Effects of pentachlorophenol on hepatic drug-metabolizing enzymes and porphyria related to contamination with chlorinated dibenzo-p-dioxins and dibenzofurans

The hepatic effects of technical and pure grade pentachlorophenol were investigated in female rats fed 20, 100 and 500 ppm of each for 8 months. Technical pentachlorophenol was contaminated with 8 ppm hexa-, 520 ppm hepta-, and 1380 ppm octachlorodibenzodioxtns and with 4 ppm tetra-, 42 ppm penta-, 90 ppm hexa-, 1500 ppm hepta- and 200 ppm octachlorodibenzofurans; pure pentachlorophenol contained less than 0.1 ppm of each of these contaminants. Technical pentachlorophenol produced hepatic porphyria and increased hepatic aryl hydrocarbon hydroxylase activity, glucuronyl transferase activity, liver weight, cytochrome P-450 and microsomal heme, but not N-demethylase activity. The peak of the CO-difference spectrum of cytochrome P-450 was shifted to 448 nm, and there was a dramatic increase in the 455-430 ratios of the ethyl isocyanide difference spectrum. The enzyme changes were observed at 20 ppm of technical pentachlorophenol. Porphyria occurred at 100 and 500 ppm. Pure pentachlorophenol had no significant effect on aryl hydrocarbon hydroxylase activity, liver weight, cytochrome P-450, microsomal heme, the ethyl isocyanide difference spectrum or N-demethylase activity at any dose level, but did increase glucuronyl transferase at 500 ppm. In contrast, both pure and technical pentachlorophenol decreased body weight gain comparably at 500 ppm. It is concluded that technical pentachlorophenol produces a number of liver changes which cannot be attributed to pentachlorophenol itself, but are consistent with the effects of biologically active chlorinated dibenzo-p-dioxins and dibenzofurans.     

Chronic toxicity of di(2-ethylhexyl)phthalate in mice.

B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at Weeks 26, 52, 78, and 104 from 10 animals per sex per group. Body weights and food consumption were measured weekly for the first 16 weeks, then monthly thereafter. Survival was reduced for mice receiving 6000 ppm DEHP. Overall weight gains were significantly lower for the 6000-ppm male group, but there was no difference among female groups. Food consumption was not affected by exposure. No biologically significant changes in clinical chemistry, hematology, or urinalysis were observed. After 104 weeks of exposure, kidney weights for the 500- and 1500-ppm male, and 6000-ppm male/female groups were significantly lower than for the controls. Significantly higher liver weight was seen for the 500-, 1500-, and 6000-ppm male groups and the 6000-ppm female group of mice. Testis weights for the 500-, 1500-, and 6000-ppm males were significantly lower than for the controls. Uterine weights for the 6000-ppm group were significantly lower than for the controls. All organs were examined for histopathology. The incidence of hepatocellular lesions has been reported separately (R. M. David et al., 1999. Toxicol. Sci. 50, 195-205). Tumors were observed at > or = 500-ppm dosages, where peroxisome proliferation was significantly increased. A NOEL for both tumors and peroxisome proliferation was 100 ppm. In the study presented here, bilateral hypospermia in the testes of male mice, hepatocyte pigmentation and cytoplasmic eosinophilia in the liver, and chronic progressive nephropathy of male and female mice were observed at 6000 ppm. Hypospermia and chronic progressive nephropathy were also observed at 1500 ppm, where peroxisome proliferation was 2.7-6.8-fold higher than controls. Many lesions observed in rats were not seen in mice. A dose level of 500 ppm (98.5-116.8 mg/kg/day) was identified as a no-observed-adverse-effect level (NOAEL) for noncarcinogenic effects.     

Chronic toxicity of di(2-ethylhexyl)phthalate in rats.

Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500 ppm di(2-ethylhexyl)phthalate (DEHP) in the diet for up to 104 weeks. Blood and urine were analyzed at weeks 26, 52, 78, and 104 from 10 animals per sex per group. Survival was slightly but not statistically reduced for rats receiving 12,500 ppm DEHP. Body weights and food consumption were significantly reduced for rats receiving the highest dose level of DEHP and occasionally for the male 2500-ppm group. BUN and albumin were significantly higher and globulin lower at nearly every sampling interval for the 12,500-ppm group compared with the controls. There was an increase in the mean activities of AST and ALT at 104 weeks, but no statistically significant differences were seen. Erythrocyte count, hemoglobin, and hematocrit values for the 12,500-ppm group were significantly lower than controls at nearly every sampling interval. No other differences in hematology were seen. No toxicologically significant changes were observed in urinalysis. At termination, relative lung weights for the 2500- and 12,500-ppm male groups of rats were significantly higher than for the controls. Absolute and relative liver and kidney weights for the 2500- and 12,500-ppm male rats, and liver weights for 12,500-ppm female rats were higher compared with the controls. Absolute and relative testes weights for the 12, 500-ppm male rats were lower compared with the controls. All organs were examined for histopathology. The incidence of hepatocellular lesions has been reported separately and correlated with the induction of peroxisomal enzyme activity (David et al., 1999). A dose level of 500 ppm was the NOEL for peroxisome proliferation. Bilateral aspermatogenesis in the testes, castration cells in the pituitary gland, spongiosis hepatis, and pancreatic acinar cell adenoma were observed for 12,500-ppm male rats. Aspermatogenesis and spongiosis hepatis were observed for 2500-ppm male rats, and aspermatogenesis was seen at 500 ppm. DEHP exposure exacerbated age-, species- or strain-related lesions such as mineralization of the renal papilla and chronic progressive nephropathy in male rats. Kupffer cell pigmentation and renal tubule pigmentation were seen in male and female 12,500-ppm rats. The increased incidence of spongiosis hepatis correlated with increased palmitoyl CoA oxidase activity, but the incidence of pancreatic acinar cell adenoma was increased only at the highest dose level of 12,500 ppm. These lesions, although typical of those seen with other peroxisome proliferators, may respond differently depending on the potency of the peroxisome proliferator. A dose level of 500 ppm (28.9-36.1 mg/kg/day) was considered to be the NOAEL.     

Subchronic feeding study of decarboxyfenvalerate in rats

Groups of 30 male and 30 female Fischer-344 rats were fed dietary concentrations of 0, 30, 100, 300, 3000, or 10,000 ppm decarboxyfenvalerate (DC-FEN) for up to 13 wk. An interim kill of 10 rats/sex X group was performed at 7 wk. Following 7 or 13 wk of dietary treatment, groups of rats were necropsied, which included evaluation of hemocellular, hemochemical, and uretic parameters, selected absolute and relative organ weights, and macroscopic and microscopic observations. DC-FEN did not affect mortality. Body weight was decreased in male rats fed 10,000 ppm DC-FEN. Statistically and toxicologically significant differences in clinicopathologic parameters were observed at either the highest or two highest exposure levels. Some statistically significant differences were noted in some hemocellular and/or hemochemical parameters at either 100 or 300 ppm. These subtle changes were either not dose-related, inconsistent, or not of sufficient difference to be determined to have biological significance. Absolute and relative liver weights of male and female rats fed greater than or equal to 300 ppm DC-FEN were all higher than control values except for absolute weights in female rats (300 ppm) at the interim kill. Consistent significant increases in absolute or relative kidney weights were observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Other statistically significant differences in absolute and/or relative organ weights were seen primarily where the higher doses had caused decreased carcass weight. Macroscopic treatment-related liver enlargement (hepatomegaly) was observed in male and female rats fed 3000 or 10,000 ppm DC-FEN. Only one female rat fed 300 ppm DC-FEN had hepatomegaly at the terminal kill. Significant treatment-related microscopic effects were limited to glomerulonephrosis in male and female rats fed 10,000 ppm and hepatocellular hypertrophy and other associated liver changes in male and female rats fed 3000 or 10,000 ppm DC-FEN. Liver effects at doses less than 3000 ppm were indicative of a physiologic adaptive response and were not toxicologically significant. Therefore, the biologically significant no-effect level was 300 ppm.     

