The value of mammography in women with focal breast complaints in addition to initial targeted ultrasound.

PURPOSE: To determine the added value of mammography in women with focal breast complaints and the utility of initial targeted ultrasound in this setting. METHODS: Women with symptomatic breast disease who were evaluated by breast imaging (mammography/digital breast tomosynthesis and ultrasound) between January 2016 and December 2016 in the Radboud University Medical Centre were included. We retrospectively collected the following data: date of birth, indication of imaging, visibility on mammography/ultrasound, whether biopsy was taken, additional findings, BI-RADS-classification, pathology and follow-up results. RESULTS: A total of 494 women were included (mean age 46.5, range 30 to 93). In 49 women (9.9%), symptomatic breast cancer was diagnosed, all visible during targeted ultrasound. The negative predictive value of targeted ultrasound was very high (99.8%). Additional findings on mammography were significantly more often malignant when the symptomatic lesion was also malignant (3.8% vs 70%, P < 0.05). In only one patient with symptoms caused by a benign finding, an incidental malignancy was detected on mammography outside the area of complaint (detection rate 2.2/1000 examinations). CONCLUSIONS: The contribution of mammography for cancer detection in women with focal breast complaints is very low when targeted ultrasound is performed. Additional findings are most common in patients with symptomatic breast cancer. Our results suggest that initial targeted ultrasound is a more appropriate initial tool for the evaluation of focal breast complaints. Mammography could be performed on indication only.

Acute, subacute, and subchronic inhalation toxicity studies of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats.

Short-term inhalation toxicity studies with respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol were performed in rats. The 4-hr LC50 was found to be 490 mg polymeric MDI/m3 (95.5% < 4.3 microns). Exposure of (4-week-old) rats to 0, 2.2, 4.9, or 13.6 mg polymeric MDI/m3 (95% < 5 microns) for 2 weeks resulted in mortality, severe growth retardation, and elevated lung weights at 13.6 mg/m3; at 4.9 mg/m3 slight growth retardation and slightly elevated lung weights were observed. A 13-week study with 6-week-old rats exposed to 0.35, 1.4, or 7.2 mg polymeric MDI/m3 (95% < 5 microns) revealed transient growth retardation and a slightly increased number of pulmonary alveolar macrophages occasionally accompanied by increased numbers of mononuclear cells and fibroblasts in alveolar septa only at 7.2 mg/m3. In a second 2-week study with 4- or 6-week-old rats exposed to 14.1 mg polymeric MDI/m3 (95% < 5 microns), 4-week-old rats died earlier and in greater numbers than 6-week-old rats. In a second 13-week study with 6-week-old rats, using exposure concentrations of 0, 4.1, 8.4, and 12.3 mg polymeric MDI/m3 (95% < 5 microns) and including a 4-week recovery period, 12.3 mg/m3 induced mortality, growth retardation, severe respiratory distress, increased lung weights, degeneration and hyperplasia of the nasal epithelium, accumulations of macrophages in the lungs and mediastinal lymph nodes, and focal inflammatory changes in the lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship: experimental comparison with standard LC50 testing.

A new design for acute inhalation toxicity testing was evaluated and compared with results obtained according to OECD guideline 403. The new design consists of a range-finding test, which is compatible with a conventional limit test, and can be followed by determination of a concentration-time-mortality relationship, enabling calculation of LC50 (50% mortality exposure concentration) values. By exposing pairs of rats for different periods of time to about four different test concentrations in a nose-only exposure unit, LT50 (50% mortality exposure time) values were obtained for five pairs of animals per concentration. The mortality data of the approximate 20 time-concentration combinations were used to calculate the probit relationship. Estimated mortality responses from these probit relations were compared with mortality figures obtained by exposing groups of five male rats and five female rats whole-body according to conventional toxicity testing. In general, there was good correspondence between the estimated and the observed mortality response. In our hands, the determination of the concentration-time-mortality relationship takes about the same number of animals (40-50) as the conventional LC50 procedure according to the OECD guideline 403. However, the new method has several additional advantages such as: (A) LC50 values are obtained over a 10-fold range in time, with the potential of decreasing the number of animals used when regulations require acute toxicity data for different periods of exposure. (B) The obtained relationship contains considerably more valuable information for risk assessment than the LC50 value.(ABSTRACT TRUNCATED AT 250 WORDS)

Subchronic (13-week) inhalation toxicity study of formaldehyde in male rats: 8-hour intermittent versus 8-hour continuous exposures.

