Preclinical toxicological evaluation of sertraline hydrochloride.

The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drug-treated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk.

[Pro and contra laparoscopic appendectomy in childhood]. / Für und Wider der laparoskopischen Appendektomie im Kindesalter.

The question should be cleared, if and to what extent the indication for appendectomy has changed since the beginning of the minimal invasive surgery in childhood. At first we had the chance to compare two patient groups in the different locations of the clinic for paediatric surgery in the Humboldt-University before their consolidation, because the indication for laparoscopic appendectomy was differently decided. The analysis of these two patient collectives (more than 50 children each) showed, beside the well known different preoperative parameters (age, sex allotment and anamnesis) the distinct indications finding for the minimal invasive procedure. In one group even the acute inflammatory appendicitis was excluded from the laparoscopic technique, in the other group only the sonographic proved perityphlitic abscess was excluded. In this group--corresponding to the more generous indication--there were more wound healing complications after phlegmonous and gangrenous appendicitis--even a little more (0.4%) than in a compared conventional operated collective. Cause of this reason the indication for the laparoscopic technique was defined more rigid (excluding the acute inflammatory disease), to get a high quality standard. The following 350 children after having appendektomy were analysed in the from now on merget locations under special consideration of postoperative complications. Including 54 laparoscopic procedures we saw significant less complications and registered a better average outcome including living quality criteria.

A study of the phototoxic potential of trovafloxacin in BALB/c mice.

Trovafloxacin, a broad-spectrum naphthyridone antimicrobial agent, was evaluated for potential phototoxicity in a standardized in-vivo test system that has been used previously to assess quinolone antibiotics. Fasted BALB/c mice were given a single oral dose of either trovafloxacin mesylate (10, 30, 90 or 250 mg/kg) or the positive control lomefloxacin hydrochloride (71 mg/kg) and immediately exposed to long-wave ultraviolet (UVA) light. Animals were irradiated for 4 h, equal to a total UV light irradiation of approximately 18 J/cm2. Before dosing, at the end of the irradiation period and at approximately 24, 48, 72 and 96 h after dosing, both ears of each mouse were evaluated for changes indicative of a positive response: erythema, oedema or a measurable increase in ear thickness. Under the conditions of this study, trovafloxacin produced a mild response (erythema and a slight increase in ear thickness) in mice given a dose of 90 or 250 mg/kg; no significant response was observed in mice given either lower doses (10 or 30 mg/kg) or the vehicle. In contrast, 71 mg/kg of lomefloxacin produced a strong and persistent phototoxic response. The results of this study demonstrate that the phototoxic potential of trovafloxacin is considerably less than that of lomefloxacin and, when compared with similar studies with related compounds, suggest that trovafloxacin is among the least phototoxic of the fluoroquinolone class.

The complementary roles of in vitro and in vivo tests in genetic toxicology assessment.

Risk of genetic alteration (genetic toxicity) in humans as a consequence of exposure to exogenous agents is determined in large degree by the results of specific laboratory tests. Although the individual test procedures are uniform and standardized, there is often confusion when effects observed in vitro are not confirmed in vivo. This in vitro/in vivo difference is commonly misrepresented as demonstrating the insensitivity of in vivo genetic toxicology tests. Consideration of the mechanistic bases of the tests leads to a more rational interpretation: In vitro procedures, by avoiding pharmacokinetic limitations and many confounding interactions, are best able to detect the potential for an agent to affect genetic fidelity, while in vivo procedures, specifically because they are influenced by pharmacokinetics and competing reactions, are more suitable for determining the probability of genetic alterations occurring in an intact, dynamic organism. Expectations that in vivo test results should always confirm in vitro findings are unwarranted, as are comparisons of perceived sensitivities for detecting genetic toxicity. Human risk estimation should be based principally on the results of in vivo genetic toxicology tests, as is the case with other, nongenetic endpoints, and the in vivo tests must be sufficiently vigorous to detect genetic injury, including substantiation of the relevancy of the target cells monitored and documentation of their exposure. In contrast, the primary role of in vitro tests should be to guide in the design and selection of in vivo tests, as well as to assist in their interpretation and assessment of adequacy.

