* National Institute of Environmental Health Sciences, 111 Alexander Drive, P.O. Box 12233, Research Triangle Park, North Carolina 27709; and
Battelle Laboratories, Columbus, Ohio 432012693
Received September 7, 2000; accepted November 27, 2000
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ABSTRACT |
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Key Words: p,p'-dichlorodiphenyl sulfone; liver toxicity; kidney toxicity; centrilobular hepatic hypertrophy; p,p'-dichlorodiphenyl sulfone carcinogenicity.
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INTRODUCTION |
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Although human exposure can be anticipated to occur mainly in the workplace, recent studies of environmental samples suggest the potential for more widespread exposure. No information is available on DDS regarding workplace exposure concentrations or the number of workers potentially exposed to this compound. However, DDS has been identified in human liver samples from Germany at concentrations ranging from 1.5 to 39 ng/g lipids (Ellerichmann et al., 1998). In addition, DDS has been detected in lakes in northern Italy, effluents from industrial sites in the Mediterranean, and in the river Elbe, although no concentrations were reported (Guzzella and Sora, 1998
; Müller et al., 1997
; Swindlehurst et al., 1995
). In perch (Perca fluviatilis) collected from the Gulf of Riga area along the Latvian coast in 1997, DDS concentrations ranged from 53 to 160 ng/g lipid weight (Valters et al., 1999
). The annual production volume of DDS in the United States was estimated to be between 0.1 and 20 million pounds in 1990 (U. S. EPA, 1991
).
DDS, a structural analogue of DDT, was selected by the National Toxicology Program for toxicity characterization and carcinogenicity evaluation based on its current high production volume and use, prospects for increased use and production in the future, and the potential for more widespread human exposure. Fourteen-week and two-year studies were performed by administering DDS in the diets of male and female F344/N rats and B6C3F1 mice. The details of these studies have been reported in a technical report (NTP 2000). Major findings from those studies are presented here.
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MATERIALS AND METHODS |
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DDS was stable as a bulk chemical for at least 14 days when stored in sealed vials with Teflon® septa and no headspace at temperatures up to 62°C. To ensure stability, the bulk chemical was stored at room temperature in amber glass bottles. Stability was monitored throughout the studies using HPLC. No degradation of the bulk chemical was detected. Periodic analyses of the dose formulations of DDS were conducted using HPLC.
Animals.
Male and female F344/N rats and B6C3F1 mice were obtained from Taconic Laboratory Animals and Services (Germantown, NY). On receipt, the rats and mice were approximately 6 weeks old. Animals were quarantined for 11 to 15 days and were approximately 8 weeks old on the first day of the studies. Before the studies began, 5 male and 5 female rats and mice were randomly selected for parasite evaluation and gross observation for evidence of disease. All tests for viral titers in sera from rats and mice were negative. Food (NIH-07 for 14-week studies and NTP 2000 meal diet for 2-year studies) and tap water were available ad libitum. Rats and female mice were housed 5 per cage; male mice were housed individually. In 2-year studies, rats were housed 2 or 3 (males) or 5 (females) per cage and mice were housed 1 (males) or 5 (females) per cage. Cages were changed twice weekly for group-housed animals and at least once weekly for individually housed animals; cages and racks were rotated once every two weeks.
Fourteen-week toxicity studies.
Groups of 10 male and 10 female rats and mice were fed diets containing 0, 30, 100, 300, 1000, or 3000 ppm DDS for 14 weeks. Food and water were available ad libitum. Clinical findings were recorded and animals were weighed weekly and at the end of the study. Feed consumption was recorded weekly.
Neurobehavioral evaluations were conducted during week 12 on groups of male and female rats and male mice exposed to 0, 100, 300, or 1000 ppm and groups of female mice exposed to 0, 300, 1000, or 3000 ppm. Body weight was recorded, as well as functional observations, to assess autonomic, convulsive, excitability, neuromuscular, sensorimotor, and general motor activity domains, according to the procedures described by Moser et al. (1997).
At the end of the 14-week studies, blood samples were collected from the retro-orbital sinuses of all animals under carbon dioxide anesthesia. Blood samples were collected for hematology and clinical chemistry analyses for rats and hematology analyses for mice. Blood samples for hematology analyses were placed in micro-collection tubes containing potassium EDTA (Sarstedt, Inc., Nümbrecht, Germany). Blood for clinical chemistry evaluations was placed in tubes devoid of anticoagulant, allowed to clot at room temperature, and centrifuged, and the serum was separated. Erythrocyte, platelet, and leukocyte counts; hematocrit; hemoglobin concentration; mean cell volume (MCV); mean cell hemoglobin (MCH); and mean cell hemoglobin concentration (MCHC) were determined using a Serono-Baker System 9000® hematology analyzer (Serono-Baker Diagnostics, Allentown, PA). Differential leukocyte counts and erythrocyte morphology were determined microscopically from blood smears stained with a modified Wright-Giemsa stain on a Hema-Tek® slide stainer (Miles Laboratory, Ames Division, Elkhart, IN). Smears made from whole blood samples incubated with new methylene blue were examined microscopically for the quantitative determination of reticulocytes. Clinical chemistry variables were measured using a Hitachi 704 chemistry analyzer (Boehringer Mannheim, Indianapolis, IN) using commercially available reagents. Endpoints included urea nitrogen, creatinine, total protein, albumin, alanine aminotransferase, alkaline phosphate, sorbitol dehydrogenase, creatine kinase and total bile acids.