Male Wistar rats were exposed for 13 weeks, 5 days a week to 0 (controls), 1 or 2 ppm formaldehyde continuously (8 h a day), or to 2 or 4 ppm formaldehyde interruptedly (eight 30-min exposure periods separated by 30-min non-exposure periods a day). Histopathological changes were only found in the nose of animals (interruptedly) exposed to 4 ppm formaldehyde and comprised an increased degree and incidence of disarrangement and squamous metaplasia accompanied by basal cell hyperplasia and occasionally by keratinization of the respiratory epithelium. Two ppm formaldehyde was the non-toxic effect level. Cell proliferation studies demonstrated a slightly higher cell turnover of the nasal respiratory epithelium exposed (interruptedly) to 4 ppm formaldehyde than in controls. It was concluded that under the conditions of repeated exposure to marginally cytotoxic concentrations during a period of 13 weeks the exposure concentration rather than the total 'dose' (= concentration x exposure time) determined the severity of the cytotoxic effects of formaldehyde on the nasal epithelium.

One-year inhalation toxicity study of formaldehyde in male rats with a damaged or undamaged nasal mucosa.

To study the effect of bilateral intranasal electrocoagulation damage on the susceptibility of rats to formaldehyde vapour, male Wistar rats with a damaged or undamaged nasal mucosa were exposed to atmospheres containing 0, 0.1, 1 or 10 ppm formaldehyde vapour during 6 h/day, 5 days/wk for 13 or 52 weeks. Electrocoagulation damage was induced in the anterior third part of the nose. The repair process followed the pattern of wound healing. Loss of turbinates and perforation of the septum were common irreversible findings. After 13 weeks basal cell hyperplasia and squamous metaplasia of the respiratory epithelium, and rhinitis were still visible. After 52 weeks effects attributable to electrocoagulation were slight basal cell hyperplasia and some rhinitis. Major formaldehyde-related adverse effects in the 10 ppm group not subjected to electrocoagulation included growth retardation, reduced urine production, and rhinitis accompanied by squamous metaplasia of the nasal respiratory epithelium. No adverse effects were seen at 0.1 or 1 ppm in rats with an intact nasal mucosa. The principal untoward effects of formaldehyde in electrocoagulation-treated rats seen after 13 and/or 52 weeks comprised increase in basal cell hyperplasia, squamous metaplasia of the nasal respiratory epithelium, damage to the olfactory epithelium at 10 ppm, and focal squamous metaplasia of nasal respiratory epithelium at 0.1 and 1 ppm.(ABSTRACT TRUNCATED AT 250 WORDS)

Nasal tumours in rats after short-term exposure to a cytotoxic concentration of formaldehyde.

Male Wistar rats were exposed to 0, 10 or 20 ppm formaldehyde vapour for 4, 8 or 13 weeks (6 h/day; 5 days/week), and were then observed for periods up to 126 weeks. Transient growth retardation occurred in both test groups. Death rate was not noticeably affected by formaldehyde. Despite recovery periods of at most 126 weeks, the nasal respiratory and olfactory epithelium of many rats of the 20 ppm group exhibited non-neoplastic histopathological changes. Similar but much less severe changes of the respiratory epithelium were seen in a small number of rats of the 10 ppm group; the olfactory epithelium was not visibly affected in rats of this group. Nasal tumours considered to be induced by formaldehyde were seen only in the 20 ppm group and mainly in rats that had been exposed for 13 weeks, the incidence being 4.5% (6/132). These tumours comprised 3 squamous cell carcinomas, 1 carcinoma in situ and 2 polypoid adenomas, all originating from respiratory epithelium. It was concluded that rat nasal respiratory epithelium severely damaged by formaldehyde vapour often does not regenerate and in some cases develops tumours.

Comparative sensitivity of histo-pathology and specific lung parameters in the detection of lung injury.