The relevance of hepatic peroxisome proliferation in rats to assessment of human carcinogenic risk for pharmaceuticals.

There exists a strong association between the ability of drugs and other chemicals to induce hepatic peroxisomes in rodents and to increase the frequency of liver tumors in these same species. Despite several years of intensive investigation, a plausible mechanism causally relating peroxisome induction to tumor formation has not been found. Two major theories of how such compounds produce tumors--prolonged oxidative stress and cellular growth dysregulation--have limited experimental support. The oxidative stress demonstrated in rodents as a consequence of peroxisomal activity may be irrelevant to man since primates appear to be much less susceptible to peroxisome proliferation than are rats or mice. Cellular growth dysregulation and other effects of test materials that often accompany--but are not directly attributable to--peroxisome proliferation in rodents can be assessed in other, more relevant species if a causal relationship between their presence and tumor development is ultimately shown in rodents. Currently, there is no reason to specifically avoid the clinical assessment and commercial development of new therapeutic drugs that induce peroxisomes in rodents if other measurements indicate the absence of DNA damage or growth dysregulation at reasonable exposures in relevant species.

Pharmacokinetics of 2',3'-dideoxyadenosine in dogs.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddAdo) and 2'-3'-dideoxyinosine (ddIno) were determined after intravenous bolus administration and long-term intravenous infusion of ddAdo in dogs. ddAdo was rapidly deaminated to ddIno and ddAdo plasma concentrations were only a fraction of ddIno concentrations. The total body clearance of ddAdo exceeded the literature value for the cardiac output of the dog, indicating an extremely rapid metabolism, and the existence of extrahepatic metabolism. Urinary excretion of unchanged ddAdo was a minor route of elimination (approximately 1%). The pharmacokinetics of ddIno was determined assuming complete conversions of ddAdo to ddIno. ddIno elimination was dose-dependent with total body clearance ranging from 4 to 55 ml/min/kg in individual animals. The plasma half-life was approximately 30 min after most routes of administration, but increased to approximately 60 min in two animals receiving a large intravenous dose of 500 mg/kg. ddIno penetrated into the cerebrospinal fluid to a limited extent, reaching concentrations of 3-11% of those in plasma. Urinary excretion of unchanged ddIno accounted for approximately 20% of the administered dose of ddAdo, while uric acid and hypoxanthine were minor urinary metabolites. Concentrations exceeding the in vitro minimal viral inhibitory concentration (2.4 micrograms/mL) could be safely maintained in plasma for a 10-day period. Infusions which gave cerebrospinal fluid concentrations of 12 to 17 micrograms/mL resulted in dose limiting myelosuppression and intestinal toxicity, after less than 10 days of infusion. Orally administered ddAdo was absorbed as ddIno, with bioavailabilities ranging from 28 to 93% in experiments where no emesis occurred. These studies indicate the rapid in vivo conversion of ddAdo to ddIno, and support the selection of ddIno over ddAdo for further drug development.

Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans: a review.

This review evaluates the available information on the effects of mainstream and environmental tobacco smoke on the immune system in animals and humans. The primary emphasis is on mainstream smoke since little information is available on the effects of environmental smoke. The effects of mainstream tobacco smoke on the immune system in humans and animals are similar. Animals exposed to mainstream tobacco smoke for periods of a few weeks generally exhibit a slight immunostimulation. However, subchronic and chronic exposure studies indicate that immunosuppressive changes develop. Lymphocyte proliferation in response to the mitogens PHA and LPS is decreased, suggesting compromise of cell function. Antibody production can be suppressed. Smoke-exposed animals that are challenged with metastasizing tumors or viruses have been shown to exhibit a higher incidence of tumorigenic and infectious diseases, respectively. Localized immunological changes in the lung can include reduction of bronchus-associated lymphoid tissue and immunoglobulin levels. Smoking-related changes in the peripheral immune system of humans have included elevated WBC counts, increased cytotoxic/suppressor and decreased inducer/helper T-cell numbers, slightly suppressed T-lymphocyte activity, significantly decreased natural killer cell activity, lowered circulating immunoglobin titers, except for IgE which is elevated, and increased susceptibility to infection. The effects of environmental tobacco smoke on the immune system, in contrast to mainstream tobacco smoke, have just begun to be investigated and information available in the literature, to date, is limited. Immunoreactive substances are known to be present in environmental tobacco smoke, but to date, environmental tobacco smoke has been more closely associated with irritation than sensitization. A few studies have indicated a potential for environmental smoke-induced hypersensitivity and suppression of immunoregulatory substances. In contrast, other investigators have failed to detect immunological or other biological changes associated with environmental smoke. Clearly, more research is needed to resolve these differences.

