Search

The excellence of a journal depends on the quality of peer review. The process of publishing scientific discoveries depends on considerable work by unpaid experts who volunteer time as peer reviewers. Peer reviewers are the essential gatekeepers who maintain high standards of scientific rigor. Equally important, many manuscripts are significantly improved when the authors respond to insightful suggestions from peer reviewers. Veterinary Pathology has been fortunate over the years in having a pool of highly dedicated and high-quality reviewers. Scientists are motivated to spend time reviewing manuscripts for a number of reasons. Altruism and service to the community of science, and to the discipline of veterinary pathology, motivate many to spend time reading and reviewing manuscripts, but these are not the only reasons. Curiosity and the desire to stay current are equally important. Reviewers enjoy the challenge involved in the careful analysis and assessment of a manuscript. Finally, for the success of Veterinary Pathology, manuscripts must be reviewed carefully and rapidly, and this would be impossible without the active participation of the broad scientific community. Conflict with other workloads is a major reason that potential reviewers decline invitations to review manuscripts. As discussed in the 2007 American College of Veterinary Pathologists (ACVP) Town Hall meeting, pathologists have increasing demands on their time, and the stresses of multitasking continue to increase. The problem is compounded by the retirement or death of some of the stalwart experts of veterinary pathology.

DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life Sciences Institute (ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair deficient models respond to genotoxic carcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.

Bemitradine is a compound that was intended for use as a diuretic antihypertensive drug. In the preclinical safety assays, it was found to be nongenotoxic in five in vitro assays (Ames, mouse lymphoma, CHO/HGPRT, CHO chromosome aberration, and UDS) and in one in vivo assay (mouse bone marrow micronucleus). In a subsequent long-term bioassay using Sprague-Dawley rats, this compound was found to be a rodent carcinogen at multiple sites. Because of the carcinogenicity, further development of this compound as a drug was halted. Because the Syrian hamster embryo (SHE) cell transformation assay at pH 6.7 has been demonstrated to be a good predictor of carcinogenic activity in animals, this nongenotoxic compound was used to determine if this in vitro assay system could be utilized to predict the potential for the carcinogenicity in rodents. The SHE cell transformation assay was validated initially for use in this laboratory using genotoxic and nongenotoxic carcinogens including benzo(a)pyrene, 20-methylcholanthrene, 2-acetylaminofluorene, methapyrilene, and phenobarbital. Each of these chemicals induced a statistically significant increase in morphological transformation frequency. Bemitradine was initially tested in a range-finding cytotoxicity assay at 10-250 microg/mL for treatment periods of 7 days. Doses used in the 7-day treatment transformation assay were 1.25, 2.5, 5.0, 7.5, and 10.0 microg/mL. Statistically significant increases in morphological transformation frequencies were observed at 1.25, 2.5, and 7.5 microg/mL, indicating a positive response. The experiment was repeated with similar results confirming the previous conclusion. These data provide additional evidence that the pH 6.7 SHE cell transformation assay may be a valuable in vitro tool to detect nongenotoxic rodent carcinogens.

The most frequent biologic events associated with multispecies multisite rodent non-genotoxic carcinogenesis include robust liver P450 enzyme induction without liver toxicity. This cancer process is not relevant for humans as exemplified by phenobarbital. A host of other pharmaceuticals, including loratidine and atorvastatin, with current sales in the billions of dollars attests to the lack of relevance of our rodent models acting via this specific process. Hopefully, the mechanism of phenobarbital will no longer draw research money in further probing the irrelevant in human carcinogenesis. The known human carcinogens not linked with genetic injury all perturb tissue growth/replication in humans as well as in rodent short-term tests at doses ultimately linked with cancer. Clearly identifying exposures perturbing growth/replication versus exposures not perturbing growth provides an effective tool for demonstrating the threshold for cancer risk in refining the risk assessment as capably described by Dr. Klaunig. Hopefully, we can begin to increasingly use data-based decisions in risk assessment versus hypothetical low- dose extrapolations and mathematical modeling, building on the wealth of current understanding in human and rodent cancer processes in arenas beyond pharmaceutics.