The sensitivity of different parameters for the determination of lung injury caused by nitrogen dioxide (NO2) was investigated. Male rats were exposed to concentrations of 0, 4, 10 or 25 ppm NO2 for 6 h/day, for 7, 14 or 21 days. Histopathology of the nasal cavity, larynx, trachea and lungs was compared with the changes in macrophage function and morphology. In addition several biochemical parameters were determined in lung lavages. Cytotoxic effects were investigated in primary cultures of rat and bovine alveolar macrophages, exposed to the same NO2-levels as in the in vivo exposure. Treatment-related histopathological changes were observed in the lungs. No differences between exposed and control animals were observed in the nasal cavity, larynx or trachea. The morphology of the lavaged alveolar macrophages was changed at all exposure concentrations on day 7, 14 and 21. An increase in the number of macrophages was found after exposure to 10 and 25 ppm NO2 on days 7, 14 and 21. The phagocytic capacity was diminished after 14 and 21 days exposure to 25 ppm and at both times exposure to 10 and 25 ppm increased the level of gamma-glutamyl transferase (GGT) in lavage fluids. Morphology of the macrophages and levels of GGT were found to be sensitive parameters of nitrogen dioxide toxicity. In vitro exposure of rat and bovine alveolar macrophages to comparable NO2-concentrations induced effects on phagocytosis similar to those observed for macrophages from exposed rats.

Effects of the exposure profile on the inhalation toxicity of carbon tetrachloride in male rats.

To examine the effect of the exposure pattern on the inhalation toxicity of carbon tetrachloride (CCl4) two 4-week inhalation studies with this compound were carried out in male rats at basic exposure concentrations of 63 and 80 ppm and basic exposure periods of 6 hours per day, 5 days per week. The two main variables studied were interruption of the daily 6-hour exposures by 1.5 hours (2 X 3-hour exposures with a non-exposure interval of 1.5 hour), and peak loads of 5-7 times the basic concentration with or without 1.5-hour interruption of the daily 6-hour exposures. Adverse effects of CCl4 included abnormal activities of several enzymes in serum and liver, decreased quantity of microsomal proteins in the liver, increased relative liver weight, and hydropic and fatty degeneration of hepatocytes. As compared with uninterrupted, interrupted exposures increased more the activities of glutamic oxalacetic and glutamic pyruvic transaminase in serum; peak exposures only slightly affected these enzyme activities. Uninterrupted exposures caused less severe fat accumulation in and hydropic degeneration of liver cells than interrupted exposures with or without peak loads. In addition, uninterrupted exposure to 63 ppm CCl4 with peak loads resulted in more severe hydropic liver degeneration than uninterrupted exposure to the same concentration without peak loads. It was concluded that interruption of the daily 6-hour exposures by 1.5 hour did not result in less severe but rather in slightly more severe hepatotoxicity, and peak loads superimposed on a fixed concentration only slightly aggravated the toxic effects of CCl4 on the liver.

Subacute (4-week) inhalation toxicity study of formaldehyde in male rats: 8-hour intermittent versus 8-hour continuous exposures.

Male Wistar rats were exposed for 4 weeks, 5 days a week, to 0 (controls), 5 or 10 ppm formaldehyde continuously (8 hours a day), or to 10 or 20 ppm formaldehyde interruptedly (eight 30 min exposure periods separated by 30 min non-exposure periods). Histopathology and cell proliferation studies indicated that under the conditions of exposure used, concentration rather than the total dose of formaldehyde determined the severity of the cytotoxic effects on the nasal epithelium.

Subchronic (13-week) inhalation toxicity study of formaldehyde in rats.

Male and female albino Wistar rats were exposed to concentrations of 0, 1, 10 or 20 ppm formaldehyde vapour during 6 h/day, 5 days/wk for 13 weeks. Treatment-related changes observed at 20 ppm included in both sexes: stared coats, uncoordinated locomotion and excitation during the first 30 minutes of each exposure, yellowing of the fur, growth retardation, a decreased level of plasma protein, severe and extensive karatinized stratified squamous metaplasia of the nasal respiratory epithelium, and focal degeneration and squamous metaplasia occasionally accompanied by keratinization of the olfactory epithelium; in males only; increased activities of plasma aspartate amino transferase (ASAT), alanine amino transferase (ALAT) and alkaline phosphatase (ALP) and squamous metaplasia of the laryngeal epithelium. Lesions seen at 10 ppm included yellowing of the fur and moderate squamous metaplasia of the nasal respiratory epithelium. The only change observed in three out of twenty 1 ppm exposed animals that might or might not be treatment-related was minimal focal epithelial hyperplasia and squamous metaplasia of the respiratory epithelium lining the nasal septum and maxillary turbinates. No histopathological evidence of hepatotoxicity was detected in any of the formaldehyde-treated groups. An in vivo/in vitro cell proliferation study showed an increase in [3H]-thymidine labeling index of the respiratory epithelium lining the nasoturbinates of rats exposed to 10 or 20 ppm formaldehyde on three successive days, whereas at the 1 ppm level the labeling index was similar to that of controls. It was concluded that under the conditions of the present 13-week inhalation study, formaldehyde at concentrations up to 10 ppm was not hepatotoxic to rats. At the 20 ppm formaldehyde level, a slight effect on the liver of male rats cannot be completely excluded. The study was inconclusive with respect to 1 ppm formaldehyde being a cytotoxic or a no-cytotoxic effect level for the nasal epithelium.