Pharmacological and toxicological evaluation of orally administered pyridostigmine in dogs.

Pyridostigmine bromide, a reversible cholinesterase inhibitor, was administered orally (capsule gavage) to beagle dogs (10-15 months of age) of both sexes once daily at 5, 10, or 20 mg/kg for 14 days; every 8 hr at 2 or 5 mg/kg for 28 days; or every 8 hr at 0.05, 0.5, or 2 mg/kg for 3 months as part of its preclinical safety assessment. A small portion of the dogs receiving pyridostigmine for 3 months were allowed an untreated recovery period of an additional 3 months. Daily doses of 10 or 20 mg/kg were lethal to some of the dogs when given for up to 14 days and caused severe intestinal distress, including diarrhea, emesis, and reddened feces in all animals. The cause of death was intestinal intussusception. Signs of systemic toxicity apparent at these doses included hypersalivation and tremors. Similar but less severe effects were produced by 5 mg/kg per day; plasma cholinesterase activities were inhibited by all three doses in a dose-related manner. Signs of toxicity in the 28-day and 3-month studies were generally limited to the gastrointestinal tract and included diarrhea or soft stools and reddened or mucoid-containing stools; these signs appeared to reverse upon discontinuation of the drug. A single dog at 2 mg/kg every 8 hr developed an apparent intussusception. There were no pathological changes in clinical chemistry, hematology, or urinalysis parameters associated with doses of 0.05, 0.5, or 2 mg/kg every 8 hr for up to 3 months, nor were any drug-related lesions observed upon gross necropsy and microscopic evaluation of the major tissues and organs. Red blood cell (RBC) acetylcholinesterase (AChE) activities in the 3-month study were inhibited by approximately 10, 50, and 70% in the 0.05, 0.5, and 2 mg/kg every 8-hr dose groups, respectively, and these degrees of inhibition were maintained throughout the period of treatment. These data suggest that prolonged oral administration of pyridostigmine at doses sufficient to cause profound and sustained inhibition of RBC AChE activity (i.e., as high as 70%) cause mainly local, gastrointestinal distress related to altered intestinal motility. At the extreme, this can be manifested as a life-threatening intestinal intussusception. Systemic anticholinesterase effects (other than enzyme inhibition) were observed only at doses of 2 mg/kg and greater, while local (gastrointestinal) effects and inhibition of RBC AChE were observed at doses as low as 0.05 mg/kg.

Influence of dietary zinc on di(2-ethylhexyl)phthalate-induced testicular atrophy and zinc depletion in adult rats.

Groups of 48 adult male F344 rats were maintained on synthetic diets containing 20 ppm (normal), 2 ppm (low), or 200 ppm (high) zinc. After 1 week of acclimation to the various diets, groups of 12 rats from each dietary regimen were gavaged for 13 consecutive days with 0.0 (vehicle), 0.33, 1.0, or 3.0 g/kg di(2-ethylhexyl)phthalate (DEHP). These were selected as relatively nontoxic, mildly toxic, and moderately toxic doses for producing testicular injury in adult male rats. At termination on the 14th day, body weight gain was reduced by 3.0 g/kg DEHP dose in the normal and low-zinc diet groups but not in the high-zinc diet group. The low-zinc diet alone reduced body weight gain, independent of DEHP treatment. DEHP had no perceptible effects on the weights of testis, seminal vesicle, prostate, or epididymis from rats maintained on normal- or high-zinc diets, but reduced the weights of all of these organs from animals on the low-zinc diet in a dose-dependent manner. Lactate dehydrogenase activity, total and free sulfhydryl contents, and zinc concentrations in testes were also reduced, and testicular degeneration was induced by DEHP in the low-zinc diet groups. In contrast, dose-dependent liver enlargement and hypolipidemia (reduction of serum cholesterol and triglyceride concentrations) were produced by equivalent doses of DEHP in all of the three zinc groups. The selectively enhanced susceptibility of adult male F344 rats on a zinc deficient diet to the gonadotoxic effects of DEHP supports the hypothesis that testicular zinc depletion is causally related to the ensuing testicular and accessory sex organ atrophies. Other biological effects of DEHP (e.g., hypolipidemia, hepatomegaly) appear to occur independent of zinc homeostasis.

