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J Odum

Publications and source records attributed to J Odum.

At least 37 records · Page 2Linked to original sources
PubMed1998

Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic.

The inadvertent estrogenicity of certain synthetic chemicals, and their subsequent effects on the endocrine system of humans and wildlife, is of concern. In this paper we report findings from in vitro and in vivo (uterotrophic) studies which confirm that a range of alkyl hydroxy benzoate preservatives (parabens) are weakly estrogenic. In a receptor-binding assay, butylparaben was able to compete with 3H-estradiol for binding to the rat estrogen receptor with an affinity approximately 5 orders of magnitude lower than that of diethylstilboestrol, and between 1 and 2 orders of magnitude less than nonylphenol. In an in vitro yeast-based estrogen assay, the four most widely used parabens (namely methyl-, ethyl-, propyl-, and butylparaben) were all found to be weakly estrogenic with the most potent (butylparaben) being 10,000-fold less potent than 17 beta-estradiol. The estrogenic activity of parabens was inhibited by 4-hydroxy tamoxifen in vitro, illustrating the requirement of these chemicals to interact with the estrogen receptor in order to activate the yeast. When administered orally to immature rats, the parabens were inactive. However, subcutaneous administration of butylparaben produced a positive uterotrophic response in vivo, although it was approximately 100,000 times less potent than 17 beta-estradiol. Given their use in a wide range of commercially available topical preparations, it is suggested that the safety in use of these chemicals should be reassessed, with particular attention being paid to estimation of the actual levels of systemic exposure of humans exposed to these chemicals. The acquisition of such data is a prerequisite to the derivation of reliable estimates of the possible human risk of exposure to parabens.

Animals↗
PubMed1997

Lack of activity of estradiol in rodent bone marrow micronucleus assays.

Estradiol has been evaluated in five independent rodent bone marrow micronucleus assays and has been found to be inactive. The dose-range evaluated extended from three daily doses of 20 micrograms/kg to the rat, a regimen that elicited a potent uterotrophic response from the animals, to single doses of between 10-150 mg/kg to the mouse. The mouse assays simulated and extended the conditions of test employed by earlier investigators who had found estradiol, and three structurally-related synthetic estrogens, to be active in mouse micronucleus assays over the dose range 1-10 mg/kg. It is concluded that estradiol is not genotoxic to the bone marrow of rodents. The top dose-level used in the present micronucleus assays (150 mg/kg) represented approximately 150,000 times the minimum estrogenic dose of this chemical to rodents, and that was considered to be above the dose at which useful genetic toxicity data would be generated for this potent estrogen. The maximum tolerated dose (MTD) of estradiol to rodents remains to be established.

Animals↗
PubMed1997

The role of glutathione conjugation in the development of kidney tumours in rats exposed to trichloroethylene.

Trichloroethylene is metabolised to a very minor extent (< 0.01% of the dose) by conjugation with glutathione, a metabolic pathway which leads to the formation of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a bacterial mutagen and nephrotoxin activated by the renal enzyme beta-lyase. The role of this metabolic pathway in the development of the nephrotoxicity and subsequent tumour formation seen in rats exposed to trichloroethylene has been evaluated. The pathway has been assessed quantitatively in vivo in rats, and in rats, mice and humans in vitro. Trichloroethylene was found to be a very weak nephrotoxin. There was no evidence of morphological change in the kidneys and only small increases in biochemical markers of kidney damage in rats dosed with 2000 mg/kg trichloroethylene by gavage for 42 days. N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine was detected in the urine of rats dosed with 500 and 2000 mg/kg trichloroethylene for up to 10 days at levels equivalent to 0.001-0.008% of the dose. In vitro, the rate of conjugation of trichloroethylene with glutathione in the liver was higher in the mouse, 2.5 pmol/min per mg protein, than the rat, 1.6 pmol/min per mg protein, and in human liver the rates were extremely low, 0.02-0.37 pmol/min per mg protein. Comparisons of the metabolism of DCVC by renal beta-lyase and N-acetyl transferase showed that metabolism by N-acetyl transferase was two orders of magnitude greater than that by beta-lyase and that beta-lyase activity in rat kidney was 11-fold greater than that in human kidney. When the nephrotoxicity of DCVC was compared in rats and mice, the mouse was found to be 5-10 fold more sensitive than the rat. The no effect level in the rat was 10 mg/kg, a dose which is three orders of magnitude higher than the amount of DCVC formed from trichloroethylene in vivo. The lack of correlation between metabolism by this pathway and the rat specific tumours, together with questions concerning the potency of DCVC at the levels formed from trichloroethylene, suggests that DCVC may not be involved in the renal toxicity and subsequent tumour development seen in rats and that further evaluation of the mechanism(s) involved in the nephrotoxic response is warranted.

