[Navicular bone fractures in horses: Prognosis after conservative and surgical treatment]. / Strahlbein-Frakturen beim Pferd: Prognose nach konservativer und chirurgischer Therapie.

INTRODUCTION: The aim of this retrospective study is to describe and compare conservative and surgical treatment of navicular fractures in horses. An attempt is made to identify critical points that can favorably influence the prognosis of this orthopedic disease. All horses treated for a navicular fracture at the Equine Clinic, Vetsuisse Faculty, University of Zurich between 2005 and 2017 were included in this study. The severity of lameness at initial examination, radiographic assessment, hoof conformation, treatment (conservative or surgical), complications and outcome were determined from the medical records. Conservative and surgical treatment consisted of stable rest, a controlled exercise program and therapeutic orthopedic shoeing. During surgical treatment, fracture reduction was also carried out with a cortical screw. Computer assisted surgery were used in five horses and computer tomography in three horses. Follow-up examinations included clinical and radiographic examinations. The outcome was divided into three categories: 1 = very good; 2 = good; 3 = poor. Twelve horses met the inclusion criteria; Four horses were treated conservatively and eight were treated surgically. After conservative treatment, two horses (50 %) had a very good outcome and two (50 %) had a good outcome. After surgical treatment, four horses (50 %) had a very good outcome and four (50 %) had a poor outcome. Overall, 67 % of horses had a very good or good outcome, although radiographic signs of bone healing was not present in any of these cases. Various complications were identified, such as the fracture of a screw, the fragmentation of the small navicular bone fragment, the development of osteoarthrosis in the coffin joint and progressive podotrochosis. This study shows that the prognosis of navicular fractures is generally cautious and that degenerative changes to the navicular apparatus worsen the prognosis. In the present study, surgical treatment did not improve the prognosis of navicular fractures despite the intrasurgical use of three-dimensional imaging. However, technical advances could reduce the complication rate in the future.

INTRODUCTION: Le but de cette étude rétrospective était de décrire et de comparer le traitement conservateur et chirurgical des fractures de l'os naviculaires chez le cheval. Une tentative est faite pour identifier les points critiques qui peuvent influencer favorablement le pronostic de cette maladie orthopédique. Tous les chevaux traités pour une fracture de l'os naviculaire à la Clinique équine de la Faculté Vetsuisse de l'Université de Zurich entre 2005 et 2017 ont été inclus dans cette étude. La gravité de la boiterie lors de l'examen initial, l'évaluation radiographique, la conformation du sabot, le traitement (conservateur ou chirurgical), les complications et le résultat ont été déterminés à partir des dossiers médicaux. Le traitement conservateur et chirurgical consistait en un repos au box, un programme d'exercice contrôlé et un ferrage orthopédique thérapeutique. Au cours du traitement chirurgical, une réduction de la fracture a également été effectuée à l'aide d'une vis corticale. La chirurgie assistée par ordinateur a été utilisée sur cinq chevaux et la tomographie assistée par ordinateur sur trois chevaux. Les examens de suivi comprenaient des examens cliniques et radiographiques. Les résultats ont été divisés en trois catégories: 1 = très bon; 2 = bon; 3 = mauvais. Douze chevaux répondaient aux critères d'inclusion ; quatre chevaux ont été traités de manière conservatrice et huit ont été traités chirurgicalement. Après un traitement conservateur, deux chevaux (50 %) ont eu un très bon résultat et deux (50 %) un bon résultat. Après le traitement chirurgical, quatre chevaux (50 %) ont eu un très bon résultat et quatre (50 %) un mauvais résultat. Dans l'ensemble, 67 % des chevaux ont eu un très bon ou un bon résultat, bien que les signes radiographiques de guérison osseuse n'aient été présents dans aucun de ces cas. Diverses complications ont été identifiées, telles que la fracture d'une vis, la fragmentation du petit fragment de l'os naviculaire, le développement d'une arthrose dans l'articulation interphalangienne distale et une podotrochlose progressive. Cette étude montre que le pronostic des fractures de l'os naviculaire est généralement réservé et que les modifications dégénératives de l'appareil naviculaire aggravent le pronostic. Dans la présente étude, le traitement chirurgical n'a pas amélioré le pronostic des fractures du naviculaire malgré l'utilisation intra-chirurgicale de l'imagerie tridimensionnelle. Cependant, les progrès techniques pourraient réduire le taux de complications dans le futur.

