung tumors in male rats and total lung tumors in male and female rats were significantly increased at exposure to 0.01 mg/m(3) ITO. In mice, no carcinogenic response occurred, but thickened pleural wall, alveolar proteinosis and alveolar macrophage infiltration were induced. Mice were less susceptible to ITO than rats. The lung content of indium was the greatest, followed by the spleen, kidney and liver. Blood indium levels increased dose-dependently., Conclusions: There was clear evidence of carcinogenicity of inhaled ITO in male and female rats but not clear evidence in mice, together with occurrence of the chronic pulmonary lesions in both rats and mice.

Objectives: Inhalation toxicities of indium-tin oxide (ITO) and indium oxide (IO) in mice were characterized in comparison with those previously reported in rats., Methods: B6C3F(1) mice of both sexes were exposed by inhalation to ITO or IO aerosol for 6 h/day, 5 day/wk for 2 wk at 0, 0.1, 1, 10 or 100 mg/m(3) or 13 wk at 0, 0.1or 1 mg/m(3)., Results: ITO and IO particles were deposited in the lung, mediastinal lymph node (MLN) and nasal-associated lymphoid tissue. Alveolar proteinosis, infiltrations of alveolar macrophages and inflammatory cells and increased lung weight were induced by 2- and 13-week exposures to ITO and IO, while alveolar epithelial hyperplasia occurred only in the 2-week exposures. Thickened pleural wall, hyperplastic MLN, extramedullary hematopoiesis in the spleen and increased levels of erythrocyte parameters were induced by 13-week exposure to ITO. The ITO- and IO-induced pulmonary lesions were milder in mice than those previously reported in rats, and the fibrotic lesions were different between these two species. Indium levels in the lung and pooled blood were analyzed in the mice exposed to ITO and IO for 13 wk. In the 13-week inhalation exposure of mice to ITO, alveolar proteinosis and significantly increased lung weight were induced at the same exposure concentration as the current threshold limit value for indium and its compounds.

The toxicity and carcinogenicity of 1,2-dichloropropane (DCP) were examined by inhalation exposure of male and female F344 rats to DCP for either 13 wk or 2 years. In the 13-wk study, the DCP concentrations used were 125, 250, 500, 1000, or 2000 ppm (v/v), and in the 2-year study the DCP concentrations were 80, 200, or 500 ppm (v/v). Thirteen-week exposure to DCP induced hyperplasia in the respiratory epithelium and atrophy of the olfactory epithelium at 125 ppm and above. At the higher levels of exposure, hemolytic anemia and lesions of liver and adrenal gland were observed. Two-year exposure to DCP significantly increased incidences of papilloma in the nasal cavity of male and female rats exposed to 500 ppm DCP. In addition, three cases of esthesioneuroepithelioma were observed in the DCP-exposed male rats. Total nasal tumors increased in a concentration-dependent manner. Hyperplasia of the transitional epithelium and squamous cell hyperplasia, both of which were morphologically different from the hyperplasia of the respiratory epithelium observed in the 13-wk exposure study, occurred in a concentration-dependent manner; these lesions are considered to be preneoplastic lesions. Atrophy of the olfactory epithelium, inflammation of the respiratory epithelium, and squamous cell metaplasia were also seen in the 2-year study. These results demonstrate that DCP is a nasal carcinogen in rats. Lifetime cancer risks for humans exposed to DCP in the ambient air and work environment were quantitatively estimated, using both nonthreshold and threshold approaches, with the data obtained from the 2-year study.

Much concern has been raised over the health consequences of workers exposed to carbon nanotubes. In order to characterize multi-wall carbon nanotubes (MWCNT) suspended in a phosphate-buffered saline containing 0.1% Tween 80 for an intratracheal instillation study. Length and width distributions of the MWCNT fibers, dispersion of MWCNT in the suspension and in the lung tissue and the MWCNT contents of metal impurities were investigated. Arithmetic mean length and width of the MWCNT fibers as measured on scanning electron microscope (SEM) photographs were 5.0 microm and 88 nm, respectively, and fibers longer than 5.0 microm were 38.9% of all fibers measured. Dynamic light scattering size measurement revealed that 5-min ultrasonication, together with addition of Tween 80 into the suspension, decreased the hydrodynamic diameters of the agglomerated MWCNT to those of finer particles below 1.0 microm. SEM observation showed good dispersion of MWCNT in the suspension, and in the alveoli on Day 1 after instillation. Concentration of iron, chromium and nickel in the MWCNT were 4,400, 48 and 17 ppm (wt/wt), respectively, all of which were below levels that would elicit positive pulmonary toxic responses to these metals. The results suggest that well-dispersed, long and thin MWCNT fibers exhibit asbestos-like pathogenicity in the lung.