A peculiar decalin-induced male rat nephropathy associated with the altered renal handling of filtered protein appears limited to the accumulation of the protein, alpha 2u-globulin. Several strains of male rats that produce alpha 2u-globulin (Fischer-344, Sprague-Dawley, Buffalo, and Norway Brown) demonstrate spontaneous renal cortical hyaline droplets which are exacerbated after exposure to decalin. In all cases, a close correlation exists between hyaline droplet formation observed histologically and alpha 2u-globulin accumulation measured biochemically. In stark contrast, the NCI-Black-Reiter strain, which does not produce measurable quantities of alpha 2u-globulin, neither forms hyaline droplets nor accumulates any filtered protein in its kidney cortex either spontaneously or after exposure to decalin. Also, female rats injected ip with male rat alpha 2u-globulin exhibit increased hyaline droplet formation and alpha 2u-globulin accumulation when treated with decalin. These data provide evidence that the presence of alpha 2u-globulin is key in understanding why this nephropathy appears unique to the male rat.

Trisodium nitrilotriacetate monohydrate was fed to male weanling Charles River rats for 28 days. Clinical evidence of urinary tract toxicity included hydronephrosis and nephromegaly. Microscopically, severe renal injury was recognized specifically as convoluted tubular cytoplasmic vacuolation and pelvic epithelial erosion. Hyperplasia occurred as a sequela to these specific cytotoxic alterations.

The reversibility of nitrilotriacetate (NTA)-associated nephrotoxicity was investigated by comparing renal tissues from rats fed nephrotoxic levels of NTA for 7 wk with those from rats allowed 5 wk of recovery after the 7-wk exposure. In addition the toxicity of 2% Na3NTA X H2O in the diet (73 mumol/g diet) was compared with that of 1.5% H3NTA (79 mumol/g diet). The two forms of NTA induced comparable renal tubular cell toxicity which was characterized by proximal convoluted cell vacuolation and hyperplasia. These effects were noted in all of the exposed animals although the extent of damage varied. This specific renal tubular cell toxicity was completely reversed during the 5-wk recovery period. Renal pelvic transitional cell toxicity was induced primarily by Na3NTA X H2O. Renal pelvic toxicity was characterized by hydronephrosis, and erosion, ulceration and hyperplasia of the transitional epithelium. All forms of renal toxicity except that accompanying hydronephrosis were reversed when Na3NTA X H2O feeding was discontinued.

“Mucocytes” were found in the white tracts of the brain of a llama (Lama glama) which had clinical signs of central nervous derangement. A morphologic and histochemical comparison with other cerebral organic and inorganic deposits is given.

The effects in the renal cortex of the male rat of continuous administration of a high dose of nitrilotriacetate (NTA) for 24 months were compared with those of the administration of a similar dose for 18 months followed by a 6-month recovery period on the control diet. The results suggest that discontinuation of treatment interrupts the sequence of events leading to tumour formation. This study indicates that all stages in the proposed pathogenesis of renal tubular tumour formation by NTA, up to the occurrence of adenomalous hyperplasia and neoplasia, are reversible. Apparently, tumour development is dependent on the continuous administration of high doses of NTA in the presence of toxic injury to the majority of nephrons.

Male Rat Unique Proximal Convoluted Tubule (PCT) Protein Reabsorption Droplets Weinbren [see 1] characterised spontaneously occurring hyaline droplets in the otherwise normal mature male rat kidney. The ultrastructural characteristics of the spontaneous PCT hyaline body was characterised by Maunsbach as a phagolysosomal protein reabsorption droplet and defined as a male rat specific increased size and propensity for crystalloid change in comparison to the female rat or higher species, including humans [1].