Toxicology and carcinogenesis studies of isophorone in F344 rats and B6C3F1 mice.

Toxicology and carcinogenesis studies of isophorone were conducted by administering 0, 250, or 500 mg/kg body weight per day by gavage in corn oil to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days/week, for 103 weeks. Dosed male rats developed proliferative lesions of the kidney including hyperplasia, adenoma, and adenocarcinoma of the renal tubule, and epithelial hyperplasia of the renal pelvis. Non-proliferative kidney lesions observed in dosed male rats included mineralization, and a more severe nephropathy in low dose animals than in controls or high dose animals. Carcinomas of the preputial gland occurred in high dose male rats. No isophorone-related lesions were observed in female rats. In male mice, isophorone exposure may have been associated with an increase in hepatocellular neoplasms and mesenchymal neoplasms of the integumentum in high dose animals, and with a marginally increased incidence of lymphoma in low dose male mice. In mice, no non-neoplastic lesions in males or females, or neoplastic lesions in females were considered associated with isophorone administration.

Carcinogenic potential of phthalic acid esters and related compounds: structure-activity relationships.

Chronic toxicity and carcinogenicity studies of several phthalic acid esters (PAEs) and compounds containing a 2-ethylhexyl moiety were conducted in Fischer 344 rats and B6C3F1 (hybrid) mice. The compounds studied were phthalic anhydride, di(2-ethylhexyl) phthalate, butyl benzyl phthalate, diallyl phthalate, di(2-ethylhexyl) adipate, tris(2-ethylhexyl) phosphate, and 2-ethylhexyl sulfate (sodium salt). Estimated maximum tolerable doses and fractionally lower doses of each compound were administered to groups of 50 male and 50 female rats and mice for 2 years, followed by sacrifice, necropsy, and histopathological examination of major organs and tissues. The low toxic potencies of most of the compounds allowed for relatively high doses to be given during the chronic studies. In general, the toxic manifestations of the PAEs were closely correlated with their ester substituents. Although many of the PAEs possessed some carcinogenic activity, target sites for such effects were dissimilar, suggesting the absence of a common mode of action. In contrast, all of the 2-ethylhexyl-containing compounds studied possessed some hepatocarcinogenic activity, indicating that this moiety may have a propensity for causing hepatocarcinogenesis in mice, particularly those of the female sex. The 2-ethylhexyl compound that caused the greatest hepatocarcinogenic response in mice, di(2-ethylhexyl) phthalate, was also hepatocarcinogenic in rats. Similarly, those with a relatively greater effect in female mice were also active in male mice. Thus, sex and species differences in 2-ethylhexyl-induced hepatocarcinogenesis in rodents are probably quantitative rather than qualitative in nature.

Effects of di(2-ethylhexyl) phthalate on the gonadal pathophysiology, sperm morphology, and reproductive performance of male rats.