Objectives: The potential applications and industrial production of multi-wall carbon nanotubes (MWCNT) have raised serious concerns about their safety for human health and the environment. The present study was designed to examine the in vitro cytotoxicity and genotoxicity of MWCNT and UICC chrysotile A (chrysotile)., Methods: Cytotoxicity using both colony formation and lactate dehydrogenase (LDH) assays and genotoxicity including chromosome aberration, micronucleus induction and hgprt mutagenicity were examined by exposing cultured Chinese hamster lung (CHL/IU) cells to MWCNT or chrysotile at different concentrations., Results: The in vitro cytotoxicity of MWCNT depended on the solvent used for suspension of MWCNT and ultrasonication duration of the MWCNT suspension. A combination of DMSO/culture medium and 3-minute ultrasonication resulted in a well-dispersed medium with dispersion and isolation of agglomerated MWCNT by ultrasonication which manifested the highest cytotoxicity. The cytotoxicity was more potent for chrysotile than MWCNT. The genotoxicity of MWCNT was characterized by the formation of polyploidy without structural chromosome aberration, and an increased number of bi- and multi-nucleated cells without micronucleus induction, as well as negative hgprt mutagenicity. Chrysotile exhibited essentially the same genotoxicity as MWCNT, except for marginal but significant induction of micronuclei. MWCNT and chrysotile were incompletely internalized in the cells and localized in the cytoplasm., Conclusions: MWCNT and chrysotile were cytotoxic and genotoxic in Chinese hamster lung cells, but might interact indirectly with DNA. The results suggest that both test substances interfere physically with biological processes during cytokinesis.

In order to assess pulmonary toxicity of multiwall carbon nanotubes (MWCNT), male F344 rats were intratracheally instilled with MWCNT suspension at a dose of 40 or 160 μg/head or α-quartz particles as a positive control at a dose of 160 μg/head and sacrificed for lung histopathology and bronchoalveolar lavage (BAL) fluid analyses on Day 1, 7, 28 or 91 after instillation. Well-dispersed MWCNT brought about dose- or time-dependent changes in lung weight, total proteins, albumin, lactate dehydrogenase and alkaline phosphatase in the BAL fluid, and pulmonary lesions including inflammation, Type II cell hyperplasia, microgranulomas and fibrosis. Phagocytosed and free forms of MWCNT were found in both bronchiolar and alveolar spaces. MWCNT deposition in the bronchus-associated lymphoid tissue gradually increased after instillation. Persistent infiltration of macrophages, transient infiltration of inflammatory cells primarily composed of neutrophils, microgranulomas associated with macrophages engulfing MWCNT, Type II cell hyperplasia and fibrosis with alveolar wall thickening as well as number of multinucleated alveolar macrophages increased dose-dependently. The MWCNT-induced lesions were more potent on Day 91 than the α-quartz-induced ones at an equal mass dose. The present results for intratracheally instilled MWCNT were extrapolated to potential inhalation exposure of humans to MWCNT at workplaces based on several assumptions.

The carcinogenicity of 1,4-dioxane was examined by giving groups of 50 F344/DuCrj rats and 50 Crj:BDF(1) mice of each sex 1,4-dioxane in the drinking-water for 2 years. The concentrations of 1,4-dioxane were 0 (control), 200, 1000 and 5000 ppm (wt./wt.) for rats and 0, 500, 2000 and 8000 ppm for mice. The highest dose levels did not exceed the maximum tolerated dose. In the rat, there was significant induction of nasal squamous cell carcinomas in females and hepatocellular adenomas and carcinomas in males and females, peritoneal mesotheliomas in males, and mammary gland adenomas in females. In the mouse, there was significant induction of hepatocellular tumors in males and females. Two nasal tumors occurring in the 8000 ppm-dosed groups were spontaneously rare and, thus, were attributed to 1,4-dioxane exposure. The present studies provided clear evidence of carcinogenicity in rats and mice. Lifetime cancer risk of humans exposed to 1,4-dioxane through drinking-water was quantitatively estimated with a non-threshold approach by application of a linearized multistage model to dose-carcinogenic response relationships, in addition to a threshold approach for estimation of the tolerable daily intake using no-observed- or lowest-observed-adverse-effect levels of the carcinogenic responses and uncertainty factors.

