Ernest E. McConnell

The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs

Abstract Mice and guinea pigs were given a single oral dose of various chlorinated dibenzo-p-dioxins (CDD) to establish and compare the LD50 and clinical and pathologic manifestations of toxicity. It was apparent that the 2,3,7, and 8 positions must be chlorinated to achieve the greatest degree of toxicity. Additional chlorine atoms at an ortho position reduced toxicity but not nearly to the degree caused by deletion of a chlorine atom at one of the lateral positions. A decrease in body weight gain was the most sensitive clinical parameter and animals severely intoxicated showed a marked weight loss, especially guinea pigs. The median time to death at a LD50 was 17 to 20 days in guinea pigs and 22 to 25 days in mice. Doses 10 times greater did not markedly shorten this period. At the toxic dose the spectrum and severity of lesions and organ weight effects were similar for all homologs and isomers within the same animal species; however, there were interspecies differences. The thymus was greatly reduced in size in both animal species due to a reduction in the number of cortical lymphocytes. Significant macroscopic and histopathologic hepatic effects including porphyria were observed only in the mouse and were found at does levels well below the LD50. Hyperplasia of the transitional epithelium in the urinary tract was found in guinea pigs. There was a reduction of total serum protein in the mouse due to lower levels of α-globulin. Other lesions were generally interpreted to be a secondary response to debilitation.

Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rhesus monkeys (Macaca mulatta) following a single oral dose

Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Rhesus Monkeys (Macaca mulatta) following a Single Oral Dose. McConnell, E. E., Moore, J. A., and Dalgard, D. W. (1978). Toxicol. Appl. Pharmacol. 43, 175–187. The oral LD50 of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female rhesus monkeys was

National Toxicology Program Nomenclature for Hepatoproliferative Lesions of Rats

Diagnostic criteria for hepatoproliferative lesions of Fischer 344 rats are presented to permit more complete categorization of the spectrum of lesions observed in two-year chemical carcinogenicity studies. A nomenclature recently adopted by the National Toxicology Program differs from previous classification schemes in that hepatocellular hyperplasia and hepatocellular adenoma are to be used for lesions which were previously combined under the diagnosis of neoplastic nodule. The term hyperplasia is reserved for proliferative lesions that are perceived to be secondary, nonneoplastic responses to degenerative changes in the liver. Foci of cellular alteration, hepatocellular adenoma, and hepatocellular carcinoma are believed to represent a spectrum of changes that comprise the natural history of neoplasia. This change in nomenclature was made subsequent to a peer review of representative hepatoproliferative lesions from two-year carcinogenicity studies. The revised nomenclature is consistent with traditional pathologic diagnoses for proliferative lesions in other epithelial tissues and should facilitate the interpretation of conventional toxicity and carcinogenicity studies in rats. Morphologic features of other selected rat liver lesions are also presented.

COMPARATIVE TOXICITY OF THREE HALOGENATED DIBENZOFURANS IN GUINEA PIGS, MICE, AND RHESUS MONKEYS

The chlorinated dibenzofurans have been reported to be present in a variety of polychlorinated biphenyls (PCBs)’” and in pentachlorophenol: They were also detected in the PCB-contaminated rice oil that was responsible for the human intoxication referred to as ‘Y~sho’.’.~ Polychlorinated dibenzofurans were also detected in tissues of patients with ‘Yusho’.’ A polychlorinated dibenzofuran fraction extracted from PCB’s was found to be highly toxic in chickens.* A mixture of polychlorinated dibenzofurans also caused toxic effects when fed to rats? 2,3,7,8Tetrachlorodibenzofuran (TCDF) has been evaluated for toxicity in chicks,” guinea pigs,” and mice.” The results reported in this manuscript extend earlier studies with TCDF in guinea pigs and mice, report the toxic effects in rhesus monkeys, and describe the toxic effects of 2,3,4,7,8-pentachlorodibenzofuran (PCDF) and 2,3,7&tetrabromodibenzofuran (TBDF) in guinea pigs.

Toxicopathology characteristics of the halogenated aromatics.

Halogenated dibenzo-p-dioxins, dibenzofurans, biphenyls and napthalenes are structurally related compounds (FIGURE 1) of considerable environmental interest because of their ubiquitous occurrence, persistance in the environment, possible magnification in the food chain and relatively high toxicity of the more potent isomers. Numerous reports can be found that describe the lesions in various species of animals caused by these chemicals using various dosing regimens given over various periods of time. The purpose of this paper is to review these lesions in the common laboratory animal species including nonhuman primates, and discuss their apparent commonality.

