Distinguishing between adverse and non-adverse effects. Session summary.
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Adaptation, Physiological↗
Biomedical subjects
G M Williams
Publications and source records attributed to G M Williams.
Protective effect of acetaminophen against colon cancer initiation effects of 3,2'-dimethyl-4-aminobiphenyl in rats.
A previous investigation demonstrated the anticarcinogenicity of acetaminophen (APAP) against colon carcinogenesis in rats induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB). DMAB was selected as a structurally related surrogate for heterocyclic amines, formed during cooking of protein, which are believed to be involved in human colon cancer. The objective of the present study was to ascertain whether the early initiating effects of this colon carcinogen are inhibited by APAP. Six groups of male F344 rats were treated over a 6-week period as follows: (1) vehicle (corn oil) for 6 weeks; (2) APAP in the diet at 1000 ppm daily for 6 weeks; (3) 50 mg/kg DMAB by gavage once a week for the last 4 weeks; (4) 5 mg/kg DMAB as for (3); (5) 1000 ppm APAP for 6 weeks and 50 mg/kg DMAB for the last 4 weeks; and (6) 1000 ppm APAP and 5 mg/kg DMAB as for (5). Colonic tissue was within normal limits in the control and APAP groups. In the APAP only group, apical enterocytic hypertrophy and hyperaemia over the entire surface epithelium was present. In the high-dose DMAB group, in the lower third of the crypts, foci of enlarged glands with hypertrophic cells exhibiting karyomegaly and anisokaryosis (FHE) of 3+ degree of severity were evident in 100% of the animals. Also, there were increases in periglandular fibrocytes, matrix and mononuclear cells (PF). In the low-dose DMAB group both FHE and PF changes with the same degree of severity were reduced. In rats given the low dose of DMAB plus APAP, FHE and PF with the same degree of severity (3+) was absent. Both DMAB exposures increased significantly the replicating fraction of colonic enterocytes in an exposure-related fashion and the replicating fractions were significantly reduced by APAP. In 32P-postlabelling of colon, liver and urinary bladder DNA, high-dose DMAB produced 2-6 distinct dose-related spots reflecting DNA adducts. These spots were reduced or were no longer detectable in all three tissues when APAP was given 2 weeks before and during DMAB exposure. Using immunohistochemical detection of DMAB adducts in the colon, a dose-related colour intensity was present for both doses of DMAB. APAP reduced this by 94-fold. Thus, APAP produced a marked protective effect in colonic enterocytes against several parameters of neoplastic development by the carcinogen.
Acetaminophen↗
Anticarcinogenicity of monocyclic phenolic compounds.
The synthetic monocyclic phenolics (MPs), acetaminophen (APAP), butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) are antimutagenic or anticarcinogenic against a diversity of chemical carcinogens affecting a variety of tissues in experimental animals. In studies in this laboratory of the anticarcinogenicity of MPs, the focus has been on delineating efficacy at low levels of MPs that do not elicit adaptive or toxic responses. To accomplish this, we are studying anticarcinogenicity against the neoplastic initiating activity of lower doses of carcinogens than have previously been studied and which are closer to human environmental exposures. In these studies, we have investigated anticarcinogenicity of BHT against liver cancer in rats induced by either 2-acetylaminofluorene (AAF) or aflatoxin B1 (AFB1) and anticarcinogenicity of APAP against colon cancer induced in rats by 3,2'-dimethyl-4-aminobiphenyl (DMAB). BHA and BHT at 100-125 ppm in the diet inhibited the initiation phase of AAF and AFB1 hepatocarcinogenesis and therefore may act intracellularly to block effects of the carcinogen. Likewise, with APAP in colon anticarcinogenicity, at 1000 ppm it reduced DNA binding and exerted a cytoprotective effect against DMAB. Thus, APAP also shows evidence of producing a blocking effect. We conclude that these MPs appear to be anticarcinogenic through a mechanism different from that of most other chemopreventive agents, possibly involving interception of the reactive chemical species of the carcinogen. Accordingly, they have promise as cancer prophylactics, including in combination with agents operating through other mechanisms.