Chronic dietary toxicity and oncogenicity evaluation of MCPA (4-chloro-2-methylphenoxyacetic acid) in rodents

The chronic toxicity and oncogenicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) were evaluated in Wistar rats at target doses of 20, 80, and 320 ppm for 2 years. Chronic effects were noted in male and/or female rats in the 80- and 320-ppm dose groups, namely elevations in triglycerides and serum glutamic transaminase levels. Nephrotoxicity was confined to male rats in the 320-ppm dose group. The systemic NOEL was determined to be 20 ppm for male and female rats. No oncogenic potential was observed. Doses in the 2-year oncogenicity study in mice were 20, 100, and 500 ppm. Kidney weight changes with corresponding minor histopathological findings in the kidney were evident in females in the 500-ppm dose group. MCPA was determined to have no oncogenic potential in B6C3F1 mice. In summary, there is no evidence of any oncogenic potential after dietary exposure of MCPA in rats or mice even at doses where limited chronic toxicity is seen.     

Chronic toxicity of photomirex in the rat

Photomirex (8-monohydromirex) was fed to rats for 21 months at dietary levels of 0, 0.2, 1.0, 5.0, 25, and 125 ppm. All 10 rats fed the 125-ppm diet died during the experiment and decreased body weight was noted preceding death. Body weight gain and food consumption were not affected by photomirex at levels up to and including 25 ppm. Increased liver weights occurred in groups dosed at 5.0 ppm photomirex and higher. Photomirex caused significant increases in the activities of serum lactic dehydrogenase, glutamic oxalacetic transaminase and sorbitol dehydrogenase, and hepatic microsomal aniline hydroxylase and aminopyrine N-demethylase. Hematological parameters were not altered by treatment. Treatment-related histological lesions were found in the livers and thyroids of rats fed the lowest dose of photomirex. A number of tumors occurred in the tissues of treated as well as control animals, but the thyroid tumors appeared to have increased frequencies in the treated groups. The results of the present study confirm our previous findings and show that photomirex is a potent hepato-and thyrotoxin.     

Characterization of inhaled alpha-methylstyrene vapor toxicity for B6C3F1 mice and F344 rats.

alpha-Methylstyrene (AMS) is a chemical intermediate used in the synthesis of specialty polymers and copolymers. Inhalation studies of AMS were conducted because of the lack of toxicity data and the structural similarity of AMS to styrene, a toxic and potentially carcinogenic chemical. Male and female B6C3F1 mice were exposed to 0, 600, 800, or 1000 ppm AMS 6 h/day, 5 days/week, for 12 days. After 1 exposure, 21% (5/24) of female mice were found dead in the 1000-ppm group, 56% (10/18) in the 800-ppm group, and 6% (1/18) in the 600-ppm concentration group. After 12 exposures, relative liver weights were significantly increased and relative spleen weights were significantly decreased in both male and female mice at all concentrations. No microscopic treatment-related lesions were observed. A decrease in hepatic glutathione (GSH) was associated with AMS exposure for 1 and 5 days. Male and female F344 rats were exposed to 0, 600 or 1000 ppm AMS for 12 days. No mortality or sedation occurred in AMS-exposed rats. Relative liver weights were significantly increased in both males and females after 12 exposures to 600 or 1000 ppm. An increased hyaline droplet accumulation was detected in male rats in both concentration groups; no significant microscopic lesions were observed in other tissues examined. Exposure of male and female F344 rats and male NBR rats to 0, 125, 250 or 500 ppm AMS, 6 h/day for 9 days resulted in increased accumulation of hyaline droplets in the renal tubules of male F344 rats in the 250 and 500 ppm concentration groups. Although AMS and styrene are structurally very similar, AMS was considerably less toxic for mice and more toxic for male rats than styrene.     

Effects of a thirteen-week inhalation exposure to ethyl tertiary butyl ether on fischer-344 rats and CD-1 mice.