Results from 86 two‐year carcinogenicity studies conducted by the national toxicology program

Five categories of evidence of carcinogenicity in rats and mice were used to group interpretative results on 86 chemicals studied in recent carcinogenicity tests carried out by the National Toxicology Program (NTP). Of these studies, 50% (43/86) were regarded as showing carcinogenic effects, 42% (36/86) gave no evidence of carcinogenicity, 6% (5/86) showed equivocal evidence of carcinogenicity, and 2% (2/86) were regarded as inadequate experiments. The liver was the most frequent site of cancer in male and female Fischer-344 rats and in male and female B6C3F1 mice. Male rats appeared more sensitive than female rats to the induction of neoplasia, while for mice the females seemed more responsive. The routes of administration yielding the highest percentage (80-83%) of positive studies were gavage and inhalation; approximately one-third of the feed, drinking water, and dermal studies showed carcinogenic effects. In feeding studies, overall survival in dosed and control groups were similar, while the majority of gavage studies showed significantly reduced survival in one or more dosed groups relative to the corresponding controls. The overall percentage of studies showing carcinogenic effects (50%) agrees closely with the rate reported by other investigators for nearly 200 earlier carcinogenicity experiments conducted by the National Cancer Institute.

The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters

Female Golden Syrian hamsters, F-344 rats, Swiss CD-1 mice, and B6C3F1 hybrid mice were exposed 6 hr/day, 5 days/week to carcinogenic levels of vinyl chloride (VC) for 6, 12, 18, or 24 months (rats and hamsters only). Other groups of rodents were held for 6 or 12 months and then exposed for 6 or 12 months. At the end of the study the incidence of VC-induced neoplasms was compared in each of the groups to assess the effects of duration of exposure and age at the start of exposure on carcinogenicity of VC. In rats, with early initial exposure, hemangiosarcomas, hepatocellular carcinomas, and mammary gland carcinomas occurred with increasing incidence with longer exposure duration. Rats held for 6 months before exposure developed VC-related neoplasms, while rats held 12 months before the start of exposure failed to show a significantly increased incidence of these neoplasms. In hamsters, hemangiosarcomas, mammary gland carcinomas, gastric adenocarcinomas, and skin carcinomas resulted from VC exposure. The highest incidence of malignant neoplasms occurred in hamsters exposed for the first 12 months, whereas exposure begun after 12 months of age did not cause neoplasms. In both strains of mice, VC exposure during the first 6 months of the experiment induced a high incidence of hemangiosarcomas and mammary gland carcinomas. Swiss mice also developed lung carcinomas after only 6 months of exposure. In all three rodent species an initial 12 month exposure to VC was adequate to detect its carcinogenic potential, but the shortened survival of VC exposed mice and hamsters precluded a meaningful comparison with longer periods of exposure. Exposures were most effective when started early in life.

Comparison of site-specific and overall tumor incidence analyses for 81 recent National Toxicology Program carcinogenicity studies

Eighty-one recent carcinogenicity studies carried out by the National Toxicology Program (NTP) were evaluated to determine how the utilization of statistical analyses based on the proportion of animals with primary tumors (all sites) or the proportion of animals with malignant neoplasms (all sites) affected the interpretation of the data compared to analyses of site-specific effects. Utilizing site-specific analyses, the NTP concluded that 45 of the 81 studies (56%) showed carcinogenic responses, 7 (9%) produced equivocal effects, and 29 (36%) showed no evidence of carcinogenicity. An analysis of tumors at all sites often resulted in site-specific carcinogenic responses going undetected. Less than half of the 45 carcinogens identified as producing site-specific carcinogenic responses showed a significant increase in the incidence of primary tumors (22 chemicals) or malignant tumors (21 chemicals). Among the 29 chemicals interpreted as not carcinogenic based on site-specific effects, only two showed significant increases in overall tumor incidence. Two major problems are associated with an evaluation based on overall (all sites) tumor rates: The pooling of various tumor types reduces study sensitivity for detecting chemically related increases in site-specific tumor incidences, and the biological relevance of combining the incidences of tumors of varying morphologies and topographies is questionable. Most national and international guidelines for studying chemicals for carcinogenicity in rodents (or in humans) emphasize site-specific effects. Thus, despite purported advantages of analyses based on overall tumor rates (e.g., simplicity; reducing concerns regarding false positive results) primary emphasis should continue to be on site-specific analyses.

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.