Influence of Gender and Self-Perceived Competence on Psychological Well-Being in Adolescent and Young Adult Cancer Survivors.

Elucidating factors associated with mental health and well-being among adolescent and young adult cancer survivors (AYAs) is increasingly important as this population continues to grow. Adolescence and young adulthood are critical times for developing self-perceived competencies (SPCs), which may be shaped by the cancer experience and may have different consequences based on the person's gender. We assessed whether gender moderated the association between perceived competencies and mental health in 61 AYAs (51% males; 11-20 years old; diagnosed between 0.33 and 17.33 years old). Gender moderated the association of SPC in close friendship, job, and scholastic domains with depression, anxiety, and optimism.

Molecular basis for the production of cyclic peptides by plant asparaginyl endopeptidases.

Asparaginyl endopeptidases (AEPs) are proteases that have crucial roles in plant defense and seed storage protein maturation. Select plant AEPs, however, do not function as proteases but as transpeptidases (ligases) catalyzing the intra-molecular ligation of peptide termini, which leads to peptide cyclization. These ligase-type AEPs have potential biotechnological applications ranging from in vitro peptide engineering to plant molecular farming, but the structural features enabling these enzymes to catalyze peptide ligation/cyclization rather than proteolysis are currently unknown. Here, we compare the sequences, structures, and functions of diverse plant AEPs by combining molecular modeling, sequence space analysis, and functional testing in planta. We find that changes within the substrate-binding pocket and an adjacent loop, here named the "marker of ligase activity", together play a key role for AEP ligase efficiency. Identification of these structural determinants may facilitate the discovery of more ligase-type AEPs and the engineering of AEPs with tailored catalytic properties.

Untangling the relationship between diet and visceral fat mass through blood metabolomics and gut microbiome profiling.

BACKGROUND/OBJECTIVES: Higher visceral fat mass (VFM) is associated with an increased risk for developing cardio-metabolic diseases. The mechanisms by which an unhealthy diet pattern may influence visceral fat (VF) development has yet to be examined through cutting-edge multi-omic methods. Therefore, our objective was to examine the dietary influences on VFM and identify gut microbiome and metabolite profiles that link food intakes to VFM. SUBJECTS/METHODS: In 2218 twins with VFM, food intake and metabolomics data available we identified food intakes most strongly associated with VFM in 50% of the sample, then constructed and tested the 'VFM diet score' in the remainder of the sample. Using linear regression (adjusted for covariates, including body mass index and total fat mass), we investigated associations between the VFM diet score, the blood metabolomics profile and the fecal microbiome (n=889), and confirmed these associations with VFM. We replicated top findings in monozygotic (MZ) twins discordant (⩾1 s.d. apart) for VFM, matched for age, sex and the baseline genetic sequence. RESULTS: Four metabolites were associated with the VFM diet score and VFM: hippurate, alpha-hydroxyisovalerate, bilirubin (Z,Z) and butyrylcarnitine. We replicated associations between VFM and the diet score (beta (s.e.): 0.281 (0.091); P=0.002), butyrylcarnitine (0.199 (0.087); P=0.023) and hippurate (-0.297 (0.095); P=0.002) in VFM-discordant MZ twins. We identified a single species, Eubacterium dolichum to be associated with the VFM diet score (0.042 (0.011), P=8.47 × 10-5), VFM (0.057 (0.019), P=2.73 × 10-3) and hippurate (-0.075 (0.032), P=0.021). Moreover, higher blood hippurate was associated with elevated adipose tissue expression neuroglobin, with roles in cellular oxygen homeostasis (0.016 (0.004), P=9.82x10-6). CONCLUSIONS: We linked a dietary VFM score and VFM to E. dolichum and four metabolites in the blood. In particular, the relationship between hippurate, a metabolite derived from microbial metabolism of dietary polyphenols, and reduced VFM, the microbiome and increased adipose tissue expression of neuroglobin provides potential mechanistic insight into the influence of diet on VFM.