The 1990 Clean Air Act Amendments require that oxygenates be added to automotive fuels to reduce emissions of carbon monoxide and hydrocarbons. One potential oxygenate is the aliphatic ether ethyl tertiary butyl ether (ETBE). Our objective was to provide data on the potential toxic effects of ETBE. Male and female Fisher 344 rats and CD-1 mice were exposed to 0 (control), 500, 1750, or 5000 ppm of ETBE for 6 h/day and 5 days/wk over a 13-week period. ETBE exposure had no effect on mortality and body weight with the exception of an increase in body weights of the female rats in the 5000-ppm group. No major changes in clinical pathology parameters were noted for either rats or mice exposed to ETBE for 6 (rats only) or 13 weeks. Liver weights increased with increasing ETBE-exposure concentration for both sexes of rats and mice. Increases in kidney, adrenal, and heart (females only) weights were noted in rats. Degenerative changes in testicular seminiferous tubules were observed in male rats exposed to 1750 and 5000 ppm but were not seen in mice. This testicular lesion has not been reported previously for aliphatic ethers. Increases in the incidence of regenerative foci, rates of renal cell proliferation, and alpha2u-globulin containing protein droplets were noted in the kidneys of all treated male rats. These lesions are associated with the male rat-specific syndrome of alpha2u-globulin nephropathy. Increases in the incidence of centrilobular hepatocyte hypertrophy and rates of hepatocyte cell proliferation were seen in the livers of male and female mice in the 5000-ppm group, consistent with a mitogenic response to ETBE. These two target organs for ETBE toxicity, mouse liver and male rat kidney, have also been reported for methyl tertiary butyl ether and unleaded gasoline.     

Octachlorostyrene: A 90-Day Toxicity Study in the Rat

Octachlorostyrerie: A 90-Day Toxicity Study in the RaL CHU,L, VILLENEUVE, D. C, SECOURS, V. E., YAGMINAS, A., REED, B.,AND VALU, V. E. (1984). Fundam. Appl. Toxicol. 4, 547–557.This study was designed to provide information on the subchronictoxicity of octachlorostyrene (OCS), a demonstrated environmentalpollutant in fish from the Great Lakes of North America andthe Norwegian coast in Europe. Groups of 15 male and 15 femalerats were administered OCS mixed in the diet at 0.05, 0.5, 5.0,50, or 500 ppm for 13 weeks. Increased liver weights were observedin male and female rats fed 50 ppm OCS and higher, while enlargedkidney and spleen were noted in the highest dose groups. Hepaticmicrosomal enzyme induction occurred at 5.0 ppm OCS and higherfor the males and 50 ppm and higher for the females. The chemicalproduced serum biochemical changes at concentrations as lowas 5.0 ppm. OCS treatment resulted in hematological disturbancesstarting with the 0.5-ppm dose group. Dose-dependent histologjcalchanges were observed in the thyroid, kidneys, and liver ofthe treated animals. OCS residues accumulated in a dose-relatedfashion in the liver and fat of treated animals. These resultsindicate that OCS produced toxic effects at low levels of exposureand accumulated in the tissues of rats.     

Chronic toxicologic investigations of phosalone in the dog and rat

Phosalone is the active ingredient in the insecticide Zolone. Experiments were conducted to determine the chronic toxicity of the compound to dogs and rats. Feeding phosalone to rats at dietary concentrations of 25, 50, and 250 ppm, and to dogs at 100, 200, and 1000 ppm, resulted in dose-dependent inhibition of RBC and plasma cholinesterase with an extrapolated level of no observable effect at 25 ppm. Brain cholinesterase was inhibited in the 1000-ppm group of male dogs and in the 250-ppm group of rats. Slight signs of cholinergic distress were observed in the 1000-ppm group of dogs during the first 6 months of treatment, but the animals appeared normal thereafter. There was a decreased growth rate in the dogs fed 200 and 1000 ppm in the diet, but there was little alteration in the growth rate of the rats at any dietary concentration. The results of these experiments indicate that phosalone exhibits a relatively low order of toxicity on long-term exposure in the dog and rat.     

Acute inhalation study of allyl alcohol for derivation of acute exposure guideline levels

