Shoji Fukushima’s research while affiliated with National Institute of Occupational Safety and Health JAPAN and other places

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Publications (737)


Experimental design.
SEM image of MWCNTs in suspension. In suspension (480 µg/mL), MWCNTs were well dispersed on the filtered samples of the suspension.
Body weight curves of rats for 91 days.
Cytological BAL analysis. Total cells, neutrophils, alveolar macrophages, and lymphocytes at day 14. *: p < 0.05, **: p < 0.01, significantly different as compared to respective controls (vehicle control), Dunnett test. #: p < 0.05, ##: p < 0.01, significantly different as compared to low-dose group, t-test. †: p < 0.05, ††: p < 0.01, significantly different in multiple-administration test as compared to single administration, t-test.
Biochemical BAL analysis. Total protein, albumin, LDH, ALP, and γGTP at day 14. **: p < 0.01, significantly different as compared to respective controls (vehicle control), Dunnett test. #: p < 0.05, ##: p < 0.01, significantly different as compared to low-dose group, t-test. †: p < 0.05, ††: p < 0.01, significantly different in multiple-administration test as compared to single administration, t-test.

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Comparison of Single and Multiple Intratracheal Administrations for Pulmonary Toxic Responses of Multi-Walled Carbon Nanotubes in Rats
  • Article
  • Full-text available

December 2024

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8 Reads

Hideki Senoh

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Hirokazu Kano

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Shoji Fukushima

The purpose of the present study is to contribute to the establishment of a standard method for evaluating the adverse effects of nanomaterials by intratracheal administration. Low and high doses of multi-walled carbon nanotubes (MWCNTs) were administered to rats in a single administration or the same final dose as the single administration but divided over four administrations. Bronchoalveolar lavage examination on day 14 showed an inflammatory reaction and cytotoxicity in the lung, generally greater at the higher dose, and tending to be greater in the rats with four administrations at both the low and high doses. Histopathologic findings showed increased alveolar macrophages and MWCNT deposition (fibers phagocytosed by alveolar macrophages and fibers that were not phagocytosed) in the alveolar space, granulomatous changes, and MWCNT deposition in bronchus-associated lymphoid tissue (BALT) and lung-related lymph nodes on days 14, 28, and 91. In addition, alveolar type II epithelial hyperplasia was observed on day 91, and fibrosis of the alveolar wall was observed on days 28 and 91. Fewer alveolar macrophages with phagocytosed MWCNTs were present at day 91 compared to day 28. MWCNT deposition tended to be higher in the BALT after a single administration, whereas deposition was higher in the lung-related lymph nodes after four administrations. MWCNTs were considered to be transported from the lungs or BALT to the lymph nodes over time. There were no significant differences in MWCNT deposition in the lung after the single administration compared with four administrations at either the low or high doses, and the histopathological findings were similar after single and four administrations, at both the low and high doses. Based on the above findings, a toxicity evaluation of the nanomaterials can be sufficiently performed by intratracheal administration, even with a single intratracheal administration.

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A critical review of the pathogenesis of nasal cavity tumors induced in rodents

Journal of Toxicologic Pathology

The pathogenesis of nasal cavity tumors induced in rodents has been critically reviewed. Chemical substances that induce nasal cavity tumors in rats, mice, and hamsters were searched in the National Toxicology Program (NTP), International Agency for Research on Cancer (IARC), and Japan Bioassay Research Center (JBRC databases), in addition to PubMed. Detailed data such as animal species, administration routes, and histopathological types were extracted for induced nasal cavity tumors. Data on nonneoplastic lesions were also extracted. The relationship between the tumor type and non-neoplastic lesions at equivalent sites was analyzed to evaluate tumor pathogenesis. Genotoxicity data were also analyzed. Squamous cell carcinoma was the most frequent lesion, regardless of the dosing route, and its precursor lesions were squamous metaplasia and/or respiratory epithelial hyperplasia, similar to squamous cell papilloma. The precursor lesions of adenocarcinoma, the second most frequent tumor type, were mainly olfactory epithelial hyperplasia, whereas those of adenoma were respiratory epithelial lesions. These pathways were consistent among species. Our results suggest that the responsible lesions may be commonly linked with chemically-induced cytotoxicity in each tumor type, irrespective of genotoxicity, and that the pathways may largely overlap between genotoxic and non-genotoxic carcinogens. These findings may support the documentation of adverse outcome pathways (AOPs), such as cytotoxicity, leading to nasal cavity tumors and the integrated approaches to testing and assessment (IATA) for non-genotoxic carcinogens.