Acetaminophen↗
Biogeochemical characterisation of a coal tar distillate plume.
The distillation of acidified coal tars for up to 50 years has given rise to a phenol plume approximately 500 m long, 50 m deep and containing up to 15 g l(-1) dissolved organic carbon (DOC) in the Triassic Sandstones aquifer. A conceptual biogeochemical model based on chemical and microbiological analysis of groundwater samples has been developed as a preliminary to more detailed studies of the controls on natural attenuation. While the development of redox zones and the production of methane and carbon dioxide provide evidence of natural attenuation, it appears that degradation is slow. The existence of sulphate in the plume indicates that this electron acceptor has not been depleted and that consequently methanogenesis is probably limited. Based on a simple estimate of sulphate input concentration, a half-life of about 15 years has been estimated for sulphate reduction. Geochemical modelling predicts that increased alkalinity within the plume has not led to carbonate precipitation, and thus within the limits of accuracy of the measurement, alkalinity may reflect the degree of biodegradation. This implies a loss of around 18% of the DOC over a 30-year period. Despite limited degradation, microbial studies show that there are diverse microbial communities in the aquifer with the potential for both anaerobic and aerobic biodegradation. Microbial activity was found to be greatest at the leading edge of the plume where DOC concentrations are 60 mg l(-1) or less, but activity could still be observed in more contaminated samples even though cells could not be cultured. The study suggests that degradation may be limited by the high phenol concentrations within the core of the plume, but that once diluted by dispersion, natural attenuation may proceed. More detailed studies to confirm these initial findings are identified and form the basis of associated papers.
Biodegradation, Environmental↗
Microcosm studies of microbial degradation in a coal tar distillate plume.
Investigation of a groundwater plume containing up to 24 g l(-1) phenolic compounds suggested that over a period of nearly 50 years, little degradation had occurred despite the presence of a microbial community and electron acceptors within the core of the plume. In order to study the effect of contaminant concentration on degradation behaviour, laboratory microcosm experiments were performed under aerobic and anaerobic conditions at four different concentrations obtained by diluting contaminated with uncontaminated groundwater. The microcosms contained groundwater with total phenols at ca. 200, 250, 660 and 5000 mg l(-1), and aquifer sediment that had been acclimatised within the plume for several months. The microcosms were operated for a period of 390-400 days along with sterile controls to ascertain whether degradation was microbially mediated or abiotic. Under aerobic conditions, degradation only occurred at concentrations up to 660 mg l(-1) total phenols. At phenol concentrations below 250 mg l(-1) a benzoquinone intermediate, thought to originate from the degradation of 2,5-dimethylphenol, was isolated and identified. This suggested an unusual degradative pathway for this compound; its aerobic degradation more commonly proceeding via catecholic intermediates. Under anaerobic conditions, degradation only occurred in the most dilute microcosm (total phenols 195 mg l(-1)) with a loss of p-cresol accompanied by a nonstoichiometric decrease in nitrate and sulphate. By inference, iron(III) from the sediment may also have been used as a terminal electron acceptor, in which case the amount of biologically available iron released was calculated as 1.07 mg Fe(III)/g of sediment. The study shows that natural attenuation is likely to be stimulated by dilution of the plume.
Aerobiosis↗
Mechanisms of chemical carcinogenesis and application to human cancer risk assessment.
The distinction between DNA-reactive and epigenetic carcinogens and their roles in oncogenesis is reviewed. An approach to cancer hazard assessment based upon mechanisms is described.
Carcinogens↗
HLA class II antigens positively and negatively associated with hepatosplenic schistosomiasis in a Chinese population.