Animals↗
PubMed1997

The oral administration of polysorbate 80 to the immature female rat does not increase uterine weight.

Some xenobiotics display estrogenic activity in in vitro and/or in vivo systems. Previous studies by Gajdova et al. have shown that polysorbate 80 (also known as Tween 80) administered by intraperitoneal injection to neonatal female rats on days 4-7 after birth produced estrogenic effects including earlier vaginal opening, prolongation of the estrus cycle and persistent vaginal estrus. Some of these effects were evident many weeks after cessation of administration of polysorbate 80. The present study has evaluated the estrogenic properties of polysorbate 80 following oral administration, a route of exposure which is more relevant for the consideration of human health hazard. The effects of polysorbate 80 at oral gavage doses of up to 5 g/kg/day for 3 consecutive days on uterine growth of immature female rats, a commonly used in vivo mammalian assay for estrogenic activity, have been determined. Estradiol benzoate administered subcutaneously was used as a positive control and significantly increased uterine weight in this age and strain of female rat (21-23 days, Alpk:APfSD Wistar derived) by up to 4.5-fold above vehicle control values. Polysorbate 80 administered orally to rats had no effect on uterine weight. Thus, intrinsic estrogenic effects of polysorbate 80 reported following its intraperitoneal injection to neonatal 4-day-old female rats are not manifest when it is administered by oral gavage to immature 20- to 22-day-old female rats. This latter route of exposure is of more relevance to human exposure scenarios and these data are, therefore, important in assessing hazard/risk of polysorbate 80 to man.

Administration, Oral↗
PubMed1997

The rodent uterotrophic assay: critical protocol features, studies with nonyl phenols, and comparison with a yeast estrogenicity assay.

The major protocol features of the immature rat uterotrophic assay have been evaluated using a range of reference chemicals. The protocol variables considered include the selection of the test species and route of chemical administration, the age of the test animals, the maintenance diet used, and the specificity of the assay for estrogens. It is concluded that three daily oral administrations of test chemicals to 21- to 22-day-old rats, followed by determination of absolute uterus weights on the fourth day, provide a sensitive and toxicologically relevant in vivo estrogenicity assay. Rats are favored over mice for reasons of toxicological practice, but the choice of test species is probably not a critical protocol variable, as evidenced by the similar sensitivity of rats and mice to the uterotrophic activity of methoxychlor. Vaginal opening is shown to be a useful, but nondefinitive, adjunct to the uterotrophic assay. The ability of test chemicals to reduce or abolish the uterotrophic response of estradiol is suggested to provide a useful extension of the uterotrophic assay for the purpose of detecting antiestrogens. The results of a series of studies on the environmental estrogen nonyl phenol (NP), and its linear isomer n-nonyl phenol, confirm that branching of the aliphatic side chain is important for activity. 17beta-Desoxyestradiol is shown to be of similar activity to estradiol in the uterotrophic assay and is suggested to represent the "parent" estrogen of NP. Benzoylation of NP and 17-desoxyestradiol did not affect their uterotrophic activity, in contrast to the enhancing effect of benzoylation on estradiol. Selected chemicals shown to be active in the immature rat uterotrophic assay were also evaluated in an in vitro yeast human estrogen receptor transactivation assay. Most of the chemicals gave similar qualitative responses to those seen in the uterotrophic assay, and the detection of the estrogen methoxychlor by the yeast assay evidenced a degree of intrinsic metabolic competence. However, the assay had a reduced ability (compared to rodents) to hydrolyze the benzoate ester of estradiol, and the estrogenic benzoate derivative of NP was not active in the yeast assay. These last results indicate that current metabolic deficiencies of in vitro estrogenicity assays will limit the value of negative data for the immediate future. The results described illustrate the intrinsic complexity of evaluating chemicals for estrogenic activities and confirm the need for rigorous attention to experimental design and criteria for assessing estrogenic activity.

Animals↗
PubMed1997

Activity of raloxifene in immature and ovariectomized rat uterotrophic assays.

