Bhola N. Gupta

Toxicological assessment of hexachlorobiphenyl isomers and 2,3,7,8 tetrachlorodibenzofuran in chicks. I. Relationship of chemical parameters.

Abstract Five hexachlorobiphenyl (HCB) isomers and 2,3,7,8-tetrachlorodibenzofuran (TCDF) were fed to chicks for 21 days. Liver weights increased, with the smallest increase produced by 2,3,6,2′,3′,6′-HCB and the largest by 2,4,6,2′,4′,6′-HCB. Weight gain was decreased by 2,3,4,2′,3′,4′-, 2,3,6,2′,3′,6′-, and 2,4,5,2′,4′,5′-HCB, while 1μg/kg of TCDF did not affect body weight or liver weight. Pathological changes in the liver were greatest in the 2,4,6,2′,4′,6′-HCB group, moderate in the 2,3,4,2′,3′,4′- and 2,3,6,2′,3′,6′-HCB groups, and mildest in the 3,4,5,3′,4′,5′-, 2,4,5,2′,4′,5′-HCB, and 5μg/kg TCDF groups, with no significant effect for the 1μg/kg TCDF group. Thymic involution and edema were observed with 3,4,5,3′,4′,5′ HCB and TCDF. 3,4,5,3′,4′,5′-HCB and 5μg/kg of TCDF were lethal. HCB retention indices from gas chromatography correlated well with adipose-tissue concentration, with the exception of the 2,4,6,2′,4′,6′-isomer, which had the smallest retention index but relatively high tissue accumulation. Extraction p -values correlated poorly, but the 2,3,6,2′,3′,6′-HCB gave the smallest p -value, whereas the 2,4,6,2′,4′,6′-HCB p -value was next to the highest. The HCB retention indices generally correlated with their overall biological response and were highest in isomers with 3,4-substitution.

The comparative effects of 1,2-dibromo-3-chloropropane (DBCP) and its metabolites, 3-chloro-1,2-propaneoxide (epichlorohydrin), 3-chloro-1,2-propanediol (alphachlorohydrin), and oxalic acid, on the urogenital system of male rats

Reported similarities in the acute toxic effects of 1,2-dibromo-3-chloropropane (DBCP), 3-chloro-1,2-propaneoxide (epichlorohydrin, ECH), 3-chloro-1,2-propanediol (alphachlorohydrin, ACH), and oxalic acid (OA) have been suggested as presumptive evidence that the metabolism of DBCP to OA, via ECH and ACH, is the cause of the resulting injuries to the kidney and, perhaps, to the epididymis and testis. To test this hypothesis, the comparative toxicities of these four chemicals were studied in male rats after single subcutaneous (sc) injections of maximally tolerated (nonlethal) doses. Kidney, testicular, and liver functions were monitored, and the occurrences of morphological changes in these and several other organs were evaluated 24 hr, 3, 8, 25, and 75 days post-treatment. DBCP caused renal dysfunction (alterations in urine composition and reduced glomerular filtration rate) and marked necrosis of the proximal tubular epithelium in the outer medulla of the kidney. ACH and OA also elicited renal dysfunction, but ACH produced only a mild swelling of the proximal tubular epithelium in the renal cortex and OA produced a focal necrosis anatomically associated with crystal deposition. ECH caused a swelling of the proximal tubular epithelium in the renal cortex, but not frank kidney dysfunction. DBCP also caused a reversible vacuolization of the tubular epithelium in the caput epididymis, progressive testicular atrophy, and a reduction of cauda epididymal sperm concentration. ACH and ECH produced similar effects, as well as epididymal sperm granulomas, spermatocoeles, and an increase in the number of morphologically abnormal spermatozoa. OA failed to produce discernible epididymal or testicular lesions at any time during the study. The development of similar lesions in the epididymis and testis following DBCP, ECH, or ACH treatments is consistent with the theory of metabolism of these chemicals to a common causative gonadotoxic agent. Oxalic acid (OA), however, would not appear to be the common gonadal toxicant. Differences in the effects, both morphological and functional, of DBCP, ECH, ACH, and OA on the kidney, moreover, indicate that DBCP nephropathy is not mediated through metabolism to OA and suggest, as well, that it differs causally from that induced by ECH or ACH. Therefore, the metabolism of DBCP to ECH or ACH, and of ECH or ACH to OA, is insufficient to explain totally the toxic effects of these agents on the urogenital system in male rats.

Polybrominated biphenyl toxicosis in the rat and mouse.