Carcinogenicity and chronic toxicity of 1,4-dioxane were examined by inhalation exposure of 50 male F344 rats to 1,4-dioxane vapor at 0 (clean air), 50, 250, or 1250 ppm (v/v) for 6 h/day, 5 days/wk, and 104 wk. Survival rates of 250 and 1250 ppm-exposed groups were decreased near the end of the 2-yr exposure period, due probably to the occurrence of malignant tumors. A statistically significant but marginal decrement of terminal body weight (<10%) was found in the 1250 ppm-exposed group, suggesting slight systemic toxicity. Significant changes in plasma levels of AST, ALT, ALP, and gamma-GTP and relative weight of the liver occurred in the 1250 ppm-exposed group. Dose-dependent and statistically significant increases in incidences of nasal squamous cell carcinomas, hepatocellular adenomas, and peritoneal mesotheliomas were found primarily in the 1250 ppm-exposed group. The incidences of renal cell carcinomas, fibroadenomas in the mammary gland, and adenomas in the Zymbal gland were also increased dose-dependently. Preneoplastic lesions occurred in the nasal cavity and liver of the 1,4-dioxane-exposed groups. As nonneoplastic lesions, the significantly increased incidences of nuclear enlargement, atrophy, and respiratory metaplasia in the nasal cavity were noted at 50 ppm and above. A LOAEL (lowest observed adverse effect level) was determined at 50 ppm for the nasal endpoint of general chronic toxicity. This study provides clear evidence of carcinogenicity for 1,4-dioxane in male rats. A cytotoxic-proliferative and in vivo genotoxic mode of action is suggested to operate in 1,4-dioxane-induced carcinogenesis.

N,N-Dimethylformamide (DMF), a ubiquitous contaminant in living and working environments, enters the human body by inhalation, as well as by oral and dermal routes of exposure. In order to provide bioassay data for carcinogenic risk assessment of humans exposed to DMF by multiple routes of exposure, hepatocarcinogenic effect of combined inhalation and oral exposures of rats to DMF was examined. A group of 50 male F344 rats, 6-week-old, was exposed by inhalation to 0 (clean air), 200, or 400 ppm (v/v) of DMF vapor-containing air for 6 hr/day and 5 days/week during a 104-week period, and each inhalation group was given ad libitum DMF-formulated drinking water at 0, 800 or 1,600 ppm (w/w) for 104 weeks. Incidences of hepatocellular adenomas and carcinomas and their combined incidences were significantly increased in the combined-exposure groups compared with the untreated control group or each of the inhalation-alone and oral-alone groups with matching concentrations. Incidences of hepatocellular adenomas and carcinomas induced by the combined exposures were greater than the sum of the two incidences of the hepatocellular adenomas and carcinomas induced by the single-route exposures through inhalation and ingestion. The combined exposures enhanced tumor malignancy. It was concluded that the combined inhalation and oral exposures markedly enhance the incidences and malignancy of hepatocellular tumors, suggesting that the hepatocarcinogenic effect of the combined exposures is greater than the effect that would be expected under the assumption that the two effects of single-route exposures through inhalation and drinking are additive.