An acute, whole-body inhalation study for allyl alcohol in Sprague-Dawley rats was designed to support derivation of AEGL values, with emphasis on establishing NOAELs for irreversible effects of different exposure concentrations and durations. Groups of 10 rats were exposed for 1 hour (0, 50, 200, or 400?ppm), 4 hours (0, 20, 50, or 100?ppm), or 8 hours (0, 10, 20, or 50?ppm). Clinical evaluations were performed during exposure and in an open field within 22-71 minutes after termination of exposure. Clinical pathology, gross necropsy, and histopathology (nasal tissues, larynx, trachea, lungs/bronchi, liver, and kidneys) were evaluated 14 days after exposure. Mortality was limited to 1 male exposed for 8 hours to 50?ppm. Clinical findings of gasping, rales, increased respiration noted at higher exposure levels were rapidly reversed. No treatment-related findings were observed in the liver and kidneys, or in the lungs of surviving animals. Histopathology in the nasal cavity was noted at all exposure levels following 1, 4, or 8 hours of exposure. Mild nasal inflammation was found at the lowest exposure levels (50-ppm/1-hour, 20-ppm/4-hour, and 10-ppm/8-hour). These effects were considered reversible and were not associated with related clinical signs. Severe, irreversible nasal olfactory epithelial lesions were present in 50?ppm/8-hour males. The NOELs for irreversible effects were 400-ppm/1-hour, 100-ppm/4-hour, and 20-ppm/8-hour. The incidence of severe findings was positively dependent on both concentration and the exposure duration. In contrast, the incidence of mild reversible findings did not appear to be dependent on duration.     

Acute inhalation study of allyl alcohol for derivation of acute exposure guideline levels

An acute, whole-body inhalation study for allyl alcohol in Sprague-Dawley rats was designed to support derivation of AEGL values, with emphasis on establishing NOAELs for irreversible effects of different exposure concentrations and durations. Groups of 10 rats were exposed for 1 hour (0, 50, 200, or 400?ppm), 4 hours (0, 20, 50, or 100?ppm), or 8 hours (0, 10, 20, or 50?ppm). Clinical evaluations were performed during exposure and in an open field within 22–71 minutes after termination of exposure. Clinical pathology, gross necropsy, and histopathology (nasal tissues, larynx, trachea, lungs/bronchi, liver, and kidneys) were evaluated 14 days after exposure. Mortality was limited to 1 male exposed for 8 hours to 50?ppm. Clinical findings of gasping, rales, increased respiration noted at higher exposure levels were rapidly reversed. No treatment-related findings were observed in the liver and kidneys, or in the lungs of surviving animals. Histopathology in the nasal cavity was noted at all exposure levels following 1, 4, or 8 hours of exposure. Mild nasal inflammation was found at the lowest exposure levels (50-ppm/1-hour, 20-ppm/4-hour, and 10-ppm/8-hour). These effects were considered reversible and were not associated with related clinical signs. Severe, irreversible nasal olfactory epithelial lesions were present in 50?ppm/8-hour males. The NOELs for irreversible effects were 400-ppm/1-hour, 100-ppm/4-hour, and 20-ppm/8-hour. The incidence of severe findings was positively dependent on both concentration and the exposure duration. In contrast, the incidence of mild reversible findings did not appear to be dependent on duration.     

A two-year inhalation study of the carcinogenic potential of ethylene oxide in Fischer 344 rats

Fischer 344 rats were exposed to 100, 33, 10, or 0 ppm of ethylene oxide vapor (EtO) by inhalation for 6 hr per day, 5 days per week, for approximately 2 years. Inhalation of EtO resulted in a significant depression of body weight gain in the 100- and 33-ppm exposure groups and a significant increase in mortality in the 100-ppm group. Through 18 months of exposure to EtO, no statistically significant increases in tumor incidence were observed. After 18 months, the incidence of primary brain tumors was increased for both sexes. Statistical evaluation indicated a treatment-related response, particularly for the male rats, in the 100- and 33-ppm exposure groups. After 24 months of exposure, histologic findings confirmed hematologic evidence that exposure to EtO resulted in an increased prevalence of mononuclear cell leukemia, which is a neoplasm that is common in aged Fischer 344 rats. This increase was dose related and increased for each of the three exposure concentrations. The percentage of female rats with multiple neoplasms was also greater in all three exposure groups than in controls. Furthermore, in both the 100- and 33-ppm exposure groups, the percentage of female rats with at least one malignant neoplasm was increased. An increased frequency of peritoneal mesothelioma was treatment related in the male rats exposed to 100 or 33 ppm of EtO. This study has shown biologically significant adverse effects at all concentrations tested. The incidences of mononuclear cell leukemia, peritoneal mesothelioma, and primary brain tumors in the air-control rats were similar to those reported in the literature. The possible contribution of a sialodacryoadenitis viral outbreak (which occurred during the 15th exposure month) to the EtO exposure-related tumors is unknown, though unlikely.     