Raloxifene is generally regarded as a tissue-selective estrogen agonist, being capable of selectively counter-acting both the loss of bone density and the increase in serum cholesterol that occur in rats following ovariectomy, without the induction of a trophic effect on the rat uterus. An implication of this activity profile is that reliance cannot be placed on the rat uterotrophic assay for the detection and assessment of xenobiotic estrogens. Within that context the estrogenic activity of raloxifene has been reevaluated in immature and ovariectomized rat uterotrophic assays. Four separate experiments were conducted. In the first two a reproducible increase (1.7-fold) was observed in the uterus wet weights of immature rats administered three daily doses of raloxifene. The maximum uterotrophic response observed over the dose range 0.01-2 mg/kg was for 0.1 mg/kg raloxifene. Further experiments utilized three daily doses of 0.1 mg/kg raloxifene. In the third experiment the uterotrophic response elicited by raloxifene in immature rats was abolished by coadministration of the estrogen receptor blocking agent Faslodex (ICI 182,780). This confirmed the direct involvement of estrogen receptors in the uterotrophic response elicited by raloxifene. Two further indications of the estrogenicity of raloxifene were obtained in this experiment. First, dry uterus weights were also shown to be increased by raloxifene administration, thereby eliminating water retention as the sole cause of the observed increases in uterus weights. Second, the height of the surface epithelium was increased by 1.7-fold in the raloxifene-treated animals, an effect that was accompanied by increases in mitotic activity and glandular formation in the stromal endometrium. The endometrial epithelium of the treated rats also showed evidence of vacuolation and, occasionally, the presence of degenerating cells. Raloxifene did not, however, cause premature vaginal opening in immature rats, unlike estradiol. In the fourth experiment the uterotrophic activity of raloxifene was confirmed in ovariectomized rats, although the response was less (1.2-fold) than in immature rats. In contrast to the effects seen for the positive control agent estradiol, the uterotrophic responses observed for raloxifene in ovariectomized animals were not accompanied by cornification of the vaginal epithelium. Premature vaginal opening and vaginal cornification may be less sensitive markers of estrogenic activity than the uterotrophic response. These collected observations confirm that raloxifene exerts a genuine trophic effect on the rat uterus, and as a consequence, the uterotrophic assay can be relied upon to detect estrogens with only a marginal effect on the uterus.

Administration, Oral↗
PubMed1997

Assessing the risks of adverse endocrine-mediated effects: where to from here?

This article is based on the closing lecture (by J. Ashby) of the meeting held in Research Triangle Park on January 13-14, 1997-"Assessing the Risks of Adverse Endocrine-Mediated Effects." Several summaries of unpublished data from Zeneca CTL are presented to illustrate concerns over the present absence of agreed criteria for the assessment of endocrine toxicity data. Reference is also made to several points raised by others during the course of the meeting. It is concluded that the substantial challenges currently faced can be met only by strict adherence to the basic principles of good scientific practice, preeminent among which are the needs to confirm data and to respond to them in a cool and dispassionate manner. The wealth of expertise and enthusiasm being devoted to the task in hand, by both governmental and industrial interests, suggests that practical means by which to address the topic of the symposium will be forthcoming in the near future. However, moves to accelerate progress unduly-"to conduct science under the gun"-are already evident. Therefore, if external influences demand that short-cuts must be taken toward achievement of the goals set out in the Wingspread Statement (Colborn and Clement, 1992), such compromises should be clearly identified in order not to confuse the underlying progress that is already evident in this new branch of toxicology.

Animals↗
PubMed1997

Failure to confirm estrogenic activity for benzoic acid and clofibrate: implications for lists of endocrine-disrupting agents.

Earlier reports that benzoic acid is uterotrophic to the rat and mouse and that clofibrate is uterotrophic to the rat have not been confirmed. The studies reported here involved the use of a range of test protocols and dose levels, including the protocols/dose levels used by the original investigators. In addition, both chemicals were inactive in a human estrogen receptor (hER alpha) yeast estrogenicity assay. It is concluded that benzoic acid and clofibrate are not estrogenic in the assays used here. This conclusion has implications for the compilation of lists of endocrine-disrupting chemicals.

Animals↗
PubMed1997

Normal sexual development of rats exposed to butyl benzyl phthalate from conception to weaning.