To identify possible associations between host genetic factors and the onset of liver fibrosis following Schistosoma japonicum infection, the major histocompatibility class II alleles of 84 individuals living on an island (Jishan) endemic for schistosomiasis japonica in the Poyang Lake Region of Southern China were determined. Forty patients exhibiting advanced schistosomiasis, characterised by extensive liver fibrosis, and 44 age and sex-matched control subjects were assessed for the class II haplotypes HLA-DRB1 and HLA-DQB1. Two HLA-DRB1 alleles, HLA-DRB1*0901 (P=0.012) and *1302 (P=0.039), and two HLA-DQB1 alleles, HLA-DQB1*0303 (P=0.012) and *0609 (P=0.037), were found to be significantly associated with susceptibility to fibrosis. These associated DRB1 and DQB1 alleles are in very strong linkage disequilibrium, with DRB1*0901-DQB1*0303 and DRB1*1302-DQB1*0609 found as common haplotypes in this population. In contrast, the alleles HLA-DRB1*1501 (P=0.025) and HLA-DQB1*0601 (P=0.022) were found to be associated with resistance to hepatosplenic disease. Moreover, the alleles DQB1*0303 and DRB1*0901 did not increase susceptibility in the presence of DQB1*0601, indicating that DQB1*0601 is dominant over DQB1*0303 and DRB1*0901. The study has thus identified both positive and negative associations between HLA class II alleles and the risk of individuals developing moderate to severe liver fibrosis following schistosome infection.
Adult↗
Repopulation of liver endothelium by bone-marrow-derived cells.
The mechanism underlying the immunological advantage of hepatic allografts relative to other organs is incompletely understood. We used molecular probes for the repetitive units on the Y chromosome, to identify an increasing number of male liver venous endothelial cells in needle biopsy samples of men who received female donor liver grafts. We have also shown repopulation of liver endothelium by bone marrow derived cells in a male to female mouse bone marrow transplant model. We conclude that the liver has unique venous endothelium characterised by turnover and replacement by bone marrow derived cells.
Animals↗
Bias influencing maternal reports of child behaviour and emotional state.
BACKGROUND: Previous research has indicated that there may be only a modest degree of agreement between different reporters of a child's behaviour (mental health). This raises the possibility that some descriptions of the child's behaviour may reflect the personal characteristics of the respondent. We examine two potential sources of bias that may influence reports of a child's behaviour/mental health. The first is the mental or emotional impairment of the respondent; the second concerns gender-related expectations of children. METHODS: Mothers (and their children after the birth) were assessed at first clinic visit, 3-5 days after the birth, then 6 months, 5 years and 14 years after the birth. Some 70% of respondents giving birth remained in the study at the 14-year follow-up, leaving some 5277 cases for this analysis. At the 14-year follow-up, child behaviour (mental health) was assessed using the Child Behaviour Check List and the Youth Self Report. Maternal mental health was determined using the anxiety and depression subscales of the Delusions-Symptoms-States Inventory. RESULTS: Mothers who were not emotionally impaired reported fewer child behaviour problems than did the children themselves. As the mother's current emotional impairment increased, so her reports of the child's behaviour problems increased, when compared with the child's own reports. Further, mothers attributed more internalising symptoms to female respondents, and more externalising symptoms to male respondents, than did the child respondents themselves. CONCLUSIONS: Mothers differ systematically from their children when they are reporting their child's behaviour (mental health). The more emotionally impaired the mother, the greater the degree to which she imputes the child to have behaviour problems. Further, female children are attributed to have more internalising behaviours and male children externalising behaviours.
Adolescent↗
Bioassay of mannitol and caprolactam and assessment of response to diethylnitrosamine in heterozygous p53-deficient (+/-) and wild type (+/+) mice.