Effect of variable versus fixed exposure levels on the toxicity of acetaldehyde in rats.

The effects of exposure pattern on the toxicity of acetaldehyde vapour were investigated in 4-week inhalation studies. Male rats were exposed to 500 or 150 and 110 ppm for 6 h per day/5 days per week. One group of animals was exposed without interruption, the exposure of a second group was interrupted for 1.5 h between the first and second 3-h periods, the exposure of a third group was similarly interrupted and for six 5 min periods exposure was increased sixfold. Peak exposures of up to 3000 ppm superimposed on 500 ppm acetaldehyde caused irritation and excitation, and reduced body weight gain. No such effects occurred after interrupted or uninterrupted exposure to 500 ppm acetaldehyde without peak loads. A reduced phagocytotic index of lung macrophages was found in each of the groups exposed to 500 ppm acetaldehyde, the effect being most marked in the group with superimposed peaks of 3000 ppm. Degeneration of the nasal olfactory epithelium was observed in rats uninterruptedly exposed to 500 ppm acetaldehyde. Interruption of the exposure or interruption combined with peak exposure did not visibly influence this adverse effect on the nose. No compound-related effects were seen in rats interruptedly or uninterruptedly exposed to 150 ppm acetaldehyde or interruptedly exposed to 110 ppm with peak loads of 660 ppm. As a consequence 150 ppm acetaldehyde can be considered a 'no-toxic-effect level' in male rats exposed for 6 h/day, 5 days/week, during a 4-week period.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study.

Male and female Wistar rats were exposed to acetaldehyde vapour at nominal concentrations of 0, 750, 1500 or 3000/1000 ppm during 6 h/day, 5 days/week for up to 28 months. Major compound-related effects included increased mortality, growth retardation, nasal tumours, and non-neoplastic nasal changes in each of the test groups. The treatment-related nasal changes comprised: (1) degeneration, hyperplasia, metaplasia and adenocarcinomas of the olfactory epithelium at all exposure levels; (2) squamous metaplasia accompanied by slight to severe keratinisation and squamous cell carcinomas of the respiratory epithelium at the 2 highest exposure levels; and (3) slight to severe rhinitis and sinusitis in top-concentration rats. In the larynx hyperplasia and keratinized squamous metaplasia of the epithelium in the vocal cord region were seen in many rats of the mid- and top-concentration groups. One female rat of the 1500 ppm group had developed a laryngeal carcinoma in situ. It was concluded that under the conditions of the present study acetaldehyde is both cytotoxic and carcinogenic to the nasal mucosa of rats. The effects of acetaldehyde on the nose were compared to those of formaldehyde.

Significance of the dog as 'second animal species' in toxicity testing for establishing the lowest 'no-toxic-effect level'.

The toxicity data of 66 compounds adequately tested in the rat (as 'prime animal species') and in the dog (as 'second animal species') were studied to find out for how many of these compounds the study in dogs led to a lower 'no-toxic-effect level' (NTEL) than that found in the rat. From a quantitative point of view such information would contribute to a better insight into the desirability of toxicity studies in dogs, because acceptable daily intakes and permissible exposure levels in man are generally based on the lowest NTEL. For 44% of the compounds the NTEL in the dog was lower than that in the rat. When rat NTEL was divided by the arbitrary factor of 10, the adjusted NTEL was lower than the dog NTEL for 86% of the compounds tested in sub-chronic studies, and for 80% of the compounds tested in chronic studies. Whether it is justifiable to substitute such an adjusted NTEL for a study in dogs should be judged from compound to compound. It mainly depends on the size of the margin between the NTEL in the rat (as 'prime animal species') and the (expected) actual exposure level in humans, and also on the acceptability of loosing additional qualitative toxicological information. When this margin is large enough (e.g. 1000 or more), a study in dogs might be superfluous, despite the loss of qualitative data. Such an approach could lead to a reduction of the number of animals in toxicity testing and also to a reduction of the costs.