An assessment of intra- and interobserver agreement of reporting orthopaedic findings on presale radiographs of Thoroughbred yearlings.

REASONS FOR PERFORMING STUDY: Radiography is commonly used in clinical practice but agreement of reporting of radiographically detected orthopaedic findings in horses has rarely been studied. OBJECTIVES: To assess agreement within and between observers for reporting of orthopaedic findings on presale radiographs of Thoroughbred yearlings. STUDY DESIGN: Retrospective analysis of archived radiographs. METHODS: Four veterinary radiology specialists each twice examined 167 sets of radiographs for orthopaedic findings in the fore feet, fore and hind fetlocks, carpi, tarsi and stifles. There were 27 findings analysed for agreement. Kappa statistic (κ), percentage of positive agreement (Ppos) and percentage of negative agreement are reported. RESULTS: An excellent percentage of negative agreement was observed for all findings, with the exception of regular vascular channels of the proximal sesamoid bones. Ppos and κ results were variable. The presence of extra carpal bones, osseous cyst-like lesions of the ulnar carpal bone, sagittal ridge defects of the third metacarpus, fracture of the fore and hind proximal sesamoid bones, regular vascular channels in the hind proximal sesamoids, osteochondrosis lesions of the distal intermediate ridge and/or medial malleoli of the tibia, and osseous cyst-like lesions in the medial femoral condyle was consistently observed with an intra- and interagreement κ≥0.5 and Ppos≥50%. Lucency within the proximal sesamoids consistently had an observed intra- and interagreement κ<0.4 and Ppos<40%. CONCLUSIONS: Observation of orthopaedic findings on yearling repository radiographs showed generally excellent agreement on the absence of findings, but variable agreement on the presence of findings. Agreement was good for larger and easy to categorise radiographic findings. More accurate definitions and training need to be developed to improve agreement within and between observers for orthopaedic findings with poor or fair to good agreement.

Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats.

Estrogen deficiency results in accelerated bone turnover with a net increase in bone resorption. Subcutaneous administration of leptin attenuates bone loss in ovariectomized (ovx) rats by reducing bone resorption. However, in addition to its direct beneficial effects, leptin has been reported to have indirect (central nervous system-mediated) antiosteogenic effects on bone, which may limit the efficacy of elevated serum leptin to prevent estrogen deficiency-associated bone loss. The present study evaluated the long-term effects of increased hypothalamic leptin transgene expression, using recombinant adeno-associated virus-leptin (rAAV-Lep) gene therapy, on bone mass, architecture, and cellular endpoints in sexually mature ovx Sprague-Dawley rats. Ovx rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained for 10 weeks. Additional controls consisted of ovary-intact rats and ovx rats pair-fed to rAAV-Lep rats. Lumbar vertebrae were analyzed by micro-computed tomography and tibiae by histomorphometry. Cancellous bone volume was lower and osteoclast perimeter, osteoblast perimeter, and bone marrow adipocyte density were greater in ovx rats compared to ovary-intact controls. In contrast, differences among ovx groups were not detected for any endpoint evaluated. In conclusion, whereas estrogen deficiency resulted in marked cancellous osteopenia, increased bone turnover and marrow adiposity, increasing hypothalamic leptin transgene expression in ovx rats had neither detrimental nor beneficial effects on bone mass, architecture, or cellular endpoints. These findings demonstrate that the antiresorptive effects of subcutaneous leptin administration in ovx rats are mediated through leptin targets in the periphery.

Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns.

Cancer is a complex disease that involves the accumulation of both genetic and epigenetic alterations of numerous genes. Data in the Genetic Alterations in Cancer database for gene mutations and allelic loss [loss of heterozygosity (LOH)] in human tumors (e.g. lung, oral, esophagus, stomach and colon/rectum) were reviewed. Results for the genes and pathways implicated in tumor development at these sites are presented. Mutation incidence, spectra and codon specificity are described for lung, larynx and oral tumors. LOH occurred more frequently than gene mutations in tumors from all sites examined. The cell cycle gene, TP53 (all sites), and cell signaling gene, APC (colorectal and gastric cancers), were the only genes with similar incidences of LOH and mutation. Alterations of one or more cell cycle and cell signaling genes were reported for tumors from each site. Site-specific activation was apparent in the cell signaling mitogen-activated protein kinase oncogenes (KRAS in lung, HRAS in oral cancers and BRAF in esophageal and colorectal cancers). Analysis of genetic changes in lung tumors showed that the incidence of mutations in the TP53 and KRAS genes and the incidence of LOH in the FHIT gene were significantly greater in smokers versus non-smokers (P < 0.01). In lung and oral cancers, the TP53 GC --> TA transversion frequency increased with tobacco smoke exposure (P < 0.05). Furthermore, the TP53 mutational hot spots for lung and laryngeal cancers from smokers included codons 157, 245 and 273, whereas for oral tumors included codons 280 and 281.

Prevalence of pharyngeal and laryngeal abnormalities in Thoroughbreds racing in Australia, and their association with performance.

REASONS FOR PERFORMING STUDY: Little information is available regarding the prevalence of abnormalities of the upper airway and their association with performance in the general population of Thoroughbred racehorses. OBJECTIVES: To describe the prevalence of selected abnormalities of the upper airway and their association with performance in Thoroughbred racehorses in Australia. HYPOTHESIS: That abnormalities of the upper airway of Thoroughbred racehorses are associated with poor race performance. METHODS: Rhinolaryngoscopy was performed after racing and presence and characteristics of abnormalities of the larynx and pharynx were recorded in a prospective cross-sectional study of Thoroughbred horses racing in Victoria, Australia. RESULTS: Rhinolaryngoscopy was performed once on each of 744 horses over 35 months. Fifty abnormalities of the upper airway were detected in 47 horses (6.3%, 95% confidence interval [CI] 4.7-83%). Epiglottic entrapment was detected in 7 horses (0.9%, 95% CI 0.4-1.9%) and was significantly (P = 0.015) associated with superior performance. Grade 2 asymmetry (4 grade scale) of the left arytenoid cartilage was detected in 9 horses (1.2%, 95% CI 0.5-2.4%) and was also associated with superior performance (P<0.001). Ulceration or erosion of the mucosa of the axial surface of one or both arytenoids was detected in 18 horses (2.4%, 95% CI 13-3.8%) and was not associated with alterations in exercise performance (P = 0.31). CONCLUSIONS: Epiglottic entrapment, Grade 2 laryngeal asymmetry and mucosal erosions detected in Thoroughbred racehorses were not associated with impaired performance; therefore, surgical correction and concern over laryngeal function in horses with Grade 2 asymmetry may not be necessary in individuals performing to expectation.

Urban Jamaican children's exposure to community violence / Niños jamaicanos en zonas urbanas expuestos a la violencia de las comunidades