Butyl benzyl phthalate (BBP) has been administered in drinking water (1000 micrograms/liter) to pregnant AP rats during gestation and lactation. The sexual development of the pups was then monitored until their termination at postnatal day 90 (pnd 90). Pups derived from animals exposed to diethylstilbestrol (DES) in drinking water (50 micrograms/liter) acted as a positive control group. Glass drinking bottles were employed following demonstration of absorption of BBP into plastic drinking bottles. Drinking water intake was monitored and the estimated average exposures of the dams was 182.6 micrograms/kg/day BBP and 8.6 micrograms/kg/ day DES. A total of 240 control pups, 204 BBP pups, and 64 DES pups were obtained for study. The sexual development of both genders of pups was monitored. The body weights of the DES pups were significantly reduced at birth, an effect that persisted until pnd 90. The body weights of the BBP pups were marginally increased at birth, but this difference resolved by pnd 90. DES affected the sexual development of the pups for all endopoints monitored-anogenital (AG) distance on pnd 2; average day of vaginal opening and prepuce separation; uterus, testes, and accessory sex gland weight; and cauda epididymis sperm count and homogenization resistant testicular sperm count at pnd 90. BBP failed to affect any of these parameters, with the exception of a 1.1-day advance in the average day of vaginal opening and a small increase in male AG distance on pnd 2. These last two effects are related to the increased weight of the BBP pups. The incidence of FSH-containing cells in the pituitary gland of animals from each group was unaffected at pnd 90. The effects observed for the DES pups are consistent with the results of earlier studies by Sharpe et al. (Environ. Health Perspect. 103, 1136-1143, 1995). However, the absence of an effect of BBP administration on pup testis weight and testicular sperm count at pnd 90 is in contrast to reductions in these measurements reported earlier by Sharpe et al. (Environ. Health Perspect. 103, 1136-1143, 1995) for similarly derived BBP pups.

Animals↗
PubMed1996

Covert dysphagia in the mentally handicapped: two case reports and a review of published literature.

Mentally handicapped patients with esophageal pathology may present a diagnostic challenge, as they may not complain of any specific symptoms or be able to give a clear history of either dysphagia or odynophagia. This paper reports 2 such patients who recently presented to the Royal Wolverhampton Hospitals. In the first case, upper gastrointestinal endoscopy under general anesthesia enabled both the identification and removal of a large esophageal foreign body. In the second case, repeated upper gastrointestinal endoscopy facilitated both the identification and nonsurgical management of a paraesophageal abscess.

Adult↗
PubMed1994

Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis.

In this review we have evaluated the relationship between peroxisome proliferation and hepatocarcinogenesis. To do so, we identified all chemicals known to produce peroxisome proliferation and selected those for which there are data (on peroxisome proliferation and hepatocarcinogenesis) which meet certain criteria chosen to facilitate comparison of these phenomena. The summarised data and definition of the methodology used has been collected in appendices. These comparisons enabled us to evaluate the relationship between these phenomena using reliable data. As there is a good correlation between them, we further explored the mechanisms of action that have been proposed (direct genotoxic activity, production of hydrogen peroxide, cell proliferation and receptor activation). The relationship between these events in other species, including humans, was also reviewed and finally an overview of the assessment of human hazard is presented in section IX. Some of the first chemicals which were shown to produce peroxisome proliferation were also hepatocarcinogens whose carcinogenicity could not be readily explained by genotoxic activity. This raised the suggestion that the unusual phenomenon of peroxisome proliferation was intricately linked to the carcinogenic activity of these agents. Three questions have exercised the attention of regulatory, industrial and academic toxicology since then; are chemicals which elicit peroxisome proliferation in the liver actually a coherent class of chemical carcinogens?; does the early biological phenomenon of peroxisome proliferation have real predictive value for and mechanistic association with rodent carcinogenesis?; and what hazard/risk do these agents pose to humans that may be exposed to them? Whether peroxisome proliferators are indeed a discrete class of rodent carcinogens would appear to be the single, most important question. If so, then the assumptions and procedures relevant to human hazard and risk assessment should be applied to the class and should be essentially generic; if not, each chemical should be considered independently. Our critical analysis of the published data for over 70 agents which have been shown to possess intrinsic ability to induce peroxisome proliferation in the livers of rodents has led to the conclusion that there exists a strong correlation between peroxisome proliferation as n early effect in the liver and hepatocarcinogenicity in chronic exposure studies. An almost perfect correlation was observed between the induction of peroxisomes in the rodent liver and the eventual appearance of tumours following chronic exposure The few exceptions to this were largely explainable (section II).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Recurrent mesangial IgA nephritis following renal transplantation.