Inhalation toxicity of acetaldehyde in rats. II. Carcinogenicity study: interim results after 15 months.

Male and female Wistar rats were exposed to acetaldehyde vapour at concentrations of 0, 750, 1500 and 3000/1000 ppm during 6 h/day, 5 days/week for up to 27 months. The present paper deals with the results obtained during the first 15 months of the study, including interim kills after 13, 26 and 52 weeks. Major compound-related lesions occurred in the nose and larynx. The nasal lesions comprised: (1) degenerative changes of the olfactory epithelium at all dose levels, frequently accompanied by focal hyperplasia of basal cells and thickening of the submucosa with loss of Bowman's glands and nerve bundles in the dorsomedial region, (2) stratified squamous metaplasia of the respiratory epithelium lining the caudoventral part of the nasal septum and the inner aspect of the ventral endoturbinates often accompanied by severe keratinisation and occasionally by papillomatous hyperplasia, almost exclusively observed at the top-dose level, and (3) malignant tumours (squamous cell carcinomas and adenocarcinomas) at all dose levels. Hyperplasia and keratinised stratified squamous metaplasia of the laryngeal epithelium were seen at the 2 highest dose levels.

Acute inhalation toxicity study of ammonia in rats with variable exposure periods.

The acute inhalation toxicity of ammonia was examined in rats using various exposure concentrations and exposure periods. Groups of male and female rats were exposed to dynamic atmospheres containing different concentrations of ammonia for 10, 20, 40 or 60 min. The aim of the study was to establish the relationship between exposure concentration and exposure period on the one hand and mortality on the other. The correlation between exposure concentration (c), exposure period (t) and mortality rate, expressed in probits was found to be Probit = 2.30 1 n [c2.20 x t] = 47.8 The following LC50 values for ammonia were calculated: 10 min LC50 : 28,130 mg/m3 air (40,300 ppm) 20 min LC50 : 19,960 mg/m3 air (28,595 ppm) 40 min LC50 : 14,170 mg/m3 air (20,300 ppm) 60 min LC50 : 11,590 mg/m3 air (16,600 ppm).

Inhalation toxicity of acetaldehyde in rats. I. Acute and subacute studies.

The 4-h LC50 of acetaldehyde in rats was determined and found to be 13,300 ppm (24.0 g/m3 air). In a 4-week study groups of 10 male and 10 female rats were exposed to 0, 400, 1000, 2200 or 5000 ppm acetaldehyde for 6 h/day, 5 days/week. Treatment-related changes observed at the 5000 ppm level included dyspnoea and excitation during the first 30 min of each exposure, yellow-brown fur, severe growth retardation, more neutrophils and less lymphocytes in the blood, a reduced production of urine with a high density, increased lung weights, and severe degenerative, hyperplastic and metaplastic changes of the nasal, laryngeal and tracheal epithelium. Major lesions seen at 1000 and 2200 ppm comprised growth retardation and an increased production of urine in males, slight to moderate degeneration with or without hyper- and metaplasia of the nasal epithelium, and only at 2200 ppm, minimal epithelial changes in the larynx and trachea. The only change observed at the 400 ppm level that could be attributed to acetaldehyde was slight degeneration of the nasal olfactory epithelium seen as loss of microvilli and thinning and disarrangement of the layer of epithelial cells.

Repeated exposure to alpha-ethylacrolein vapour: subacute toxicity study in rats.

The subacute inhalation toxicity of alpha-ethylacrolein was examined in rats by repeated exposure of 4 groups of 10 males and 10 females each to alpha-ethylacrolein vapour at concentrations of 0, 2.0, 9.8 or 48.4 ppm, respectively, (6 h/day, 5 days/week) for a period of 13 weeks. The effects at 48.4 ppm were found to include growth retardation, focal alopecia, increased activity of glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase and alkaline phosphatase in the blood serum, decreased concentrations of total protein and albumin in the blood serum, increased relative weight of the heart, liver, adrenals and lungs, and histopathological changes in the respiratory tract mainly consisting of hyper- and metaplasia of respiratory epithelium and atrophy of the nasal olfactory epithelium. While at the 9.8 ppm level only a few relatively minor effects were noticed, viz. decreased concentrations of total protein and albumin in the blood serum and minimal hyper- and metaplasia of the tracheobronchial epithelium, no changes attributable to alpha-ethylacrolein were observed at the 2.0 ppm level.