Objectives: This study was carried out to clarify the subchronic and chronic toxicity, and carcinogenicity of 2-amino-4-chlorophenol(ACP)., Methods: Carcinogenicity, and chronic and subchronic toxicity of ACP were examined by feeding 10 rats of both sexes ACP-containing diet at a dose level of 0 (control), 512, 1,280, 3,200, 8,000 or 20,000 ppm (w/w) for 13 wk and 50 rats of both sexes at a dose level of 0, 1,280, 3,200 or 8,000 ppm for 2 yr., Results: The 13-wk oral subchronic toxicity of ACP was characterized by proliferative lesions leading to development of tumors in the forestomach and urinary bladder and by erythrocyte toxicity as evidenced by decreases in red blood cell counts, hemoglobin and hematocrit and concurrent increases in methemoglobin levels and reticulocyte counts. Both simple and papillary and/or nodular types of transitional cell hyperplasias were observed in the urinary bladder of ACP-fed male rats. The proliferative lesions appeared at higher doses of ACP after the 13-wk administration than clear erythrocyte toxicity did. The 2-yr oral administration of ACP significantly increased incidences of squamous cell papillomas and carcinomas in the forestomach of male and female rats and transitional cell carcinomas in the urinary bladder of male rats. These tumor incidences increased dose-dependently. Notably, clear signs of erythrocyte toxicity were not evident after the 2-yr administration of ACP., Conclusion: Clear evidence of carcinogenic activity of ACP was shown in male and female rats. These data might be useful for the health risk assessment of workers exposed to ACP.

A gas exposure system using rotating vessels was improved for exposure of cultured mammalian cells to gaseous compounds in the chromosomal aberration assay. This system was composed of 12 square culture vessels, a device for preparation of air containing test gas, and positive and negative control gases at target concentrations and for supplying these gases to the culture vessels, and a roller apparatus in an incubator. Chinese hamster lung cells (CHL/IU) were grown on one side of the inner surface of the square culture vessel in the MEM medium. Immediately prior to exposure, the medium was changed to the modified MEM. Air in the culture vessel was replaced with air containing test gas, positive or negative control gas. Then, the culture vessels were rotated at 1.0 rpm. The monolayered culture cells were exposed to test gas during about 3/4 rotation at upper positions and alternatively immersed into the culture medium during about 1/4 rotation at lower positions. This system allowed the chromosomal aberration assay simultaneously at least at three different concentrations of a test gas together with positive and negative control gases with and without metabolic activations, and duplicate culture at each exposure concentration. Seven gaseous compounds, 1,3-butadiene, chlorodifluoromethane, ethyl chloride, methyl bromide, methyl chloride, propyne, and vinyl chloride, none of which has been tested to date, were tested on CHL/IU for the chromosomal aberration assay using this gas exposure system. All the compounds except chlorodifluoromethane showed positive responses of the structural chromosomal aberrations, whereas polyploidy was not induced by any of these gases. This improved gas exposure system proved to be useful for detecting chromosomal aberrations of gaseous compounds.

Carcinogenicity and chronic toxicity of carbon tetrachloride were examined by inhalation exposure of 50 F344 rats and 50 BDF1 mice of both sexes to carbon tetrachloride at 0 (clean air), 5, 25, or 125 ppm (v/v) for 6 h/day, 5 days/wk, for 104 wk. Incidences of hepatocellular adenomas and carcinomas in rats and mice of both sexes and of adrenal pheochromocytomas in mice of both sexes were significantly increased dose-dependently. Hepatocellular carcinomas and cirrhosis significantly occurred in the 125-ppm-exposed rats of both sexes, and 3 cases of hepatocellular carcinomas and increased incidences of hepatic altered cell foci were noted in the 25-ppm-exposed female rats. Hepatocellular carcinomas were induced in mice of both sexes at 25 and 125 ppm, and hepatocellular adenomas occurred in females at 5 ppm without any degenerative or necrotic change in hepatocytes. Hepatocellular carcinomas metastasized to the lung. The chronic hepatotoxicity was characterized by cirrhosis, fibrosis, and fatty change in rats, and ceroid deposition, bile-duct proliferation, and hydropic change in mice. Survival rates were decreased in the 125-ppm-exposed rats and mice of both sexes and in the 25-ppm-exposed female mice, in association with decreased body weights. The decreased survival rates were considered to be causally related to both various tumors including hepatocellular carcinomas and severe chronic progressive nephropathy in rats and to hepatocellular carcinomas in mice. This study provided clear evidence of carcinogenicity for carbon tetrachloride in rats and mice. A cytotoxic-proliferative and genotoxic mode of action for carbon tetrachloride-induced hepatocarcinogenesis was suggested.