Body burden of hexachlorobenzene and its effects on some esterases in tissues of young male rats

Feeding male Wistar rats 50 or 100 ppm HCB in the diet for 62 days evoked induction of liver esterase activity toward thiophenyl, p-nitrophenyl, and indophenyl acetates. The induction rate, as well as the HCB residues, in liver, brain, kidney, and heart were dose-dependent. An increase in esterase activity toward thiophenyl acetate was also observed in the kidney at the 100-ppm HCB level. Serum esterase activity toward malaoxon was elevated at 50 and 100 ppm HCB and that toward paraoxon was increased at 100 ppm. Liver esterase hydrolysis of malaoxon was induced only at 100 ppm HCB. Under the condition used, the rats fed 10 ppm HCB were observed to be similar to the controls; the concentrations of HCB residues found in the liver, brain, kidney, and heart were dose dependent.     

Toxicity of methylmercury chloride in rats I. Short-term study

In the range-finding test, 6 groups of 4 male and 4 female weanling rats were given dietary levels of 0, 0.1, 0.5, 2.5, 12.5 and 250 ppm methylmercury chloride (MeHgCl) for 2 weeks. Signs of central nervous system toxicity, weight los and high mortality appeared at 250 ppm but not at lower levels. No haematological changes were observed at 0.1–12.5 ppm. The relative weights of the liver in females on 2.5 and 12.5 ppm and of the kidneys in females on 12.5 ppm were significantly increased; the effects in males were less marked. Total mercury concentration in the kidneys increased proportionally with increasing dietary levels of MeHgCl.In the short-term test, 5 groups of 15 male and 10 female weanling rats were given dietary levels of 0, 0.1, 0.5, 2.5 and 25 ppm MeHgCl for 12 weeks. Toxic signs, weight loss and restricted food intake were observed at 25 ppm starting from week 9 onwards. Haematological, serum enzyme and urinalysis changes were seen at 25 ppm. Liver microsomal enzyme activity was increased non-significantly and lvier glycogen was depressed at 25 ppm. Organ weight changes were evident at 25 ppm and hitological changes seen in the spleen, kidneys, brain, spinal cord and peripheral nerves were confined to the 25 ppm level. Histochemical changes in kidney enzymes occurred at 2.5 and 25 ppm. Hg concentrations in blood, hair, kidneys, liver and brain were higher at 12 weeks than 6 weeks and generally increased with increasing MeHgCl level in the diet.     

Chlordane: 24-month tumorigenicity and chronic toxicity test in mice

Four groups of 80 ICR SPF mice of each sex were fed 0-12.5 ppm technical chlordane for 104 weeks. Male and female mice were examined for hematological, biochemical, urinary, and pathological changes at 52 and 104 weeks of exposure. Serum AST (= SGOT) and ALT (= SGPT) were elevated in treated males and females, liver weights were increased in the 12.5-ppm groups, and masses were seen in the livers of 12.5-ppm males. Increased liver cell volume was seen in 5- and 12.5-ppm males and females, while hepatocyte degeneration and necrosis were seen only in treated males. Hepatic hemangiomas and hepatocellular adenomas typically occurred together and were significantly increased in 12.5-ppm males. No other significant changes were detected. However, the incidence of tumors in the 12.5-ppm males was within the range of historical controls. Accordingly, there was no evidence that chlordane induced tumors in the ICR mice. A long-term no-observed-effect level (NOEL) of 1 ppm chlordane in the diet was found.     

Acute and subchronic toxicity of mirex in the rat, dog, and rabbit.

