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Terpenes and Terpenoids
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Exposure to isoprene by inhalation caused tumors at several different tissue sites in mice and rats.12 In mice of both sexes, isoprene caused blood vessel cancer (hemangiosarcoma) and benign or malignant tumors of the Harderian gland (adenoma or carcinoma) and the lung (alveolar/bronchial adenoma or carcinoma).13 In male mice, it also caused cancer of the hematopoietic system (histiocytic sarcoma) and benign or malignant tumors of the liver (hepatocellular adenoma or carcinoma) and for stomach (squamous cell papilloma or carcinoma). In rats of both sexes, isoprene caused benign or malignant tumors of the mammary gland (fibroadenoma or carcinoma) and kidney (renal cell adenoma or carcinoma). In male rats, it also caused benign tumors of the testes (adenoma).12–14 Inhaled isoprene appeared to initiate or trigger chemical sensitivity and some chronic degenerative diseases.
Hazard Characterization and Dose–Response Assessment
Published in Ted W. Simon, Environmental Risk Assessment, 2019
Modeling key events in dose and time may also be useful. Figure 5.2B shows another example based on TCDD. Again, data in both dose and time were available for an early key event, inhibition of apoptosis within altered hepatic foci, and for another key event, occurring later—toxic hepatopathy. These dose–time relationships helped reach the conclusion that the MOA for both combined liver tumors—cholangiocarcinoma and hepatocellular adenoma—was nonlinear.
a,j]acridine
Published in Roger O. McClellan, Critical Reviews in Toxicology, 2017
David Warshawsky, Glenn Talaska, Weiling Xue, Joanne Schneider
The next two studies involved using a strain more sensitive to skin carcinogenesis, the Hsd:ICR(BR) mouse, that was equivalent to the CD-1 mouse. The rationale used was that this strain showed a good correlation between the tumor-initiating activity of PAHs and NHA and their ability to covalently bind to DNA, and this strain had been used in several metabolism and DNA binding studies that had been reported in the literature.47 In a complete carcinogenicity study, 50 nmol of DBC, DBA, BaP, or DBC plus BaP (25 nmol + 25 nmol) were applied to the shaved backs of 50 female Hsd:ICR(BR) mice per group twice a week in 50 μ1 of acetone for 99 weeks or until the appearance of a tumor. Fifty mice each were used in two control groups: acetone and notreatment groups. The histopathology data indicated primary skin lesions in 42, 27,48, and 47 of 50 mice each for DBC, DBA, BaP, and DBC plus DBA, respectively, the majority of them being squamous cell carcinomas. In addition, primary liver lesions were present in 37 mice in the DBC group; 17 of the lesions were hepatocellular adenomas and 22 were hepatocellular carcinomas with only slight necrosis in only five animals, of which only one had a liver lesion. The no-treatment group had two animals with skin lesions, but no squamous cell carcinomas, and one animal with a liver lesion with one hepatocellular adenoma. The acetone-treatment group had three animals with skin lesions, with one squamous cell carcinoma, and two animals with liver lesions, with a total of two hepatocellular adenomas. Coincident with the tumor data, the morphological and morphometric data indicated a significant increase (p <0.05) in mononuclear cells in the dermis for the BaP and DBC plus BaP groups relative to the control (non-treated plus acetone-treated) group. Significant increases (p <0.05) were observed in the nuclear area, nucleoli per nucleus, and cellular area of hepatocytes in the DBC-treatment group relative to the control group. These data indicated that DBC was a two-target organ carcinogen, a potent liver as well as a skin carcinogen following topical application with noted changes in the liver, whereas BaP was only a potent skin carcinogen and DBA a moderate skin carcinogen. It should also be noted that BaP produced skin tumors with a shorter latency period than DBC or DBA in this mouse strain. With this strain, skin tumors appeared more slowly for DBC than with the C3H strain, thus allowing for the appearance of liver tumors beginning around 45 to 50 weeks.
Concordance between sites of tumor development in humans and in experimental animals for 111 agents that are carcinogenic to humans
Published in Journal of Toxicology and Environmental Health, Part B, 2019
Daniel Krewski, Jerry M. Rice, Michael Bird, Brittany Milton, Brian Collins, Pascale Lajoie, Mélissa Billard, Yann Grosse, Vincent J. Cogliano, Jane C. Caldwell, Ivan I. Rusyn, Christopher J. Portier, Ronald L. Melnick, Robert A. Baan, Julian Little, Jan M. Zielinski
Although PeCDF provided sufficient evidence of carcinogenicity in animals, no animal site was identified. PeCDF was tested by the United States National Toxicology Program in a 2-year animal bioassay (female rats only) with exposure by oral gavage (National Toxicology Program 2006). There was some evidence of carcinogenic activity of PeCDF, based upon elevated incidences of hepatocellular adenoma and cholangiocarcinoma of the liver and gingival squamous cell carcinoma of the oral mucosa. The occurrence of cystic keratinizing epithelioma of the lung, neoplasms of the pancreatic acinus, and carcinoma of the uterus may have been related to administration of PeCDF. There were also three rat experiments with PeCDF in combination with N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and N-nitrosodiethylamine (NDEA), where increased tumor multiplicity was found in each case (IARC 2012c). These observations led to the conclusion that there is sufficient evidence for carcinogenicity of PeCDF in animals, although there was no specific organ site that might be designated as responsible for this sufficient evidence. Because of the absence of a specific tumor site in animals, PeCDF is not included in the concordance analyses.
Development of updated RfD and RfC values for medium carbon range aromatic and aliphatic total petroleum hydrocarbon fractions
Published in Journal of the Air & Waste Management Association, 2021
Chad M. Thompson, Virunya S. Bhat, Gregory P. Brorby, Laurie C. Haws
The National Toxicology Program (NTP) conducted a 2-year bioassay on Stoddard solvent IIC5Stoddard solvent IIC is a widely used white spirit mixture. in rats and mice (NTP 2004). Male and female mice, as well as female rats, were exposed to 550, 1100, and 2200 mg/m3, whereas male rats were exposed to 138, 550, and 1100 mg/m3, 6 hours per day, 5 days per week for 2 years. Nonneoplastic lesions were only noted in male rats,6Based on the lesions that NTP reported in their summary table on page 10 of their report (NTP 2004). which consisted of renal tubule hyperplasia and nephropathy. These lesions were accompanied by changes consistent with a α2u-globulin-related mechanism that is well known to have little human relevance (Hard et al. 1993). According to the NTP (2004) study authors, “In general, the current studies confirmed previous findings on Stoddard solvent IIC toxicity. Most of the studies found in the literature for short- and long-term toxicity identified the kidney and liver as the major target organs” (NTP 2004). The NTP (2004) study authors also stated that mice could have tolerated higher concentrations but were exposed to the maximum attainable vapor generation. NTP (2004) further noted that, “Chronic exposure did not cause significant microscopic lesions while possibly exposure-related increases occurred in the incidences of hepatocellular adenoma and eosinophilic foci of the liver.” Based on these findings, the study NOAEC was considered 2200 mg/m3 in mice and female rats, and 1100 mg/m3 in male rats. Therefore, HEC values were calculated extrapolating from rats and mice, treating Stoddard IIC as a Category 3 systemically acting gas (U.S. EPA 1994).