Exposure to violence in childhood is associated with aggression in adulthood. The high level of community violence in Jamaica is likely to expose Jamaican children to violence. There has been no detailed study of the exposure of Jamaican children to violence in their daily lives. Some 1674 urban 11-12-year-old children, previously part of a national birth cohort study, completed a questionnaire detailing their exposure to violence as witnesses, victims and aggressors. Their parents completed a socio-economic questionnaire. Jamaican children had high levels of exposure to physical violence. A quarter of the children had witnessed severe acts of physical violence such as robbery, shooting and gang wars, a fifth had been victims of serious threats or robbery and one in every twelve had been stabbed. Children reported being least exposed to sexual violence and to being shot at. Robbery was an almost universal experience affecting children from all schools and socio-economic groups. The single commonest experience as a victim of violence was the loss of a family member or close friend to murder, affecting 36.8 of children. Children's experiences of witnessing violence occurred chiefly in their communities but their personal experiences of violence occurred at school. Boys and children attending primary school had greater exposure to violence as witnesses and victims. Socio-economic status discriminated exposure to physical violence as witnesses but not as victims. Intervention strategies to reduce children's exposure to violence should include community education on the impact of exposure to violence on children, particularly the loss of a significant person, and the development of a range of school-based violence prevention programmes

La exposición a la violencia en la niñez se halla asociada con la agresión en la edad adulta. El alto nivel de violencia comunitaria en Jamaica, tiende a exponer a los niños jamaicanos a la violencia. Hasta el momento no ha habido un estudio detallado de la exposición de los niños jamaicanos a la violencia en sus vidas diarias. Unos 1 674 niños urbanos de 11 a 12 años de edad, quienes previamente formaban parte de un estudio de cohorte de nacimientos a escala nacional, respondieron a una encuesta dando detalles de su exposición a la violencia como testigos, víctimas y agresores. Sus padres respondieron una encuesta socioeconómica. Los niños jamaicanos presentaban altos niveles de exposición a la violencia física. Una cuarta parte de los niños había sido testigo de serios actos de violencia física, tales como robo con fuerza, tiroteos y guerras entre pandillas rivales. Una quinta parte de ellos había sido víctima de serias amenazas o de robo, y uno de cada doce había sido apuñalado. Los niños informaron haber estado menos expuestos a la violencia sexual y a los disparos. El robo fue casi una experiencia universal que afectó a los niños de todas las escuelas y grupos socio-económicos. La experiencia más común en cuanto a ser víctimas de la violencia estuvo dada por la pérdida de algún miembro de la familia o algún amigo cercano por asesinado, lo cual afectó al 36.8% de los niños. Las experiencias de los niños en relación con haber sido testigos de hechos violentos, tuvieron lugar principalmente en sus comunidades, pero sus experiencias personales de violencia ocurrieron en la escuela. Los niños que asistían a la escuela primaria estuvieron más expuestos a la violencia como testigos y como víctimas. El estatus socio-económico resultó un criterio discriminante en cuanto a la exposición a la violencia física en forma de testigo, pero no como la víctima. Las estrategias de intervención para reducir este problema deben incluir la educación de la comunidad respecto al impacto de la exposición de los niños a la violencia - particularmente con respecto a la pérdida de alguna persona importante para ellos - así como el desarrollo de una serie de los programas de prevención de la violencia

A review of the genetic and related effects of 1,3-butadiene in rodents and humans.

In this paper, the metabolism and genetic toxicity of 1,3-butadiene (BD) and its oxidative metabolites in humans and rodents is reviewed with attention to newer data that have been published since the latest evaluation of BD by the International Agency for Research on Cancer (IARC). The oxidative metabolism of BD in mice, rats and humans is compared with emphasis on the major pathways leading to the reactive intermediates 1,2-epoxy-3-butene (EB), 1,2:3, 4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBdiol). Results from recent studies of DNA and hemoglobin adducts indicate that EBdiol may play a more significant role in the toxicity of BD than previously thought. All three metabolites are capable of reacting with macromolecules, such as DNA and hemoglobin, and have been shown to induce a variety of genotoxic effects in mice and rats as well as in human cells in vitro. DEB is clearly the most potent of these genotoxins followed by EB, which in turn is more potent than EBdiol. Studies of mutations in lacI and lacZ mice and of the Hprt mutational spectrum in rodents and humans show that mutations at G:C base pairs are critical events in the mutagenicity of BD. In-depth analyses of the mutational spectra induced by BD and/or its oxidative metabolites should help to clarify which metabolite(s) are associated with specific mutations in each animal species and which mutational events contribute to BD-induced carcinogenicity. While the quantitative relationship between exposure to BD, its genotoxicity, and the induction of cancer in occupationally exposed humans remains to be fully established, there is sufficient data currently available to demonstrate that 1,3-butadiene is a probable human carcinogen.