Dietary exposure of adult male F344 rats to 0, 320, 1250, 5000, or 20,000 ppm DEHP for 60 consecutive days resulted in a dose-dependent reduction in total body, testis, epididymis, and prostate weights at 5000 and 20,000 ppm. Degenerative changes were observed in testis, along with decreased testicular zinc content, reduced epididymal sperm density and motility, and increased occurrence of abnormal sperm at 20,000 ppm. There was a trend towards reduced testosterone and increased luteinizing hormone and follicle stimulating hormone in serum at 5000 and 20,000 ppm. The mean percentage of fertile animals was unchanged and reduction in fertility parameters, although not marked in severity, were correlated with gonadal effects. Average litter size was reduced at 20,000 ppm, but initial pup weights and growth were unaffected. There were no grossly observed abnormalities in the offspring and the rate of neonatal deaths was similar in control and DEHP treated groups. Characteristic toxicity manifestations of DEHP included dose-dependent enlargement of liver and reduced sperm triglycerides and cholesterol. Additionally, serum albumin and total proteins were dose dependently increased upon treatment with DEHP. Cessation of exposure to DEHP initiated partial to complete recovery from toxicity in most cases. The magnitude of recovery were variable with that of the gonads being slower than other systems. These data suggest a lack of reproductive dysfunction in F344 male rats at DEHP doses below 20,000 ppm which produced measurable testicular degeneration and afflicted epididymal sperm morphology under the present experimental conditions.

Comparative chronic toxicities and carcinogenic potentials of 2-ethylhexyl-containing compounds in rats and mice.

Four compounds containing a 2-ethylhexyl moiety [di(2-ethylhexyl)phthalate (DEHP), di(2-ethylhexyl)adipate (DEHA), tris(2-ethylhexyl)phosphate (TEHP), and 2-ethylhexyl sulfate (EHS)] were tested for carcinogenic and other chronic and subchronic toxic effects in 90-day and 2-year studies in male and female Fischer 344 rats and B6C3F1 mice. The low generalized toxic potencies of the test chemicals allowed relatively high doses of all of these compounds to be administered. Despite differences in chemical structure, all four chemicals were related to increased occurrences of hepatocellular neoplasms, principally carcinomas, in female mice. DEHA and DEHP also induced hepatocellular neoplasms in male mice, while DEHP caused hepatocellular neoplasms in both male and female rats. No other neoplasms were considered to be unequivocally related to compound administration in these studies. There was a positive correlation between the magnitude of the hepatocarcinogenic response in female mice and the probability of a hepatocarcinogenic response in male mice and in male and female rats, suggesting quantitative differences in the carcinogenic potentials of these agents. These results suggest that compounds containing a 2-ethylhexyl moiety (and 2-ethylhexanol, by implication) may possess some carcinogenic potential, especially for the rodent liver. No other organ-specific toxic effects common to two or more test chemicals were observed in these studies.

Adverse effects of butyl benzyl phthalate on the reproductive and hematopoietic systems of male rats.

A 14-day dietary study was conducted in adult, male, Fischer 344 rats at levels of 0.0, 0.625, 1.25, 2.5 and 5.0% butyl benzyl phthalate (BBP) to evaluate potential effects of this plasticizer on the male reproductive and hematopoietic systems. Total body, thymus, testis, epididymis, prostate and seminal vesicle weights were reduced in the 2.5% and 5% BBP dose groups, while pituitary weight was unaffected. Histological evaluations revealed dose-dependent atrophy of the testis, prostate and seminal vesicles at 2.5% and 5%, atrophy of the thymus and epididymis at 5%, and the presence of immature sperm cells in the tubular lumens and necrosis of the tubular epithelium in the epididymis at 2.5% and 5% BBP. Plasma testosterone concentration was decreased at 5%, while follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations were increased at 2.5% and 5.0% BBP. The circulating components of blood, and clotting times (prothrombin time, activated partial thromboplastin time), were unaffected although bone marrow cellularity was reduced at 2.5% and 5%. Changes in non-reproductive organs included enlargement of liver and kidneys, thymic atrophy and associated morphological abnormalities in these organs. These data indicate a direct toxic effect of BBP on the testis with secondary effects on other reproductive organs. Pituitary and hypothalamic responses did not appear to be affected. The reduced bone marrow cellularities suggest that prolonged exposures to BBP could affect circulating blood components or compromise clotting ability.

Initial and residual toxicity following acute exposure of developing male rats to dibromochloropropane.