Exposure of Rats to Multi-Walled Carbon Nanotubes: Correlation of Inhalation Exposure to Lung Burden, Bronchoalveolar Lavage Fluid Findings, and Lung Morphology

September 2023

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20 Reads

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5 Citations

To evaluate lung toxicity due to inhalation of multi-walled carbon nanotubes (MWCNTs) in rats, we developed a unique MWCNT aerosol generator based on dry aerosolization using the aerodynamic cyclone principle. Rats were exposed to MWNT-7 (also known as Mutsui-7 and MWCNT-7) aerosolized using this device. We report here an analysis of previously published data and additional unpublished data obtained in 1-day, 2-week, 13-week, and 2-year inhalation exposure studies. In one-day studies, it was found that approximately 50% of the deposited MWNT-7 fibers were cleared the day after the end of exposure, but that clearance of the remaining fibers was markedly reduced. This is in agreement with the premise that the rapidly cleared fibers were deposited in the ciliated airways while the slowly cleared fibers were deposited beyond the ciliated airways in the respiratory zone. Macrophage clearance of MWNT-7 fibers from the alveoli was limited. Instead of macrophage clearance from the alveoli, containment of MWNT-7 fibers within induced granulomatous lesions was observed. The earliest changes indicative of pulmonary toxicity were seen in the bronchoalveolar lavage fluid. Macrophage-associated inflammation persisted from the one-day exposure to MWNT-7 to the end of the two-year exposure period. Correlation of lung tumor development with MWNT-7 lung burden required incorporating the concept of area under the curve for the duration of the study; the development of lung tumors induced by MWNT-7 correlated with lung burden and the duration of MWNT-7 residence in the lung.


FEMA GRAS assessment of natural flavor complexes: Sage oil, Orris Root Extract and Tagetes Oil and related flavoring ingredients

July 2023

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56 Reads

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5 Citations

Food and Chemical Toxicology

In recent years, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) has conducted a program to re-evaluate the safety of natural flavor complexes (NFCs) used as flavor ingredients. This publication, twelfth in the series, details the re-evaluation of NFCs whose constituent profiles are characterized by alicyclic or linear ketones. In its re-evaluation, the Expert Panel applies a scientific constituent-based procedure for the safety evaluation of NFCs in commerce using a congeneric group approach. Estimated intakes of each congeneric group of the NFC are evaluated using the well-established and conservative Threshold of Toxicological Concern (TTC) approach. In addition, studies on the toxicity and genotoxicity of members of the congeneric groups and the NFCs under evaluation are reviewed. The scope of the safety evaluation of the NFCs contained herein does not include added use in dietary supplements or any products other than food. Thirteen (13) NFCs derived from the Boronia, Cinnamomum, Thuja, Ruta, Salvia, Tagetes, Hyssopus, Iris, Perilla and Artemisia genera are affirmed as generally recognized as safe (GRAS) under conditions of their intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.


FEMA GRAS assessment of natural flavor complexes: Lemongrass oil, chamomile oils, citronella oil and related flavoring ingredients

March 2023

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39 Reads

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12 Citations

Food and Chemical Toxicology

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, eleventh in the series, evaluates the safety of NFCs characterized by primary alcohol, aldehyde, carboxylic acid, ester and lactone constituents derived from terpenoid biosynthetic pathways and/or lipid metabolism. The Expert Panel uses the scientific-based evaluation procedure published in 2005 and updated in 2018 that relies on a complete constituent characterization of the NFC intended for commerce and organization of the constituents of each NFC into well-defined congeneric groups. The safety of the NFCs is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on estimated intake, metabolism and toxicology of members of the congeneric groups and for the NFC under evaluation. The scope of the safety evaluation contained herein does not include added use in dietary supplements or any products other than food. Twenty-three NFCs, derived from the Hibiscus, Melissa, Ricinus, Anthemis, Matricaria, Cymbopogon, Saussurea, Spartium, Pelargonium, Levisticum, Rosa, Santalum, Viola, Cryptocarya and Litsea genera were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.


