Pathology is the study of the structural and functional changes produced by diseases or − more specifically − the lesions they cause. To achieve this pathologists employ various approaches. These include description of lesions that are visible to the naked eye which are the subject of anatomic pathology and changes at the cellular level that are visible under the microscope, the subject of histopathology. Changes at the molecular level which are identified by probes that target specific molecules − mainly proteins that are detected using immunohistochemistry (IHC). As transmissible spongiform encephalopathies (TSEs) do not cause visible lesions anatomic pathology is not applicable to their study. For decades the application of histopathology to detect vacuoles or plaques was the only means of confirming TSE disease. The subsequent discovery of the cellular prion protein (PrPC) and its pathogenic isoform, PrPSc, which is a ubiquitous marker of TSEs, led to the production of anti-PrP antibodies, and enabled the development of PrPSc detection techniques such as immunohistochemistry, Histoblot and PET-blot that have evolved in parallel with similar biochemical methods such as Western blot and ELISA. These methods offer greater sensitivity than histopathology in TSE diagnosis and crucially they can be applied to analyze various phenotypic aspects of single TSE sources increasing the amount of data and offering higher discriminatory power. The above principles are applied to diagnose and define TSE phenotypes which form the basis of strain characterisation.
Atypical BSE is an invariably fatal neurologic disease of cattle caused by misfolded prion proteins with different conformations than those associated with classical BSE. Evidence suggests that these atypical BSE types are sporadic or genetic prion diseases of cattle and the relevance of these diseases, as far as natural transmissibility, is still unknown. Different misfolded prion protein conformations also result in unique biochemical characteristics. This raised concerns about detection of atypical BSE on rapid test platforms designed and validated for classical BSE prions. Despite the differences in the misfolded prion protein characteristics, studies have shown that the tests also work well for detecting the known types of atypical BSE. A new question that has recently emerged is related to the possibility of additional forms of atypical BSE. Initially reactive bovine brain samples on certain rapid surveillance tests have sparked debate about the true BSE status of these samples. Work is currently underway to determine if these samples are infectious and if they eventually result in neurologic disease in cattle. Results of these studies could impact future BSE diagnostic testing programs as well as human and animal health policies.
In the early 90s’, Europe was shaken by the fear that the prions from “mad cow disease” (bovine spongiform encephalopathy) would transmit the disease to humans via beef products. In 1996, the first variant Creutzfeldt-Jakob (vCJD) patients were described, and the same year our Bovine Spongiform Encephalopathy (BSE) transmission studies to cynomolgus macaques demonstrated that the BSE prion was highly infectious for primates, inducing brain lesions identical to those observed in vCJD patients. These studies provided the first experimental evidence that vCJD was BSE in humans. Subsequent studies established the BSE/vCJD-infected cynomolgus macaque as a robust model to study the pathogenesis of vCJD. We showed rapid adaptation of BSE prions to primates upon subsequent passage, and their distribution in peripheral tissues and blood. Some key studies are summarized in the present paper.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on antimicrobial-resistant bacteria arising from the use of colistin sulfate, which is used as a feed additive and veterinary medicinal products in the livestock. Both Salmonella and E. coli were considered as potential antimicrobial-resistant bacteria to be selected under the use of colistin sulfate in the livestock. As only limited reports were available on the colistin-resistance in Salmonella, FSCJ conducted a risk assessment focusing on E. coli as a hazard, on which the information was rather available. In the release assessment, the degree of possible selection of the hazard was evaluated as “Medium”. Considering proper cooking of the livestock products, the degree of possible human exposure to the resistant bacteria via livestock products was evaluated as “Low”. The degree of possible reduction or loss of clinical effectiveness was evaluated as “High” considering the current situation of colistin use in human medicine. From the above, the overall estimation of the risk was “Medium”.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of cyclaniliprole (CAS No. 1031756-98-5), an anthranilamide insecticide, based on results from various studies. Major treatment-related effects of cyclaniliprole were observed on liver (increased liver weight and increased alkaline phosphatase) in dogs and on thyroid (hypertrophy of follicular epithelial cells) in rats. None of neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity, immunotoxicity and genotoxicity were observed. Based on the results from various studies, only parent cyclaniliprole was identified as the relevant substance to the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the toxicity studies was 1.29 mg/kg bw/day in a one-year chronic toxicity study in dogs. FSCJ has established an acceptable daily intake (ADI) of 0.012 mg/kg bw/day, by applying a safety factor of 100 to the NOAEL. FSCJ judged it unnecessary to specify an acute reference dose (ARfD) since no adverse effects, possibly elicited by a single oral administration, was observed.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of isofetamid (CAS No. 875915-78-9), a phenacyl amide fungicide, based on results from various studies. Major treatment-related effects of isofetamid were observed on liver (hepatocellular hypertrophy) and on thyroid (hypertrophy of follicular epithelial cell). None of neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity, immunotoxicity and genotoxicity were observed. Based on the results from various studies, only parent isofetamid was identified as the relevant substance to the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the toxicity studies was 5.34 mg/kg bw/day in a one-year chronic toxicity study in dogs. FSCJ has established an acceptable daily intake (ADI) of 0.053 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects that would be likely to be elicited by a single oral administration of isofetamid was 300 mg/kg bw/day, which is obtained on the maternal toxicity in rabbits. FSCJ specified an acute reference dose (ARfD) of 3 mg/kg bw/day, applying a safety factor of 100 to the NOAEL.