Alternative bioassays of mannitol (MAN) and caprolactam (CAP) were conducted in transgenic p53-deficient mice. Also, to assess the sensitivity of the transgenic mice to a model DNA-reactive carcinogen, the hepatic effects of diethylnitrosamine (DEN) were compared in the wild type background strain of mouse and in the transgenic derivative. Fifty-one male wild type strain C57BL/6 mice p53 (+/+), 8 weeks old, and 51 heterozygous p53 (+/-) C57BL/6 Tac-[KO] Trp53 N5 mice, 8 weeks old, were allocated to six experimental groups as follows: groups 1 (wild type +/+) and 2 (p53 +/-) served as room controls, groups 3 (+/+) and 4 (+/-) were exposed orally (gavage) to 50 mumol/kg body weight DEN weekly for a total of ten doses during the first 10 weeks of the study, group 5 (+/-) was exposed to 15,000 ppm CAP in the diet for up to 26 weeks, and group 6 (+/-) was exposed to 50,000 ppm MAN in the diet for up to 26 weeks. After 10 weeks, liver from control and DEN-exposed mice was used for O4-ethylthymidine (O4-EtT) DNA adduct analysis by the immunoslot blot method. The cell replicating fraction (RF) in the liver was determined by quantification of the percentage of immunohistochemically stained hepatocytes positive for proliferating cell nuclear antigen. No significant or consistent body or liver weight changes were present in any of the treatment groups. No consistent and pertinent changes in RF values were present in any of the treatment groups. None of the tested substances produced neoplasms of any type in p53 (+/-) mice. DEN induced comparable levels of O4-EtT adducts in the liver in both wild type and p53 +/- genotypes, but no morphologic changes were evident in the livers of either genotype. The lack of response to DEN, in spite of formation of DNA adducts, may reflect the resistance to hepatocarcinogenesis of the background C57BL/6 strain of the transgenic, and calls into question the general sensitivity of this transgenic for detection of carcinogenic effects.
Administration, Oral↗
Scientific analysis of the proposed uses of the T25 dose descriptor in chemical carcinogen regulation.
The uncertainties that surround the methods used for risk assessment of exposure to carcinogens have been highlighted by a recent document advocating an approach based on the T25 dose (the dose giving a 25% incidence of cancer in an appropriately designed animal experiment). This method relies on derivation of the T25 dose then assesses risk at the exposure dose using proportionality provided by a linear extrapolation (T25/linear). To promote discussion of the scientific issues underlying methods for the risk assessment of chemical carcinogens, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) hosted a one-day workshop in Brussels on 10 November 2000. Several invited presentations were made to participants, including scientists from regulatory authorities, industry and academia. In general, it was felt that there was sufficient basis for using the T25 dose as an index of carcinogenic potency and hence as part of the hazard assessment process. However, the use of the T25 in risk assessment has not been validated. The T25/linear and other extrapolation methods based on metrics such as LED 10 assume linearity which may be invalid. Any risk calculated using the T25/linear method would provide a precise risk figure similar to the output obtained from the Linearised Multistage (LMS) method formerly used by the Environmental Protection Agency (EPA) in the United States of America. Similarity of output does not provide validation but rather reflects their reliance on similar mathematical approaches. In addition to the T25 issue, evidence was provided that using two separate methods (linearised non-threshold model for genotoxic carcinogens; no-observable-effect level with a safety factor (NOEL/SF) method for all other toxicity including non-genotoxic carcinogens) is not justified. Since the ultimate purpose of risk assessment is to provide reliable information to risk managers and the public, there was strong support at the workshop for harmonisation of approaches to risk assessment for all genotoxic and nongenotoxic carcinogens. In summary, the T25 method has utility for ranking potency to focus efforts in risk reduction. However, uncertainties such as the false assumption of precision and non-linearity in the dose-response curve for tumour induction raise serious concerns that caution against the use of T25/linear method for predicting human cancer risk.
Animals↗
Vascular smooth muscle cells of recipient origin mediate intimal expansion after aortic allotransplantation in mice.
Intimal expansion by vascular smooth muscle cells (SMCs) is a characteristic feature of graft vascular disease. Whether graft intimal SMCs arise from donor or recipient tissue is not well established but has important pathogenetic implications. We examined for the presence of male cells in the expanded intima of sex-mismatched mouse aortic allografts (C57BL/6-to-BALB/c) at 30 or 60 days after transplant by in situ hybridization using a Y-chromosome probe. Study groups included male-to-female allografts, female-to-male allografts, and female-to-female allografts in recipients previously engrafted with male bone marrow. Although intimal expansion developed in all allografts, male-to-female allografts lacked Y-chromosome-positive intimal cells. In contrast, such cells were abundant in female-to-male allografts and most of these cells co-labeled for smooth muscle alpha-actin by immunostain. Female-to-female allografts in recipients with male bone marrow showed a limited number of intimal Y-chromosome-positive cells. However, none of these clearly co-labeled for smooth muscle alpha-actin and their numbers declined throughout time, consistent with graft-infiltrating inflammatory cells. We conclude that intimal expansion of mouse aortic allografts is mediated by SMCs that originated from the recipient. There was little evidence of their derivation from the bone marrow, suggesting instead the adjacent host aorta as the primary source of intimal SMCs.