Refinement of regions with allelic loss on chromosome 18p11.2 and 18q12.2 in esophageal squamous cell carcinoma.

Esophageal cancer ranks among the 10 most common cancers worldwide and is almost invariably fatal. The detailed genetic repertoire involved in esophageal carcinogenesis has not been defined. We have shown previously that the esophageal squamous cell carcinoma genome exhibits a frequent loss of heterozygosity (LOH) in the pericentromeric region of chromosome 18. To construct a fine deletion map, we screened 76 new samples composed of microdissected esophageal squamous cell carcinoma and matched morphologically normal epithelial cells using closely spaced markers. Maximal LOH frequency (54%) was displayed by D18S542 on 18p11.2. The pattern of LOH in selected patients indicated that the short region of overlap extends 3 cM on either side of D18S542. On the long arm of chromosome 18, the highest frequency of allelic loss (42%) was detected by D18S978 on 18q12.2-q21.1. This analysis revealed a short region of overlap of approximately 0.8 cM. These findings further implicate unreported tumor suppressor genes encoded by 18p11.2 and 18q12.2 in esophageal squamous cell carcinogenesis and they indicate a refinement of their map location.

Neck dissection and ipsilateral radiotherapy in the management of cervical metastatic carcinoma from an unknown primary.

BACKGROUND: In a small proportion of patients presenting with metastases to cervical lymph nodes the primary cancer remains occult despite thorough evaluation. The present report examines patterns of failure and outcome following an initial treatment strategy directed principally at the clinically involved side of the neck. METHODS: From a prospectively compiled computerized database 38 patients were identified with metastatic squamous cell carcinoma from an occult primary site. These patients were evaluated with respect to initial treatment, subsequent detection of a primary tumour, neck recurrence and survival characteristics. RESULTS: Thirty-seven of 38 patients were treated with curative intent and all had neck dissection. Adjuvant radiotherapy was given to 34 of the 37 (90%; 32 postoperatively and two pre-operatively). Radiotherapy was directed at the ipsilateral neck alone in 24 patients while 10 received comprehensive treatment to both sides of the neck and potential occult primary sites. The rate of control of disease in the ipsilateral neck was 91% while the failure rate in the contralateral neck was 16% (six patients). A primary cancer was ultimately identified in five patients (13%). Disease-specific survival was 63% at 4 years. Clinical N3 stage, extracapsular tumour extension and involved surgical margins predicted for poorer survival on univariate analysis. Analysis using multiple risk factors found that only involved surgical margins predicted for treatment failure. CONCLUSIONS: Despite generally advanced disease at presentation, patients presenting with cervical metastasis from an unknown primary carcinoma have a reasonable survival expectation and aggressive treatment is warranted, but approximately half will develop recurrent disease. Careful follow-up is required if effective salvage treatment is to be instituted.

A survey of EPA/OPP and open literature on selected pesticide chemicals. II. Mutagenicity and carcinogenicity of selected chloroacetanilides and related compounds.