Survival curves, body weight curves, and final body weights. (A) Survival curves of male. (B) Survival curves of female. (C) Body weight curves of male. (D) Body weight curves of female. (E) Final body weight of male. (F) Final body weight of female.
Zymbal's gland tumor. (A) A macroscopic image of the canal nodules (bilateral) of a male rat with malignant Zymbal's gland tumors. Malignant Zymbal's gland tumors are observed on both sides (male, 600 ppm group). (B) Malignant Zymbal's gland tumor (male, 600 ppm group). The tumor is characterized by the papillary structures of epithelial cells composed of a both of squamous cells and sebaceous cells. (C) High magnification of B. (D) Lung metastasis of malignant Zymbal's gland tumor (male, 600 ppm group).
Skin/appendage tumor. (A) Macroscopic image of skin/appendage nodules, (B) Basal cell carcinoma (male, 600 ppm group). (C) Sebaceous adenoma of the skin/appendage (male, 600 ppm group), (D) Squamous cell carcinoma of the Skin (male, 600 ppm group).
Large intestine tumor. (A) Adenocarcinoma of the large intestine (male, 600 ppm group). (B) High magnification of A. The tumor has structural atypia and cellular atypia.
Mammary gland tumor. (A) A macroscopic image of a mammary gland tumor (female, 600 ppm group). (B) Adenocarcinoma of the mammary gland (female, 600 ppm group). (C) Metastasis of mammary gland adenocarcinoma to the lung, (female, 600 ppm group). (D) Fibroadenoma of the mammary gland (female, 200 ppm group).
Multi-organ carcinogenicity by inhalation exposure to 2-Bromopropane in rats

February 2023

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170 Reads

Journal of Occupational Health

Objective: The purpose of this study was to investigate the carcinogenicity of 2-bromopropane (2-BP) in rats. Methods: Male and female F344 rats were exposed by whole body inhalation to 2-BP vapor at concentrations of 0, 67, 200, and 600 ppm for 6 h/day, 5 days/week for 2 years. Results: All rats of both sexes exposed to 600 ppm died or became moribund within 85 weeks. Death/moribundity was caused by 2-BP induced tumors. In males, significantly increased tumors were malignant Zymbal's gland tumors; sebaceous adenoma and basal cell carcinoma of the skin/appendage; adenocarcinoma of the small/large intestine; follicular cell adenoma of the thyroid; fibroma of the subcutis, and malignant lymphoma of the lymph node. In addition, an increased trend in tumor incidence was found in the preputial gland, lung, forestomach, pancreas islet, brain, and spleen. In females, significantly increased tumors were adenocarcinoma and fibroadenoma of the mammary gland, squamous cell papilloma of the vagina, and large granular lymphocytic leukemia of the spleen. In addition, an increased trend in tumor incidence was found in Zymbal's gland, the clitoral gland, skin, large intestine, pancreas islet, uterus, and subcutis. Particularly, malignant Zymbal's gland tumors were induced even in males exposed to the lowest concentration, 67 ppm. Conclusion: Two-year inhalation exposure to 2-BP resulted in multi-organ carcinogenicity in rats. Based on sufficient evidence of carcinogenicity in this study, 2-BP has the potential to be a human carcinogen.


FEMA GRAS assessment of derivatives of basil, nutmeg, parsley, tarragon and related allylalkoxybenzene-containing natural flavor complexes

February 2023

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72 Reads

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7 Citations

Food and Chemical Toxicology

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavoring ingredients in food. In this publication, ninth in the series, NFCs containing a high percentage of least one naturally occurring allylalkoxybenzene constituent with a suspected concern for genotoxicity and/or carcinogenicity are evaluated. In a related paper, tenth in the series, NFCs containing anethole and/or eugenol and relatively low percentages of these allylalkoxybenzenes are evaluated. The Panel applies the threshold of toxicological concern (TTC) concept and evaluates relevant toxicology data on the NFCs and their respective constituent congeneric groups. For NFCs containing allylalkoxybenzene constituent(s), the estimated intake of the constituent is compared to the TTC for compounds with structural alerts for genotoxicity and when exceeded, a margin of exposure (MOE) is calculated. BMDL10 values are derived from benchmark dose analyses using Bayesian model averaging for safrole, estragole and methyl eugenol using EPA's BMDS software version 3.2. BMDL10 values for myristicin, elemicin and parsley apiole were estimated by read-across using relative potency factors. Margins of safety for each constituent congeneric group and MOEs for each allylalkoxybenzene constituent for each NFC were determined that indicate no safety concern. The scope of the safety evaluation contained herein does not include added use in dietary supplements or any products other than food. Ten NFCs, derived from basil, estragon (tarragon), mace, nutmeg, parsley and Canadian snakeroot were determined or affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.