Animals↗
Vascular endothelial-cell turnover: a new factor in the vascular microenvironment of the liver.
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Animals↗
The effect of breastfeeding on child development at 5 years: a cohort study.
OBJECTIVE: It is uncertain to what degree the relationship between breastfeeding and later cognitive development is a true biological effect, or is confounded by psychosocial factors. The study aim was to further investigate this relationship and the effect of duration of breast feeding on cognitive development. METHODS: A total of 3880 children were followed from birth. Breastfeeding duration was measured by questionnaire at 6 months of age and a Peabody Picture Vocabulary Test Revised (PPVT-R) was administered at 5 years. PPVT-R scores were adjusted for the effects of a large array of biological and psychosocial confounders. The relationship between breastfeeding and the mean PPVT-R scores were examined using analysis of variance and multiple linear regression. RESULTS: A strong positive relationship was demonstrated between breastfeeding and the PPVT-R scores with increasing scores with increased duration of breastfeeding. After adjusting for a wide range of biological and social factors, the adjusted mean for those breastfed for 6 months or more was 8.2 points higher for females and 5.8 points for males when compared to those never breastfed. CONCLUSION: These findings suggest a significant benefit to child development is conferred by breastfeeding and is related independently to longer periods of breastfeeding.
Adult↗
Aneurysmal expansion of the visceral patch after thoracoabdominal aortic replacement: an argument for limiting patch size?
INTRODUCTION: Thoracoabdominal aortic replacement requires visceral vessel revascularization and is usually performed with Crawford's inclusion technique or a large Carrel patch. This segment of retained native aorta may be prone to recurrent aneurysmal disease. We reviewed our experience with patients in whom aneurysmal expansion of the visceral patch was detected. METHODS: The records of 107 patients undergoing thoracoabdominal aortic replacement operations performed or followed up at the Johns Hopkins Hospital between 1992 and 2000 were reviewed. All patients had visceral patches created for type II, III, or IV aneurysms. Visceral patches were considered aneurysmal if the maximal diameter of the aortic prosthesis and patch was 4.0 cm or more. RESULTS: Patch aneurysmal expansion (mean, 5.4 cm) was detected in eight patients (7.5%). All three women had connective tissue disorders (mean age, 36 years), and all five men had atherosclerotic disease (mean age, 73 years). Five patients were symptom free with their aneurysms detected by surveillance computed tomography scans; two patients had back pain prompting computed tomography scans; and one patient presented with an emergency patch rupture. Aneurysmal patches were successfully revised in three patients. Two patients died in the operating room, and three patch aneurysms (< 5 cm) are still being observed. The mean time to the detection of aneurysmal expansion was 6.5 years after the original operation. Therapy consisted of replacement of a segment of the thoracoabdominal aortic graft and refashioning a smaller patch, including only the visceral artery orifices with separate attachment of the left and possibly right renal artery. CONCLUSIONS: Although Crawford's inclusion method of visceral patch construction is generally durable, patients undergoing thoracoabdominal aortic replacement require yearly surveillance for the detection of aneurysmal expansion of the visceral patch. We recommend limiting visceral patch size at the original operation by routinely excluding the orifice of the left renal artery. Patients at high risk for recurrent aneurysmal expansion, such as those with connective tissue disorders, will benefit from creating small visceral patches and possibly implanting both renal arteries separately during the original operation.
Adult↗
Assessment of chronic toxicity and carcinogenicity in an accelerated cancer bioassay in rats of moxifloxacin, a quinolone antibiotic.