Abstract Rats and mice were given 22 oral doses of Firemaster FF-1 or pure 2,2′,4,4′,5,5′-hexabromobiphenyl (HBB) over a 30-day period and held for 90 additional days to determine the pathobiological manifestations of toxicity. Female mice and rats given Firemaster FF-1 became porphyric after 45 and 120 days, respectively. The liver was enlarged due to swelling of hepatocytes, fatty infiltration and proliferation of endoplasmic reticulum. There was a marked increase in serum protein which was primarily due to β-globulin fraction in the rat. γ-Glutamyl transpeptidase was elevated in female rats in both groups given Firemaster FF-1 and HBB. A significant dose related increase in serum glutamic pyruvic transaminase was found in male rats at Day 60 only. There was a decrease in the packed cell volume accompanied by a proportional decrease in hemoglobin and red blood cell values in male rats given 30 mg of FF-1 at 30 and 45 days but returned to normal at 60 and 90 days. Hepatocellular alterations in rats and mice given FF-1 at 30.0 mg/kg (22 total doses) persisted when examined at 120 days. FF-1 was more toxic than pure HBB as determined by measurement of porphyrins and pathologic findings. Rats or mice treated with HBB tended to recover when examined during postexposure periods.

The chronic toxicity of technical and analytical pentachlorophenol in cattle. I. Clinicopathology.

Abstract The objectives of this study in female yearling Holstein cattle were to define the toxic effects of (1) long-term exposure to analytical pentachlorophenol (aPCP), and (2) to determine the influence of the contaminants in technical pentachlorophenol (tPCP) in the toxic syndrome. Four groups of three heifers each were exposed for 160 days to aPCP, tPCP, or a mixture thereof in the feed. A fifth group of three animals served as unexposed controls. All treated cattle received the same amount of PCP; 20 mg/kg/day for 42 days which was reduced to 15 mg/kg/day for the remainder of the study because of a suspected decrease in body weight gain in all PCP-exposed animals compared to controls. Fat and liver samples for chemical analyses were collected at the end of the study. Major findings in the tPCP-exposed heifers included a dose-related decrease in body weight, decreased feed efficiency, progressive anemia, a dose-related increase in liver and lung weights, and a decrease in thymus weight. The most conspicuous lesion was market villous hyperplasia of the urinary bladder mucosa in two of three animals exposed to the highest level of tPCP. There were minimal hepatic lesions although hyperplasia of the mucosal lining of the gali bladder and bile duct was noted in some animals exposed to tPCP. Animals exposed to aPCP were, in general, comparable to the controls. Hepatic mixed function oxidases were increased by aPCP, but more so by tPCP. A decrease in thyroxine concentration was found in all PCP-treated cattle. Immunologic studies suggested a progressive tPCP dose-related enhancement in the lymphoproliferative response, an in vitro correlate for cell-mediated immunity. Observed effects on humoral immune parameters were equivocal. The results of this study indicate that toxicity of PCP in cattle is primarily attributable to its contamination with toxic impurities.

Toxicity of selected symmetrical hexachlorobiphenyl isomers in the mouse

Abstract Five-week-old male mice were given: 0.3, 1, 3, 10, 30, 100, or 300 ppm of 3,4,5,3′,4′,5′-hexachlorobiphenyl (HCB); 10, 30, 100 or 300 ppm of 2,4,5,2′,4′,5′-HCB, 2,3,6,2′,3′,6′-HCB, or 2,4,6,2′,4′,6′-HCB in feed daily for 28 days. HCB residue levels were determined in adipose tissue and liver. There were marked differences in dose response and severity of pathologic effects among the isomers. 3,4,5,3′,4′,5′-HCB was the most toxic isomer causing mortality, and body and organ weight effects at all dose levels, and was the only isomer which produced excess porphyrin accumulation. It was also the most concentrated isomer in fat and liver. 3,4,5,3′,4′,5′-HCB caused subcutaneous edema, enlargement of liver with accentuated hepatic lobular markings, fatty infiltration, hepatocellular swelling and necrosis, and atrophy of the thymus. 2,4,6,2′,4′,6′-HCB and 2,4,5,2′,4′,5′-HCB caused the same lesions but to a lesser degree. Slight cardiomyopathy was observed with 2,4,6,2′,4′,6′-HCB. The decreasing order of overall toxicity was 3,4,5-HCB >> 2,4,6-HCB > 2,4,5-HCB > 2,3,6-HCB.

Reproductive toxicity of dimethyl methyl phosphonate (DMMP) in the male Fischer 344 rat.

Dimethyl methyl phosphonate (DMMP) has been considered for use by the U.S. Armed Forces as a nerve gas simulant in a variety of experimental situations to simulate the physical properties of nerve gases, but not the neurotoxic properties. Dimethyl methyl phosphonate is also used as a flame retardant for urethane foams and polyester resins. This study was conducted to determine the reproductive toxicity of DMMP after subchronic dosing. DMMP was administered to male Fischer 344 rats by gavage 5 days/week for 90 days at dosages of 0, 250, 500, 1000, and 2000 mg/kg, and all animals survived this dosing schedule. At Day 84, the rats were mated to untreated female Fischer 344 rats. There was a dose-related decrease in sperm count, sperm motility, and the male fertility index. The male fertility index was 70, 75, 60, 40, and 0% in the 0, 250, 500, 1000, and 2000 mg/kg dose groups. DMMP acted as a dominant lethal mutagen as demonstrated by an increase in the number of resorptions with increasing doses of the drug. The percentage of resorptions in the control group was 6.1% and increased to 14.9, 37.8, and 79.1% in the 250, 500, and 1000 mg/kg groups, respectively. The testes of the male rats were examined histologically to determine the relationship between reproductive function and pathologic abnormalities. DMMP altered reproductive function at all dose levels, while histologic abnormalities of the testis were seen only in the high-dose group. Changes in the testes of the high-dose animals were characterized by lack of spermatogenesis or by degeneration, vacuolization, and necrosis of cells in the spermatogenic tubules. Histopathologic abnormalities of the kidney were seen in some animals from each of the dosed groups and microscopic changes of the prostate were seen in some of the high-dose animals.