With this effort, we continue our examination of data on selected pesticide chemicals and their related analogues that have been presented to the U.S. Environmental Protection Agency's (USEPA's) Office of Pesticide Programs (OPP). This report focuses on a group of selected chloroacetanilides and a few related compounds. As part of the registration process for pesticidal chemicals, interested parties (registrants) must submit toxicity information to support the registration including both mutagenicity and carcinogenicity data. Although this information is available to the public via Freedom of Information (FOI) requests to the OPP, publication in the scientific literature allows greater dissemination and examination of the data. For this Special Issue, graphic profiles have been prepared of the mutagenicity and carcinogenicity data available in the submissions to OPP. Also, a discussion is presented about how toxicity data are used to help establish tolerances (limits of pesticide residues in foods). The mutagenicity results submitted by registrants are supplemented by data on these chemicals from the open literature to provide a full perspective of their genetic toxicology. The group of chloroacetanilides reviewed here display a consistent pattern of mutagenic activity, probably mediated via metabolites. This mutagenic activity is a mechanistically plausible factor in the development of tumors seen in experimental animals exposed to this class of chemicals.

Genetic toxicology data in the evaluation of potential human environmental carcinogens.

In 1969, the International Agency for Research on Cancer (IARC) initiated the Monographs Programme to evaluate the carcinogenic risk of chemicals to humans. Results from short-term mutagenicity tests were first included in the IARC Monographs in the mid-1970s based on the observation that most carcinogens are also mutagens, although not all mutagens are carcinogens. Experimental evidence at that time showed a strong correlation between mutagenicity and carcinogenicity and indicated that short-term mutagenicity tests are useful for predicting carcinogenicity. Although the strength of these correlations has diminished over the past 20 years with the identification of putative nongenotoxic carcinogens, such tests provide vital information for identifying potential human carcinogens and understanding mechanisms of carcinogenesis. The short-term test results for agents compiled in the EPA/IARC Genetic Activity Profile (GAP) database over nearly 15 years are summarized and reviewed here with regard to their IARC carcinogenicity classifications. The evidence of mutagenicity or nonmutagenicity based on a 'defining set' of test results from three genetic endpoints (gene mutation, chromosomal aberrations, and aneuploidy) is examined. Recommendations are made for assessing chemicals based on the strength of evidence from short-term tests, and the implications of this approach in identifying mutational mechanisms of carcinogenesis are discussed. The role of short-term test data in influencing the overall classification of specific compounds in recent Monograph volumes is discussed, particularly with reference to studies in human populations. Ethylene oxide is cited as an example.

Short-term tests for defining mutagenic carcinogens.

The results of short-term tests for mutagenicity were first included in the IARC Monographs in the mid-1970s on the basis of the observation that most carcinogens are also mutagens, although not all mutagens are carcinogens. The experimental evidence at that time showed a strong correlation between mutagenicity and carcinogenicity and indicated that the short-term tests were useful for predicting carcinogenicity. Although the correlations have become weaker over the past 20 years, and with them the predictive value of short-term tests, such tests still provide vital information for identifying and understanding mechanisms involved in carcinogenicity. The results of short-term tests compiled in the US Environmental Protection Agency-IARC Genetic Activity Profile database over the past 12 years are summarized and reviewed here in relation to the classification of agents for carcinogenicity within the system used at IARC. The role of the information from short-term tests in making overall classifications of specific compounds in recent Monographs is discussed. The usefulness of data on three genetic end-points, gene mutation, chromosomal aberrations and aneuploidy, and the criteria for mutagenicity and lack of mutagenicity based on a 'defining set' of test results are examined. Recommendations are made for assessing chemicals on the basis of the strength of the evidence from short-term tests, and the implications of this approach for identifying putative mutational mechanisms of carcinogenicity are discussed.

Activity profiles of carcinogenicity data: application in hazard identification and risk assessment.