Recurrence of mesangial IgA deposits in renal allografts of patients whose original disease was primary IgA nephropathy (IgAN) has been studied. Forty-six patients with primary IgAN received 51 renal allografts and have been followed for 3-183 months. A prospective study of 11 patients (11 biopsies) and a retrospective analysis of 17 patients (16 biopsies; 2 nephrectomy specimens) have been combined. Seventeen of the 29 allografts had recurrent mesangial IgA deposits and of these three patients have negative urinalysis, normal glomeruli by light microscopy, and stable renal function; six patients have microhaematuria, mesangial proliferative nephritis, but at present stable renal function; and five have mesangial proliferative glomerulonephritis with microhaematuria, heavy proteinuria, hypertension, and progressive allograft failure secondary to IgA disease alone, and one of these is now back on dialysis. Three other grafts with recurrent deposits are failing because of transplant glomerulopathy or rejection. The only predictor identified for recurrence of mesangial IgA deposits was length of time post-transplantation, with allograft tissue being studied at 45.9 +/- 10.0 versus 15.3 +/- 4.8 months (P = 0.008) post-transplantation in patients with and without recurrent deposits respectively. Cyclosporin A did not prevent recurrence. By virtue of a longer follow-up of patients post-transplantation than all other reported series, these results suggest that with increasing time post-transplantation recurrence of mesangial IgA disease will become increasingly important as a cause of progressive allograft dysfunction and failure unless effective treatment is found for the primary disease.

Complement C3↗
PubMed1994

Influence of differing classes of antihypertensive agents on mesangial kinetics following partial renal ablation in rats.

Mesangial kinetics were studied in six groups of rats. Rats were either sham operated or were subjected to 1 1/3 nephrectomy (4/6 Nx). Each group was either untreated or was treated with enalapril (EN) or the drug regimen of hydralazine, hydrochlorothiazide, and reserpine (HHR). Four weeks after surgery rats were injected with iodinated aggregated bovine serum albumin (I-aggBSA) and mesangial localization quantified 2, 4, or 8 h later. Mesangial kinetics in untreated 4/6 Nx rats were characterized by accumulation of I-aggBSA to 4 h after injection with rapid clearance over the 4-8-h period; i.e. mesangial trafficking was increased following 4/6 Nx. Mesangial trafficking in 4/6 Nx rats treated with EN was reduced by virtue of lesser uptake of I-aggBSA at 4 h and retarded clearance over 4-8 h when compared with untreated 4/6 Nx animals. Treatment of 4/6 Nx rats with HHR maintained the increased trafficking observed in untreated 4/6 Nx rats. At 30 weeks untreated 4/6 Nx rats had severe albuminuria and glomerulosclerosis. Both indices of renal damage were significantly less in 4/6 Nx rats treated with enalapril. Treatment with HHR did not prevent albuminuria and had only limited effectiveness in preventing glomerulosclerosis. The different effects of EN and HHR on mesangial trafficking and glomerulosclerosis provide further evidence for a relationship between mesangial trafficking following partial renal ablation and subsequent development of glomerulosclerosis.

Albuminuria↗
PubMed1993

Mesangial kinetics after partial nephrectomy in rats fed a normal or a low-protein diet.

Mesangial kinetics of aggregated BSA (aggBSA) were studied in rats subjected to 1 1/3 nephrectomy (4/6 Nx) fed either a normal (16%) or a low-protein (8%) diet. At 4 weeks postsurgery, ablated rats exhibited modest elevations in blood pressure but had neither significant proteinuria nor evidence of glomerular damage. Following injection of aggBSA into 4/6 Nx rats (16% diet) there was a marked increase in mesangial localization at 4 h compared with control animals, followed by rapid clearance over 4-8 h, in keeping with increased trafficking in this model. The increased trafficking was significantly reduced by dietary protein restriction with 4/6 Nx rats fed an 8% protein diet exhibiting mesangial kinetics not significantly different from control animals. Control animals exhibited identical kinetics irrespective of diet. In separate studies, the 8% protein diet significantly reduced proteinuria and glomerulosclerosis when compared with untreated animals when studied at 30 weeks postsurgery.

Animals↗