Effects of a polybrominated biphenyl mixture in the rat and mouse: II. Lifetime study

This study was undertaken to characterize the long-term toxic and carcinogenic potential of a polybrominated biphenyl (PBB) mixture in rats and mice of both sexes. Fischer 344 rats and B6C3F1 mice were given 125 po doses of PBB over a 6-month period at 0 (control), 0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg body weight/day (5 days/week) and observed for an additional 23 months for rats and 24 months for mice (lifetime observation). The treatments (0.3 mg/kg or higher dosages) shortened the survival time in male rats whereas no such effect was observed in treated females. There was also evidence of shortened survival time in mice treated with 10.0 mg/kg PBB. As observed by uv light, hepatic porphyrin markedly increased at the 6-month observation, then tended to decrease, primarily in mice, following cessation of exposure. Significantly higher incidences of atypical hepatocellular foci, neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas were observed in exposed rats. The incidence of hepatocellular carcinoma was also increased in both male (95%) and female (88%) mice (highest dose level) compared with control male (48%) and female (0%) mice. The incidence of hepatic neoplasms appeared to be dose dependent in both species. Liver tumors were observed primarily in those groups of animals to which PBB was given in doses sufficient to induce readily observable hepatic toxicity. Under the conditions of this experiment, polybrominated biphenyl mixture (Firemaster FF-1) was carcinogenic for Fischer 344 rats and B6C3F1 mice of both sexes. Lesions included neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas in rats and hepatocellular carcinomas in mice. Other manifestations of toxicity included porphyrogenic effects and hepatotoxicity. A significantly higher incidence of chronic progressive nephropathy was observed in male rats of the 1.0, 3.0, and 10.0 mg/kg dosage groups when compared with control males. Gastric ulcers and hyperplastic gastropathy of the glandular portion of the stomach were observed more frequently in male rats, primarily in the high dosage groups.

Inhalation Studies With a Glycol Complex of Aluminum-Chloride-Hydroxide

Inhalation studies were performed with a propylene glycol complex of aluminum-chloride-hydroxide (alchlor), a compound found in some aerosol antiperspirant preparations. Hamsters were given either three exposures to 150 mg alchlor/cu meter or 30 exposures to 50 mg/cu meter and killed at various times for histopathological examination. The lungs of animals given 20 or more exposures to 50 mg/cu meter showed a granulomatous lesion in the respiratory bronchioles that persisted throughout a six-week postexposure period. Alveolar thickening and increased numbers of macrophages were seen in lungs of hamsters soon after three exposures to 150 mg/cu meter but with time these changes regressed. Lung weights in hamsters given three exposures to 35 mg/cu meter or higher were increased on the fourth day. Mixed function oxidase (MFO) activities of rabbit and hamster microsomes from both lung and liver were examined after three daily exposures. No changes were seen in the MFO activity of liver microsomes. Lung microsom...

The intrasanguineous host-mediated assay procedure distribution and retention of yeast in the mouse.

A study of the factors that could affect a method to detect mutations in cells recovered from different organs after intravenous injection in mice, was performed by using the D4 strain of Saccharomyces cerevisiae. The recovery of the yeast cells 5 min to 3 days after injection in the host animal was investigated. The circulation, distribution and localization of the cells were determined, and histopathologic analysis was performed in order to detect possible interactions between the mice and the microorganisms. We found that the yeast cells were trapped primarily in the capillaries of the organs; 3 days after injection no cells were found outside of the tissue-blood vessels. The spontaneous gene-conversion frequency of the yeast cells recovered at different times after injection was increased, but this increase was not time-dependent.

The effect of aerosol hair spray inhalation in the hamster

Hamsters were exposed to a commercially available aerosol hair spray actuated for a total of 8 minutes over a 4-hour-period, 5 days/week. They were examined after 1, 2, 3, 4, and 6-week exposures, and 2,4 and 8 weeks after a 6-week exposure. There was a significant increase in the lung weight of exposed hamsters at every time point except 8 weeks after the 6-week exposure. Microscopic changes in the lung were characterized by the presence of a few to a moderate number of macrophages and neutrophils in the alveolar lumina. The number of macrophages and neutrophils appeared directly related to the duration of exposure. Lung changes were minimal during the first 2-weeks of exposure, and 8 weeks after the 6-week exposure (recovery period). Pathologic changes in the lungs of hamsters were reversible after cessation of the hair spray inhalation exposure.