Male Fischer 344 rats were given a single, sc injection of 1,2-dibromo-3-chloropropane (DBCP) at 6 or 25 days of age. One group of treated animals was killed 1 to 3 days afterward to compare the dose and time relationships of the acute toxic response of neonatal and weanling male rats to DBCP and another group at approximate sexual maturity (approximately 120 days of age) to detect residual toxic effects resulting from acute exposure. The 6-day-old rats were more susceptible than the 25-day-old rats to the acute toxic effects of DBCP, as characterized by reduced 48-hr survival, renal dysfunction, and renal and hepatic necrosis over the dose range of 80 to 320 mg/kg. The lowest dose tested, 20 mg/kg, and all higher doses reduced subsequent body and gonadal weight gains, and caused hypospermatogenesis or seminiferous tubular atrophy in animals exposed at 6 days of age and killed at sexual maturity. Similar effects were observed in animals exposed at 25 days of age, except that doses of 160 mg/kg or greater were required to produce residual toxic effects. These data indicate enhanced susceptibility of neonatal male rats to the gonadotoxic effects of dibromochloropropane, including the possibility of apparent irreversible injury caused by acute exposure.

Toxic responses to acute, subchronic, and chronic oral administrations of monochlorobenzene to rodents.

Acute (single exposure), 14-d repeated exposure, 91-d subchronic, and 103-wk chronic toxicity studies of orally administered (gavage, in corn oil) monochlorobenzene were conducted in male and female Fischer-344 rats and B6C3F1 hybrid mice. A single exposure to 4000 mg/kg was lethal to male and female rats, while a single exposure to a dose as low as 1000 mg/kg was lethal to mice. Fourteen daily exposures to 1000 mg/kg caused death in rats of both sexes, but neither survival nor clinical health were compromised at 500 mg/kg in rats or mice. In the 91-d studies, wherein monochlorobenzene was administered once daily, 5 d/wk, survival was reduced by doses of 500 mg/kg and higher in rats, and by doses of 250 mg/kg and higher in mice. Dose-dependent necrosis of the liver (hepatocytes), degeneration or focal necrosis of the renal proximal tubules, and lymphoid or myeloid depletion of the spleen, bone marrow, and thymus (mild to severe) were produced by doses of 250 mg/kg or greater of monochlorobenzene in both sexes of rats and mice, although the incidences of these lesions varied considerably by sex and species. Consistent changes in the circulating blood components were not observed, but a mild porphyrinuria was detected at the higher doses. No toxic effects were observed at doses of 125 mg/kg or less. In the 2-yr studies, wherein monochlorobenzene was administered once daily, 5 d/wk, doses of 30 or 60 mg/kg in male mice and 60 or 120 mg/kg in female mice and male and female rats did not produce any evidence of toxicity. Doses of 60 or 120 mg/kg caused slight (statistically significant at 120 mg/kg; p less than 0.05) increases in the frequencies of male rats with neoplastic nodules of the liver. Increased tumor frequencies were not observed in female rats or in male or female mice receiving monochlorobenzene.

Chronic kidney disease and organic chemical exposures: evaluations of causal relationships in humans and experimental animals.

Chronic renal failure is a serious health problem in the United States and other developed countries, and large amounts of public funds are being expended for what is essentially palliative treatment of this disease. Historical data also indicate increasing trends for urinary tract cancers of both sexes in the United States. Although the data on humans are not definitive, causal associations appear to exist between occupational exposures to some hydrocarbon solvents and chronic kidney disease, and there is preliminary evidence that suggests an association between organic chemical exposures and cancers of the urinary tract in humans. A review of more than 230 chemicals tested in two-year chronic toxicity studies by the National Toxicology Program (NTP)/National Cancer Institute (NCI) has identified two chemical classes that commonly produced nonneoplastic chronic renal disease in rodents: aromatic amines and organohalides. Tumors of the kidney were most frequently produced by alkyl or alkenyl halide compounds, while tumors of the bladder were caused by aromatic amines. Consistent with many literature reports, short-chain halogenated hydrocarbons appeared to have a propensity for causing a low incidence of renal tubular carcinoma in exposed rodents. Comparative analyses of the NTP/NCI studies did not indicate consistent sex or species differences in the nonneoplastic chronic toxic response, but chemically induced urinary tract cancers occurred more commonly in rats than in mice, and chemically induced cancers of the kidney occurred more commonly in males than in females. Viewed collectively, these data indicate a potential for organic chemicals, especially halogenated hydrocarbons and aromatic amines, to produce chronic kidney injury in humans and other mammalian species.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between bromobenzene dose, glutathione concentrations, and organ toxicities in single- and multiple-treatment studies.