Animal cancer data play a primary role in human risk assessment due to the limited epidemiological data. The current database of test results from the NCI/NTP rodent bioassays provide valuable information concerning the carcinogenic potential of hundreds of environmental agents. An approach is presented to reduce and graphically display these data as activity profiles to allow visualization and assessment of tumor response trends across multiple parameters, e.g. species, sex, target site, and route of exposure. Spreadsheet graphics are used to construct the profiles organized on the multiple parameters of carcinogenicity in a format that enables comparative analysis among chemicals. Several example applications are described to illustrate the value of activity profiles in hazard identification and risk assessment. The NCI/NTP data used in developing this concept are from the Carcinogen Potency Database (CPDB) complied by Gold et al. (Environ. Health Perspect. 103 (Suppl. 8) (1995) 3-122). Computer links to the underlying details in the CPDB are maintained such that specific histopathologies at individual tumor sites, duration of the study, dose-response data, and notes related to diet, survival, treatments, and the authors evaluation are available to aid in the assessment process. The profiles display carcinogen potency based on the tumorigenic dose rate 50 (TD50), i.e. the chronic dose rate that would induce tumors in half of the test animals at the end of their standard lifespan adjusting for spontaneous tumors. The TD50 values provide an index for establishing a relative potency ranking of the chemicals for any specific parameter, such as species or target site. An example ranking of hepatocarcinogens is presented to illustrate relative potencies for chemical analogs. The rank order indicates that the degree and type of halogenation of alkanes has a direct bearing on the carcinogenic potency of these compounds.

Genetic activity profiles of anticancer drugs.

The results from short-term tests for genetic and related effects, abstracted from the open literature for 36 anticancer drugs, are examined in this review. Data for 27 of these agents are available in the EPA/IARC Genetic Activity Profile (GAP) database. Data summaries, including data listings and activity profiles, are presented for nine anticancer drugs added to the GAP database for this analysis. Genetic toxicity data from the recent literature are included for the additional agents to provide a broader representation of the categories of drugs being evaluated. These categories, based on the chemical mode of action, are covalent and noncovalent DNA-binding drugs, topoisomerase II inhibitors, antimetabolites, mitotic spindle inhibitors, and drugs which affect endocrine function. The qualitative data for all 36 drugs are summarized in this report and findings are presented from pair-wise matching of genetic activity profiles, based on test results in common, for some chemical analogs. The significance of germ cell test results for some of these drugs and their implication in assessing risk of heritable genetic disease are discussed.

Activity profiles of antimutagens: in vitro and in vivo data.

In this review, retinol, chlorophyllin, and N-acetylcysteine are examined and compared with regard to their antimutagenic activity against some promutagens and a group of direct-acting alkylating agents. The promutagens included aflatoxin B1, certain polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene), and certain heterocyclic amines (e.g., food pyrolysates). Results of antimutagenicity testing selected from data surveyed in the published literature are displayed graphically as activity profiles of antimutagens showing both the doses tested and the extent of inhibition or enhancement of mutagenic activity. All three antimutagens are discussed in terms of their putative mechanisms of action in vitro and in vivo with emphasis on the xenobiotic metabolizing enzyme systems.

Interpretation of short-term test data: implications for assessment of chemopreventive activity.

The same short-term tests that have been used extensively to identify mutagens and potential carcinogens are increasingly being used to identify antimutagens and potential anticarcinogens. It is not yet known whether the inhibition of carcinogen-induced mutation is a good indicator of anticarcinogenicity, as the available data on the inhibition of both carcinogenicity and mutagenicity In vivo are still quite incomplete. Furthermore, in vitro tests will detect only those compounds that show an effect that is demonstrable in vitro, such as direct inhibition of the metabolism of the carcinogen or inactivation of the carcinogen by direct reaction. Thus it is essential to confirm putative antimutagenic activity observed in vitro through the use of animal models. Indeed, the interpretation of antimutagenicity data from short-term tests must be subjected to all of the considerations that apply in the interpretation of mutagenicity test results. Moreover, the experimental variable of the antimutagens used must be considered in addition to the variables of the mutagens and short-term tests used. To analyse published results on antimutagens in short-term tests, we have developed the concept of activity profile listings and plots for antimutagens - an approach already used successfully for mutagenicity data. The activity profiles permit rapid visualization of considerable data and experimental parameters, including the inhibition as well as enhancement of mutagenic activity. Here we focus on the use of this methodology to interpret antimutagenicity data for retinol and chlorophyllin against several classes of mutagens in short-term tests.