The chronic toxicity and carcinogenicity of Moxifloxacin (MOX), a bacterial gyrase-inhibiting fluoroquinolone antibiotic, were studied in male and female Wistar rats in an accelerated cancer bioassay (ACB). The ACB is a mechanistic initiation/promotion chronic toxicity and carcinogenicity study designed to assess potential carcinogenic activity of a test substance in critical organs in which human carcinogens are active. The organs studied were liver, lungs, urinary bladder, mammary gland, bone marrow, thymus, spleen and stomach. MOX was given daily by intragastric instillation at 500 mg/kg bw/day for the first 13 weeks to produce potential initiation, followed by promoters (PROs) for 24 weeks, or for the last 24 weeks after 13 weeks of exposure to initiators (INs). The INs, administered during the first 13 weeks, were diethylnitrosamine for the liver, N-n-butyl-N-(4-hydroxybutyl)nitrosamine for the urinary bladder, ethylnitrosourea for the hematolymphoreticular system, N-nitrosodimethylamine for lungs, methylnitrosourea for the stomach and 7,12-dimethylbenz(a)-anthracene for the mammary gland. The PROs, administered during the last 24 weeks after MOX, were phenobarbital for the liver, nitrilotriacetic acid for the urinary bladder, azathioprine for the bone marrow, butylated hydroxytoluene for the lung, butylated hydroxyanisole for the forestomach, and diethylstilbestrol for the mammary gland. The INs produced preneoplastic and neoplastic lesions which were not enhanced by MOX, and MOX plus PROs elicited no neoplastic effects, documenting that MOX did not produce either initiation or promotion of neoplasia in any of the target sites, or in any of the other twenty tissues examined.
Administration, Oral↗
Descriptions of the Anopheles (Cellia) farauti complex of sibling species (Diptera: Culicidae) in Australia.
Descriptions of the three sibling species of the Anopheles farauti complex in Australia, A. farauti Laveran (formerly A. farauti No. 1), A. hinesorum Schmidt sp.n. (formerly A. farauti No. 2) and A. torresiensis Schmidt sp.n. (formerly A. farauti No. 3) are provided. These species form a part of the punctulatus group, which contains the major malaria vectors in the southwest Pacific. Morphological markers are described for adult females, fourth instar larvae and pupae which identify most specimens, and are presented in keys.
Animals↗
Determinants of hepato- and spleno-megaly in Hunan, China: cross-sectional survey data from areas endemic for schistosomiasis.
In order to understand the determinants of schistosome-related hepato- and spleno-megaly better, 14,002 subjects aged 3-60 years (59% male; mean age = 32 years) were randomly selected from 43 villages, all in Hunan province, China, where schistosomiasis caused by Schistosoma japonicum is endemic. The abdomen of each subject was examined along the mid-sternal (MSL) and mid-clavicular lines, for evidence of current hepato- and/or spleno-megaly, and a questionnaire was used to collect information on the medical history of each individual. Current infections with S. japonicum were detected by stool examination. Almost all (99.8%) of the subjects were ethnically Han by descent and most (77%) were engaged in farming. Although schistosomiasis appeared common (42% of the subjects claiming to have had the disease), only 45% of the subjects said they had received anti-schistosomiasis drugs. Overall, 1982 (14%) of the subjects had S. japonicum infections (as revealed by miracidium-hatching tests and/or Kato-Katz smears) when examined and 22% had palpable hepatomegaly (i.e. enlargement of at least 3 cm along the MSL), although only 2.5% had any form of detectable splenomegaly (i.e. a Hackett's grade of at least 1). Multiple logistic regression revealed that male subjects, fishermen, farmers, subjects aged > or = 25 years, subjects with a history of schistosomiasis, and subjects who had had bloody stools in the previous 2 weeks were all at relatively high risk of hepato- and/or spleno-megaly. In areas moderately endemic for Schistosoma japonicum, occupational exposure and disease history appear to be good predictors of current disease status among older residents. These results reconfirm those reported earlier in the same region.
Adolescent↗