A single oral dose of 4.0 mmol/kg bromobenzene transiently depleted hepatic and renal reduced nonprotein sulfhydryl group (NPS) concentrations, caused hepatocellular necrosis, and increased serum glutamic-pyruvic transaminase activity in male Fischer 344 rats. The depletion of NPS had partially reversed by 24 hr, and NPS concentrations were approximately twice normal values by 48 hr post-treatment. When the effects of single and repeated (once daily for 2, 4, or 10 days) treatments with 4.0 mmol/kg were compared, it was apparent that the severity of hepatotoxicity lessened and the percentage depletions of hepatic and renal NPS concentrations decreased with increasing length of bromobenzene treatment. There were essentially no signs of toxicity following the tenth treatment with 4.0 mmol/kg. Single-treatment studies indicated the following dose-response: 2.0 mmol/kg bromobenzene depleted liver NPS and was hepatotoxic, 0.5 mmol/kg caused a lesser depletion of liver NPS and was not (overtly) hepatotoxic, and 0.0625 mmol/kg was the maximum dose that did not deplete liver NPS. The responses to single and multiple (ten) treatments with these representative doses were compared. Liver injury was observed after a single but not after the tenth daily treatment with 2.0 mmol/kg. Both the single and the tenth administrations of 2.0 mmol/kg depleted hepatic NPS, but the percentage of depletion was greater after the first than after the tenth dose. Liver injury was not detected with lower dose regimens. The patterns of NPS depletion in liver and kidney were similar after single or multiple (ten) treatments. The minimum NPS concentrations produced, however, were lower after single than after multiple treatments. The molar amounts of liver NPS depleted after the tenth treatment appeared to be equivalent to or greater than those after the first, but prior bromobenzene exposure resulted in a higher concentration of tissue NPS being present at the time of the final treatment. Thus, the minimum tissue concentrations of NPS were greater after multiple treatments than after single treatments, despite the loss of equivalent amounts of NPS. It is concluded from these studies that repeated treatment produces resistance to bromobenzene hepatotoxicity. This protective adaptation may be due to a chemically induced increase in liver glutathione concentration.

Toxicity of hexachlorocyclopentadiene: subchronic (13-week) administration by gavage to F344 rats and B6C3F1 mice.

A 13-week subchronic study was conducted by administering hexachlorocyclopentadiene ( HCCP ) in corn oil by gavage to groups of ten male and ten female F344 rats at doses of 150, 75, 38, 19, 10 or 0 mg kg-1, and to groups of ten male and ten female B6C3F1 mice at doses of 300, 150, 75, 38, 19 or 0 mg kg-1. The doses were administered once a day, five days per week for 13 weeks. Chemically induced deaths occurred at 150 and 300 mg kg-1 in rats and at 300 mg kg-1 in mice. A significant (P less than 0.05) depression in mean body-weight change relative to controls was observed in male and female rats receiving greater than or equal to 38 and greater than or equal to 75 mg kg-1, respectively, and in male and female mice receiving 150 and 300 mg kg-1, respectively. There was a significant (P less than 0.05) increase in liver and kidney weight: brain weight ratios in the high-dose female rats (75 and 150 mg kg-1) and female mice at all doses (19-300 mg kg-1). HCCP caused proliferative and inflammatory changes of the epithelia in the forestomach of male rats, and male and female mice receiving greater than or equal to 38 mg kg-1 and in female rats receiving greater than or equal to 19 mg kg dose level. Nephrosis characterized by proximal tubular dilation, cytoplasmic vacuolization, cytomegaly, karyomegaly and anisokaryosis occurred in male and female rats and female mice receiving greater than or equal to 38 mg kg-1.