The acute and subchronic (13 weeks) toxicity of orally administered mirex was studied in mongrel dogs, beagle dogs, and rats. Percutaneous toxicity was evaluated in rabbits. The acute oral LD50 in male mongrel dogs was found to be > 1000 mg/kg. Beagles of both sexes fed 4 and 20 ppm of mirex for 13 weeks exhibited no toxic effects. Two animals receiving 100 ppm died during the test period. Also observed at this dosage level were a reduced rate of weight gain, abnormal blood chemistry values, increased liver/body weight ratios, and decreased spleen/body weight ratios. No histopathologic changes were attributed to mirex. Male and female rats received diets containing 0, 5, 20, 80, 320, and 1280 ppm. No significant adverse effects were observed at levels of 5, 20, and 80 ppm. The following were observed at 320 and 1280 ppm; depressed growth, decreased hemoglobin concentrations, elevated white cell counts, enlarged livers showing histopathological changes, and deaths in the 1280-ppm groups. Rabbits exposed percutaneously to 3.33 or 6.67 g of mirex bait/kg, 6–7 hr each day, 5 days a week, for 9 weeks, exhibited no evidence of mirex intoxication.     

Effects of pentachlorophenol on rat liver changes induced by hexachlorobenzene,with special reference to porphyria,and alterations in mixed function oxygen ases

Hexachlorobenzene (HCB, 1000 ppm) and 500 ppm pentachlorophenol (PCP) were fed separately or in combination to female Wistar rats. A control group was provided with standard food without HCB or PCP. Subgroups of 4 rats were killed after 1,2,4,6 and 8 weeks. No significant difference was found between the amounts of HCB accumulated in the livers of the HCB and HCB + PCP fed rats. Administering HCB together with PCP caused a noticeable accumulation of PCP in the liver, compared to the results after administering HCB and PCP separately. In the HCB and HCB + PCP fed groups liver weight increased continuously during the experiments. Microsomal cytochrome P-450, NADPH-cytochrome c reductase, ethoxyresorufin O-de-ethylase, aminopyrine N-demethylase, and glucuronyl transferase increased to a maximum in 2–4 weeks in HCB and HCB + PCP fed rats. Pentachlorophenol accelerates the onset of HCB porphyria, in other words it increases the total urinary porphyrin excretion and causes an earlier disturbance of the porphyrin pattern.     

Sex difference in inhalation toxicity of p-dichlorobenzene (p-DCB) in rats

The organ distribution and toxicity of p-dichlorobenzene (p-DCB) were compared in male and female rats after inhalation of 500 ppm of p-DCB for 24 h in a whole-body chamber. Concentrations of p-DCB in the serum, liver, kidney and fatty tissues were measured by gas chromatography at intervals during and up to 24 h after the treatment. Though no significant differences in the serum levels were observed between male and female rats, the p-DCB values in the livers of female rats were significantly higher than those of male rats. Conversely, significantly higher levels were found in the kidneys of male than of female rats. The distribution results thus appeared to correlate with the fact that nephrotoxic changes were observed only in male rats and that the appearance of minor hepatotoxic changes was limited to females.     

Short-term toxicity of photomirex in the rat.

When photomirex (8-monohydromirex) was fed to rats at dietary levels of 0, 0.5, 5.0, 50, or 500 ppm, all 10 animals receiving the highest dose levels died within 7 days, and two of 10 animals in the 50-ppm group died after 24 days. All other animals (10 per group) survived until the experiment was terminated at 28 days. Animals receiving 50 ppm showed decreased body weight gain and food consumption. Liver hypertrophy and increased microsomal enzyme activity (aniline hydroxylase) were observed in groups of animals receiving 5.0 ppm and greater. Serum sorbitol dehydrogenase activity was increased in animals receiving 5.0 ppm and greater. Photomirex accumulated in all tissues examined, with fat and liver having the highest residues. Histological alterations were observed in the liver at 0.5 ppm and consisted of mild midzonal cytoplasmic enlargement. At a level of 5 ppm, the midzonal cytoplasmic enlargement was more pronounced and was accompanied by mild anisokaryosis and nuclear hyperchromicity. At the highest dose, these alterations were accompanied by perivenous fatty infiltration. Lesions of the thyroid were observed in the group of animals receiving 50 ppm (6.61 mg/kg/day) and consisted of a generalized reduction in follicle size and colloid density. Animals which died showed pronounced thyroid follicular atrophy accompanied by severe colloid depletion and epithelial exfoliation. Animals receiving 50 ppm also had lesions in the testes consisting of a mild to marked reduction in spermatogonia and complete cessation of spermatogenesis.