Subchronic toxicity of carbon tetrachloride (CCl4) was examined by inhalation exposure of F344 rats and BDF1 mice of both sexes to 0, 10, 30, 90, 270 or 810 ppm (v/v) CCl4 vapor for 13 wk (6 h/d and 5 d/wk). In the high exposure levels at 270 and 810 ppm, altered cell foci in the livers of both rats and mice, and fibrosis and cirrhosis in the rat liver were observed. Hematoxylin and eosin-stained altered cell foci of rats were recognized as glutathione-S-transferase placental form (GST-P) positive foci, which are preneoplastic lesions of hepatocarcinogenesis. The most sensitive endpoint of CCl4-induced toxicity was fatty change with large droplets in rats of both sexes and male mice, and cytoplasmic globules in male mice, as well as increased relative liver weight in male rats. Those endpoints were manifested at 10 ppm and the LOAEL was determined as 10 ppm for the hepatic endpoints in rats and mice. Enhanced cytolytic release of liver transaminases into plasma in rats and mice and its close association with hepatic collapse in mice were observed at medium and high levels of inhalation exposure. Both CCl4-induced hematotoxicity and nephrotoxicity were observed in both rats and mice, but those toxicities were manifested at higher exposure concentrations than hepatotoxicity. The LOAEL for the hepatic endpoint and the GST-P-stained altered cell foci provide relevant animal data for reconsidering the occupational exposure limit val1ue of 5 ppm for CCl4 and strengthen the evidence of CCl4-induced hepatocarcinogenicity which is used in its carcinogenicity classification.

Dose- and time-dependent effects of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) on the liver were examined by single administration of TBDD by gavage to male and female rats. Fifteen Wistar rats of each sex per group received 0, 10, 30, 100 or 300 microg TBDD/kg body weight. Rats surviving to scheduled necropsy on Day 2, 7 or 36 after the TBDD administration were examined for hepatic histopathology, activities of hepatic microsomal enzymes and serum levels of lipids, total cholesterol and transaminases and hepatic concentrations of TBDD. Tigroid basophilic cytoplasm and hepatocellular hypertrophy were observed at 10 microg/kg on Day 2 or 7 through 36, whereas degenerative and aggressive lesions such as necrosis, fibrosis, multinucleated hepatocytes and disarrangement of hepatocytes occurred later at higher dose levels. Persistently increased activities of hepatic aryl hydrocarbon hydroxylase (AHH), ethoxycoumarin O-deethylase (ECOD) and ethoxyresorufin O-deethylase (EROD), increased serum levels of total cholesterol and phospholipid and increased relative liver weight were observed in all groups dosed 10 mug/kg and above, suggesting that hepatic microsomal monooxygenases and basophilic cytoplasm of hepatocytes were early and sensitive indicators among those TBDD-induced effects. A dose-dependent increase in liver concentrations of TBDD on Day 2 was followed by logarithmic decreases in TBDD concentrations against the days elapsed after the TBDD administration. An elimination half-life (t(1/2)) of TBDD from the liver was estimated to range from 12 to 16 days. It was suggested that females were more susceptible to TBDD than males, and that acute hepatotoxicity of TBDD was as potent as that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Nasal, respiratory, reproductive and developmental toxicities of propylene oxide (PO) were examined by exposing male and female Sprague-Dawley rats to PO vapor by inhalation at a concentration of 0 (control), 125, 250, 500 or 1,000 ppm for 6 h/d, 7 d/wk, during a 5- to 6-wk period, including premating, mating and postmating or gestation. The inhalation exposure to 1,000 ppm PO seriously affected parental survival, the upper and lower respiratory tract, male and female reproductive systems, motor function, and fetal survival and development, whereas the exposure to 500 ppm or less primarily caused nasal lesions without any sign of reproductive or developmental toxicity. Because atrophy of the olfactory epithelium in the male rats exposed to 250 ppm was the most sensitive endpoint for PO toxicity, the NOAEL was determined to be 125 ppm for the nasal endpoint. An additional inhalation experiment was carried out to further examine developmental toxicity by exposing pregnant rats to 0, 125, 250, 500, 750 or 1,000 ppm PO during a 2-wk period of gestation, Day 6 through Day 19. The 2-wk inhalation experiment revealed that reduced fetal body weights and delayed ossification occurred in association with significantly reduced body weights of the dams exposed to 750 and 1,000 ppm, whereas neither fetal death nor teratogenicity occurred at those two exposure levels. It was concluded that the developmental toxicity of fetal death was manifested at parentally toxic exposure levels above 500 ppm, a level which seriously affected parental survival, the upper and lower respiratory tracts and reproductive system.