FEMA GRAS assessment of natural flavor complexes: Allspice, anise, fennel-derived and related flavoring ingredients

February 2023

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54 Reads

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15 Citations

Food and Chemical Toxicology

The FEMA Expert Panel program to re-evaluate the safety of natural flavor complexes (NFCs) used as flavoring ingredients in food has resulted in the publication of an updated constituent-based procedure as well as publications on the safety evaluation of many botanical-derived NFCs. This publication, tenth in the series and related to the ninth publication, describes the affirmation of the generally recognized as safe (GRAS) status for NFCs with propenylhydroxybenzene and allylalkoxybenzene constituents under their conditions of intended use as flavoring ingredients added to food. The Panel's procedure applies the threshold of toxicological concern (TTC) concept and evaluates relevant data on absorption, metabolism, genotoxic potential and toxicology for the NFCs themselves and their respective constituent congeneric groups. For NFCs containing allylalkoxybenzene constituent(s) with suspected genotoxic potential, the estimated intake of the individual constituent is compared to the TTC for compounds with structural alerts for genotoxicity and if exceeded, a margin of exposure is calculated using BMDL10 values derived from benchmark dose analyses using Bayesian model averaging, as presented in the ninth article of the series. Safety evaluations for NFCs derived from allspice, anise seed, star anise, sweet fennel seed and pimento leaves were conducted and their GRAS status was affirmed for use as flavoring ingredients. The scope of the safety evaluation contained herein does not include added use in dietary supplements or any products other than food.



Citations (80)


... Residual cobalt had little impact on the inflammatory parameters; although the levels of MWCNT used for this comparison, 11 mg/m 3 , had only mild inflammatory activity. The duration of exposure was much less than in the study by Ma-Hock (2009) [53]; however, the highest concentration used by Ellinger-Ziegelbauer and Pauluhn was approximately 100-fold greater than the highest concentration used by Ma-Hock. Thus, the high exposure levels in the study by Ellinger-Ziegelbauer and Pauluhn and the long exposure period in the study by Ma-Hock would account for the induction of inflammation reported in these two studies. ...

Reference:

A Review of the Carcinogenic Potential of Thick Rigid and Thin Flexible Multi-Walled Carbon Nanotubes in the Lung
Exposure of Rats to Multi-Walled Carbon Nanotubes: Correlation of Inhalation Exposure to Lung Burden, Bronchoalveolar Lavage Fluid Findings, and Lung Morphology

... Solely in Italy, about 1000 tons of fresh iris rhizomes is used annually to produce iris EO (orris oil) [34]. According to the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) assessment, Orris Root Extract (FEMA 2830) and Orris Concrete Liquid Oil (FEMA 2829), which are obtained from the same three species, have an annual usage greater than or up to 1000 kg [37]. The abovementioned species belong to the group of bearded irises, which have multicellular caterpillar-like hairs on the external tepals of their ...

FEMA GRAS assessment of natural flavor complexes: Sage oil, Orris Root Extract and Tagetes Oil and related flavoring ingredients
  • Citing Article
  • July 2023

Food and Chemical Toxicology

... The FTIR spectra overall provided detailed insight into the chemical composition and molecular structure of LGEO, ZnONPs, and the nanoformulation. The spectra indicated the presence of hydroxyl groups similar to the observations conducted on the lemon grass extract in a previous study [57], alkane-CH stretching [58], conjugated carbonyl groups [59], and nonconjugated aldehydic groups [60] could also be observed for LGEO as per previous reports. The spectra also indicated the presence of zinc-oxygen bonds for the ZnONPs and the stretching vibrations of hydroxyl groups on the surface of the nanoparticles similar to that reported in a study conducted on the antibacterial activity of ZnONPs [61]. ...

