Acute and repeated inhalation exposures (for 28 days) to polymeric methylene diphenyl diisocyanate (PMDI) were performed in rats. Investigations were made at the end of exposures and after 3, 10 and 30 days of recovery following single acute exposures and after 30 days of recovery following 28 days of exposure. Acute exposures to 10, 30 or 100 mg m(-3) PMDI produced clinical signs in all animals that were consistent with exposure to irritant aerosols. An exposure concentration-related body weight loss and increase in lung weight were seen post-exposure, with complete recovery by day 8. The time course of changes in the lung over the initial days following exposure consisted of a pattern of initial toxicity, rapid and heavy influx of inflammatory cells and soluble markers of inflammation and cell damage, increased lung surfactant, a subsequent recovery and epithelial proliferative phase and, finally, a return to the normal status quo of the lung. During these stages there was evidence for perturbation of lung surfactant homeostasis, demonstrated by increased amounts of crystalline surfactant and increased number and size of lamellar bodies within type II alveolar cells. Repeated exposure over 28 days to the less toxic concentrations of 1, 4 or 10 mg m(-3) PMDI produced no clinical signs or body weight changes, but an increase in lung weight was seen in animals exposed to 10 mg m(-3), which resolved following the 30-day recovery period. Other effects seen were again consistent with exposure to irritant aerosols, but were less severe than those seen in the acute study. Analysis of bronchoalveolar lavage fluid revealed similar changes to those seen in the acute study. At both 10 and 4 mg m(-3) PMDI increased numbers of 'foamy' macrophages in lung lavage cell pellet correlated with the increased phospholipid content of the pellet. Changes in lung lavage parameters and electron microscopic evidence again suggested perturbations in surfactant homeostasis. Histologically, bronchiolitis and thickening of the central acinar regions was seen at 10 and 4 mg m(-3), reflecting changes in cell proliferation in the terminal bronchioles and centro-acinar regions. Almost all effects seen had recovered by day 30 post-exposure. Both acute and subacute studies demonstrate rapid recovery of effects in the lung following exposure to PMDI, with no progression of these effects even at concentrations higher than those shown to produce tumours in a chronic study. These findings add weight to the hypothesis that pulmonary tumours seen following chronic exposure to PMDI are most likely due to a combination of the chronic irritant effects of repeated exposure, coupled with the presence of insoluble polyureas formed by polymerization of PMDI (found in studies reported here and previous chronic studies), and therefore acute or short-term exposures to PMDI are likely to be of little concern for long-term pulmonary health.
Administration of the phytoestrogen coumestrol to ovariectomized rats leads to increases in both wet and dry uterine weights in the absence of an increase in uterine DNA content, as reported by Markaverich et al. [Effects of Coumestrol on Estrogen Receptor Function and Uterine Growth in Ovariectomized Rats. Environ Health Perspect 103:574-581 (1995)]. It was not possible to know if the observed atypical uterotrophic response of coumestrol was associated uniquely with the ovariectomized uterotrophic assay protocol. This question is answered in the present paper. Two experiments are described in which three daily oral gavage administrations of 60 mg/kg/day coumestrol to immature AP rats were followed by assessment of the reproductive tract on the fourth day. In both experiments coumestrol increased uterine fluid content and increased the weights of the uterus, cervix, and vagina. In addition, bromodeoxyuridine staining of uterine sections enabled confirmation of uterine hyperplasia for the coumestrol-treated animals. In the second experiment, total uterine DNA was determined; it doubled in the coumestrol-treated animals. Estradiol benzoate acted as the positive control agent for both of these experiments, and in each case it gave similar responses to those seen for coumestrol. We conclude that the uterotrophic activity of the phytoestrogen coumestrol in the immature intact rat is typical of the activity of the natural estrogen estradiol.
The involvement of the immediate-early (IE) genes c-fos, c-jun, and c-myc in regenerative liver hyperplasia is accepted, but their involvement in direct hyperplasia is uncertain. We have examined the hypothesis that the ability to induce IE genes may reflect the hepatocarcinogenic potential of a chemical. The ability of 1,4-dichlorobenzene (DCB) (300 mg/kg) (a noncarcinogemc rat liver mitogen), diethylhexyl phthalate (DEHP) (950 mg/kg), and chlorendic acid (120 mg/kg) (both nongenotoxic hepatocarcinogens) to induce c-fos, c-jun. and c-myc expression in rat liver was determined by Northern blot analysis and by in situ hybridization. Results were correlated to hepatic labeling index (LI) as determined by incorporation of BrdU in each of three lobes for each of three male F344 rats per group. Carbon tetrachioride (CCl4 (2 ml/kg) was used as a positive control. Increased LI was preceded by elevated expression of all three IE genes after CCl4., but also after DCB and DEHP, although induction by these was less marked. In all cases, there was considerable interanimal variation within groups, but little interlobe variation. Interestingly, there was a good correlation (r2 ≥ 0.85) between c-myc expression and LI, but not between LI and c-fos or c-jun. Despite the disparate carcinogenic potential of DEHP and DCB, both chemicals induced similar patterns of IE gene expression, suggesting that this cannot distinguish hepatocarcinogenic liver mitogens from noncarcinogenic liver mitogens. These data assist in the evaluation of IE gene expression both as a marker of direct versus regenerative hyperplasia and as an indicator of the hepatocarcinogenic potential of liver mitogens.
Makaverich et al. [Environ Health Perspect 103:574-581 (1995)] reported that the uterotrophic activity of the phytoestrogen coumestrol in the immature ovariectomized rat was atypical in that it was not associated with increased uterine hyperplasia and DNA content. We previously reported that coumestrol gave a typical estradiol-type uterotrophic response in the immature intact rat, yielding increases in uterine epithelial cell height, glandular formation, cell labeling, and DNA content. These papers did not answer the question of whether there is a basic difference between the ovariectomized and the intact rat uterotrophic assays. In this paper, we report that coumestrol gives a typical estradiol-type uterotrophic response in uterotrophic assays using immature intact, immature ovariectomized, and mature ovariectomized rats. We concluded that the uterotrophic activity of coumestrol is typical of the natural estrogen estradiol.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