Carcinogenicity and chronic toxicity of 1,2-dichloroethane (DCE) were examined by inhalation exposure of groups of 50 F344 rats and 50 BDF1 mice of both sexes to DCE vapor or clean air as control for 6 h/d, 5 d/wk and 104 wk. The rats were exposed to 10, 40 or 160 ppm (v/v) DCE, while the mice were exposed to 10, 30 or 90 ppm. The 2-yr exposure to DCE produced a dose-dependent increase in incidences of benign and malignant tumors, including subcutaneous fibroma, mammary gland fibroadenoma and peritoneal mesothelioma in male rats; subcutaneous fibroma and mammary gland adenoma, fibroadenoma and adenocarcinoma in female rats; and bronchiolo-alveolar adenoma and carcinoma, endometrial stromal polyp, mammary gland adenocarcinoma and hepatocellular adenoma in female mice. No exposure-related change in the incidence of non-neoplastic lesions or in any hematological, blood biochemical or urinary parameter occurred in any DCE-exposed rat or mouse group. The types of tumors and their target organs found in this study were consistent with those observed in rats and mice administered DCE by gavage in a NCI study. Selection of the exposure concentrations was considered appropriate with reference to the maximum tolerated dose for the highest doses and an occupational exposure limit of DCE for the lowest dose. The present findings suggest that those carcinogenic responses be primarily considered for standard setting of occupational and environmental exposure to DCE.

Chloroform, ubiquitously present in indoor and outdoor air, drinking water, and some foodstuffs, enters the human body by inhalation, oral and dermal routes of exposure. In order to provide bioassay data for risk assessment of humans exposed to chloroform by multiple routes, effects of combined inhalation and oral exposures to chloroform on carcinogenicity and chronic toxicity in male F344 rats were examined. A group of 50 male rats was exposed by inhalation to 0 (clean air), 25, 50, or 100 ppm (v/v) of chloroform vapor-containing air for 6 h/d and 5 d/wk during a 104 w period, and each inhalation group was given chloroform-formulated drinking water (1000 ppm w/w) or vehicle water for 104 wk, ad libitum. Renal-cell adenomas and carcinomas and atypical renal-tubule hyperplasias were increased in the combined inhalation and oral exposure groups, but not in the oral- or inhalation-alone groups. Incidences of cytoplasmic basophilia and dilated tubular lumens in the kidney, as well as incidence of positive urinary glucose, were markedly increased by the combined exposures, compared with those after single-route exposures. It was concluded that combined inhalation and oral exposures markedly enhanced carcinogenicity and chronic toxicity in the proximal tubule of male rat kidneys, suggesting that carcinogenic and toxic effects of the combined exposures on the kidneys were greater than the ones that would be expected under an assumption that the two effects of single route exposures through inhalation and drinking were additive.

Carcinogenicity and chronic toxicity of ortho-chloronitrobenzene (o-CNB) were examined by feeding groups of 50 F344 rats and 50 BDF(1) mice of both sexes o-CNB-containing diets for 2 years. The dietary concentration of o-CNB was 0, 80, 400 or 2000 ppm (w/w) for rats and 0, 100, 500 or 2500 ppm for mice. The 2-year administration of o-CNB produced a dose-dependent increase in incidences of hepatocellular adenomas and carcinomas in rats and mice of both sexes and hepatoblastomas in mice of both sexes. Incidences of altered cell foci in the liver were increased in the o-CNB-fed rats of both sexes. Metastasis from mouse malignant liver tumors occurred predominantly in the lung. The hepatocarcinogenic response to o-CNB was found to be more potent in mice than in rats. Marginally increased incidences of renal cell adenomas in the 2000 ppm-fed female rats and renal cell carcinomas in the 2000 ppm-fed male rats were noted, together with a significantly increased incidence of atypical tubule hyperplasias. Spontaneous, age-related chronic progressive nephropathy was exacerbated in a dose-related manner, and caused the death of 47 male rats fed 2000 ppm before the end of the 2-year administration period. The highest dose levels of o-CNB except for the administration of 2000 ppm to male rats were thought to meet the criteria of the maximum tolerated dose set by both NCI and IARC guidelines. Causative factors of o-CNB-induced carcinogenicity were discussed with reference to our previous rodent studies of subchronic toxicity of o-CNB and carcinogenicity and chronic toxicity of para-chloronitrobenzene.