FEMA GRAS assessment of natural flavor complexes: Lemongrass oil, chamomile oils, citronella oil and related flavoring ingredients
  • Citing Article
  • March 2023

Food and Chemical Toxicology

... The MOE is calculated based on the lower confidence limit of the benchmark dose resulting in a 10% extra cancer incidence (BMDL 10 ) determined from the mathematical modeling of in vivo study data on tumor formation in experimental animals. For this safety evaluation, a BMDL 10 value for estragole of 10 mg/kg bw/day was calculated with BMD modeling using Bayesian algorithms and model averaging (Davidsen et al., 2023b). The MOE for the estimated intake of estragole from the consumption of Tagetes Oil (FEMA 3040) is 10,000,000, greatly exceeding the threshold of 10,000 that the FEMA Expert Panel, in agreement with EFSA, determined to be of low public health concern and of low priority for risk management actions (EFSA, 2005, 83 Fed. ...

FEMA GRAS assessment of derivatives of basil, nutmeg, parsley, tarragon and related allylalkoxybenzene-containing natural flavor complexes
  • Citing Article
  • February 2023

Food and Chemical Toxicology

... EO, with the chemical composition consisting of monoterpenes, sesquiterpenes, and phenylpropanoids, among which trans-anethole stands out, potentially representing 90% of the EO (Tabanca et al., 2005). Trans-anethole is considered "GRAS" (Generally Recognized as Safe) by the Food And Drug Administration (FDA) and the Flavor Extract Manufacturers Association (FEMA) in the United States (Rietjens et al., 2023). It has a strong and characteristic smell capable of masking unpleasant odors and, for this reason, is used as a flavoring by the food industry in beverages, sweets, and gums, as well as in industrial products such as medicines, pesticides, and synthetic flavors (Rocha & Fernandes, 2016;Cantó-Tejero, Pascual-Villalobos, & Guirao, 2022). ...

FEMA GRAS assessment of natural flavor complexes: Allspice, anise, fennel-derived and related flavoring ingredients
  • Citing Article
  • February 2023

Food and Chemical Toxicology

... Recently, Sahu et al. [31] indicated that diallyl disulfide is the most promising fumigant toxicant among the examined five different phytocompounds. Furthermore, the US Food and Drug Administration (FDA), recognized the garlic essential oil and its sulphur constituents under Generally Regarded As Safe (GRAS) status, which ensures human safety and health [32]. ...

FEMA GRAS assessment of natural flavor complexes: Asafetida oil, garlic oil and onion oil
  • Citing Article
  • January 2023

Food and Chemical Toxicology

... MWCNTs are reported to have genotoxic activity [42][43][44][45][46][47][48]; however, MWNT-7 in particular is thought to induce genotoxicity through secondary mechanisms rather than as a direct DNA mutagen [42][43][44][45]. Macrophages produce reactive oxygen species (ROS) during the phagocytic response to MWCNT exposure [45,49], and ROS production by these macrophages is considered to be closely related to bronchiolo-alveolar hyperplasia and tumor development [41,43,45]. ...

Contribution of toxicological pathology to occupational health: lung carcinogenicity of fibrous and particulate substances in rats

Journal of Toxicologic Pathology

... In this context, great endeavors have been made to utilize natural bioactive compounds in food preservation. Essential oils are natural bioactive substances derived from plants, with a wide range of antimicrobial and antifungal properties, and they are generally recognized as safe (GRAS) [5][6][7][8]. Nevertheless, their strong aroma and volatile nature, in addition to the suppression of their antimicrobial activity in case of direct contact with complicated food systems [9] (e.g., proteins, lipids), restrain their direct application for food preservation. ...

FEMA GRAS assessment of natural flavor complexes: Origanum oil, thyme oil and related phenol derivative-containing flavoring ingredients

Food and Chemical Toxicology

... Essential oils (EOs) have been widely used in pharmaceutical and food industries due to the safe, efficient, and non-toxic tag of the US Food and Drug Administration [1]. Plant EOs as a natural preservative, both in-vitro and in-vivo, have been extensively utilized. ...

FEMA GRAS assessment of natural flavor complexes: Eucalyptus oil and other cyclic ether-containing flavoring ingredients

Food and Chemical Toxicology