Objective: Systemic and myelotoxic effects of 2,3,7,8-tetrabromodibenzo-p-dioxin (TBDD) were examined by the single administration of TBDD by gavage to rats., Methods: Fifteen Wistar rats of both sexes per group received 0, 10, 30, 100 or 300 μg TBDD/kg body weight. Rats surviving to the scheduled necropsy on Days 2, 7 and 36 after TBDD administration were examined for growth rate, organ weight, hematology, histopathology and adipose tissue levels of TBDD., Results: Three 300 μg/kg-dosed females died on Days 21, 23 and 27, and exhibited a marked decrease in body weight, severe thymic atrophy, decreased bone marrow hematopoiesis and hemorrhage in the subarachnoid space of brain and spinal cord. TBDD-dosed surviving rats exhibited growth retardation, decreased bone marrow hematopoiesis, decreases in red blood cell counts, hemoglobin concentrations, and hematocrit values, an increase in reticulocytes and decreases in platelet counts, white blood cell counts and eosinophils. These signs suggested TBDD myelotoxicity. Splenic extramedullary hematopoiesis was increased in both sexes given TBDD, whereas atrophy of the splenic white pulp occurred only in TBDD-dosed females. Marked decreases in body weights and the size and weight of the thymus, severe thymic atrophy and death in TBDD-dosed females suggested a wasting syndrome. The adipose tissue level of TBDD culminated on Day 7 and decreased to 20-30% of the Day 7 level on Day 36., Conclusions: The TBDD-induced effects were characterized by a wasting syndrome and myelotoxicity that appeared at the dose levels of 30 μg/kg and higher and caused death in 300 μg/kg-dosed females.

Developmental toxicity of N,N-dimethylacetamide (DMAC) was examined by exposing pregnant rats by inhalation to DMAC vapor at 0 (control), 100, 300, 450 or 600 ppm (v/v) for 6 h/d during Gestation Days 6 through 19. Fetal body weight and the number of male live fetuses were significantly decreased, along with a tendency of the number of intrauterine deaths to increase. The number of fetuses with visceral and skeletal malformations was significantly increased in the 450 and 600 ppm groups, while the number of fetuses with anasarca as an external malformation was increased at 600 ppm. Observed cardiovascular malformations included ventricular septum defect, persistent truncus arteriosus, malpositioned subclavian branch and retroesophageal subclavian artery. Persistent truncus arteriosus was accompanied by ventricular septal defect (VSD). Incidences of the persistent truncus arteriosus, which was classified as a serious congenital heart disease affecting postnatal survival, were increased at 450 and 600 ppm. Increased liver weights and hepatocellular swelling occurred in the dams exposed to 300 ppm and above, whereas neither hepatocellular necrosis nor increased serum activity of liver transaminases was observed in any of the exposed groups. Maternal body weights were decreased at 450 and 600 ppm. The most sensitive signs of developmental toxicity appeared at the exposure level of 300 ppm which was also the level of slight maternal toxicity. The No-Observed-Adverse-Effect-Level (NOAEL) was determined as 100 ppm for the endpoints of fetal and maternal toxicities. The NOAEL of 100 ppm and the induction of serious cardiovascular malformations occurring at 450 ppm and above were discussed with reference to the existing occupational exposure limit for DMAC.

Carcinogenicity and chronic toxicity of 1,4-dichloro-2-nitrobenzene (DCNB) were examined by feeding each group of 50 F344 rats and 50 BDF1 mice of both sexes a DCNB-containing diet at a concentration of 0 (control), 320, 800 or 2,000 ppm (w/w) for 2 yr. In rats, incidences of hepatocellular adenomas and carcinomas and their combined incidence were increased in the 2,000 ppm-fed males, together with increased incidence of basophilic cell foci in the 800 and 2,000 ppm-fed males. A dose-related increase in combined incidences of renal cell adenomas and carcinomas was noted. Incidence of Zymbal gland adenomas tended to increase in the 2,000 ppm-fed males. In mice, incidences of hepatocellular adenomas in the 800 and 2,000 ppm-fed females and hepatocellular carcinomas in the 2,000 ppm-fed males and in the 800 and 2,000 ppm-fed females were increased. Incidence of hepatoblastomas was increased in all DCNB-fed males and in the 2,000 ppm-fed females. Signs of chronic toxicity were characterized by centrilobular hypertrophy of hepatocytes with nuclear atypia in mice, increased relative liver weight in rats, a dose-related increase in incidences of chronic progressive nephropathy with advanced grades of severity in male rats, and decreased hemoglobin concentration and hematocrit accompanied by increased bone marrow hematopoiesis in female rats. Carcinogenic activity of DCNB was evaluated for the three different tumors, and sensitive signs of the chronic toxicity were dis-

Para- and ortho-chloronitrobenzene (p- and o-CNB) were compared for subchronic toxicity by feeding F344 rats and BDF(1) mice of both sexes p-CNB-or o-CNB-containing diets at 5 different concentrations for 13 weeks. The two isomers induced hematotoxicity and hepatotoxicity of different toxic potencies. p-CNB produced an anemic sign of external appearance in rats and mice, while o-CNB did not. Significant increases in the incidences of increased erythropoiesis in the bone marrow and increased extramedullary hematopoiesis in the spleen and liver, and in serum total bilirubin in rats and mice appeared at lower dose levels of p-CNB than o-CNB. A significant increase in serum ALT activity appeared at lower dose levels of o-CNB than p-CNB, together with appearance of both necrosis and hydropic degeneration of hepatocytes only in the o-CNB-fed rats and nuclear enlargement with atypia of hepatocytes only in the o-CNB-fed mice. BMDL(10)s of p- and o-CNB for the hematotoxic endpoint, substitutes for NOAELs, were 0.177 mg/kg/day and 1.03 mg/kg/day for the rats, respectively. For the mice, the NOAELs of p-and o-CNB for the hematotoxic endpoint were 10.5 mg/kg/day and 10.4 mg/kg/day, respectively. A NOEL of o-CNB for the hepatotoxic endpoint resulted in 13.8 mg/kg/day for the rats and 12.2 mg/kg/day for the mice. These results suggest that p-CNB is a more potent hematotoxicant than o-CNB, whereas o-CNB is a more potent hepatotoxicant than p-CNB, and that the rat hematopoietic system is more susceptible to p-CNB than the mouse hematopoietic system.

Carcinogenicity and chronic toxicity of para-chloronitrobenzene (p-CNB) were examined by feeding diets containing p-CNB to rats and mice of both sexes for two years. The dietary concentration of p-CNB was 0 (control), 40, 200, or 1000 ppm (w/w) for rats and 0, 125, 500, or 2000 ppm for mice. Survival rates of the high-dosed male rats and male mice were significantly decreased compared with those of the respective controls, and this was attributed to the increased number of cancer deaths. Therefore, the high-dose levels were considered not to exceed the maximum tolerated dose. Significant decreases in red blood cell counts and hematocrit value and an increase in mean corpuscular volume were noted in the p-CNB-fed rats and mice. Nonneoplastic splenic lesions were characterized by capsule hyperplasia, fibrosis, fatty metamorphosis, and increased extramedullary hematopoiesis in rats, and congestion, increased extramedullary hematopoiesis, hemosiderin deposition, and ossification in mice. Incidences of fibromas, fibrosarcomas, osteosarcomas, sarcomas (NOS), and hemangiosarcomas in males and fibrosarcomas in females were significantly increased in the spleen of high-dosed rats. The most frequently observed splenic tumor was fibrosarcomas, followed by fibromas. The tumor incidences were increased in a dose-related manner and were more prevalent in males than in females. The malignant tumors metastasized mainly to the liver, peritoneum, and pancreas. Adrena/medullary hyperplasia and pheochromocytomas were significantly increased in the p-CNB-fed females. No tumor was induced in any of the p-CNB-fed mice of either sex except hepatic hemangiosarcomas in the 2000 ppm-fed females. Causative factors of p-CNB-induced carcinogenicity and chronic toxicity are discussed in light of the subchronic and chronic hematotoxicity reported in our present and previous studies and in the literature.