Necropsy was performed on all animals. The heart, right kidney, liver, ovary, right testis, thymus, and uterus were weighed. Tissues for microscopic examination were fixed and preserved in 10% neutral-buffered formalin, processed, embedded in paraffin, sectioned to a thickness of 4 to 6 µm, and stained with hematoxylin and eosin. A complete histopathologic examination was performed on all 0 and 3000 ppm DDS-treated rats and mice. In addition, target tissues were examined in animals in all groups.
Two-year carcinogenicity studies.
Groups of 50 male and 50 female rats and mice were fed diets containing 0, 10 (male rats only), 30, 100, or 300 (female rats only) ppm DDS for 104 to 105 weeks.
Feed consumption was measured by cage once every 4 weeks. All animals were observed twice a day for morbidity and mortality. Clinical findings were recorded monthly. Animals were weighed initially, weekly for the first 13 weeks, monthly thereafter, and at study termination. All study animals were killed by carbon dioxide asphyxiation and received a complete necropsy and microscopic examination. At necropsy, all organs and tissues were examined for grossly visible lesions. Tissue samples were embedded in paraffin, sectioned to a thickness of 5 to 6 µm, and stained with hematoxylin and eosin.
All studies were conducted at Battelle Columbus Laboratories, Columbus, Ohio, accredited by the American Association for the Accreditation of Laboratory Animal Care (AAALAC, Rockville, MD). Institutional Animal Use and Care Committees approved the experimental protocols. Animal use was in accordance with the United States Public Health Service policy on humane care and use of laboratory animals and the Guide for the Care and Use of Laboratory Animals.
Statistical methods.
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958). Statistical analyses for possible dose-related effects on survival used Cox's method (Cox, 1972) for testing 2 groups for equality, and Tarone's life-table test to identify dose-related trends. Dunnett's test (Dunnett, 1955
) was used to analyze body weight data and Williams's test (Williams, 1972
) for organ weight data. The Poly-3 test (Bailer and Portier, 1988
; Portier and Bailer, 1989
) was used to assess neoplasms and nonneoplastic lesion prevalence.
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RESULTS |
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There was evidence of a minimal treatment-related effect on the erythron (Table 2). Alteration of the erythron was demonstrated by minimal decreases in the hemoglobin concentrations in the 1000 and 3000 ppm male and female rats; and erythrocyte counts in the 1000 ppm male group. Decreases in mean cell volume (1000 and 3000 ppm females) and mean cell hemoglobin and mean cell hemoglobin concentration (300 and 1000 ppm females and 3000 ppm males and females) provided additional evidence suggestive of treatment-related erythropoietic effect. Also, reticulocyte counts were minimally increased in 3000 ppm males. Minimal to mild increases in platelet counts occurred in the 1000 and 3000 ppm males and females.
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Liver weights of male and female rats exposed to 100 ppm or greater were significantly increased in a dose-related fashion, compared to the controls (Table 3). Kidney and testis weights of 1000 and 3000 ppm male rats were also significantly greater than those of the controls. The thymus weights of male rats exposed to 300 ppm or greater were significantly less when compared to controls.
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Based on lower final mean body weights, organ weight changes, and increased incidence and/or severity of centrilobular hypertrophy in the liver, and renal nephropathy at the higher dietary concentration, in the 14-week studies, p,p'-dichlorodiphenyl sulfone exposure concentrations selected for the 2-year feed study in rats were 10, 30, and 100 ppm for males, and 30, 100, and 300 ppm for females.
Two-year carcinogenicity studies.
Survival of all exposed groups of male and female rats was similar to that of the control groups. Mean body weights of 30 and 100 ppm male rats were generally less than those of the controls from week 66 through the end of the study; mean body weights of 300 ppm female rats were less than those of the controls from week 18; mean body weights of females exposed to 100 ppm were also less after week 30. All treatment groups remained within 10% of the control, except for the female 300 ppm group, which decreased as much as 14% during the study. Feed consumption by the exposed groups was similar to that by the controls throughout the study. Dietary concentrations of 10, 30, and 100 ppm resulted in an average daily exposure of approximately 0.5, 1.5, and 5.0 mg DDS/kg/day to males. Dietary concentrations of 30, 100, and 300 ppm resulted in average daily doses of approximately 1.6, 5.4, and 17 mg/kg/day to females. There were no clinical findings attributed to DDS exposure.
The incidence of several nonneoplastic lesions of the liver in exposed groups were significantly increased compared to those in the control groups (Table 5). The incidences of centrilobular hepatocyte hypertrophy were increased in 100 ppm males and 100 and 300 ppm females. The incidences of bile duct hyperplasia and centrilobular degeneration were significantly increased in 100 and 300 ppm females. Hepatocyte hypertrophy was a minimal to mild change characterized by increased size of the centrilobular hepatocytes compared to those of the concurrent controls and to the affected animals' midzonal or periportal hepatocytes. Hypertrophic hepatocytes also had decreased staining intensity due to fine cytoplasmic vacuolization. Bile duct hyperplasia was of minimal severity and consisted of increased bile duct profiles within the portal areas. Centrilobular degeneration was a minimal to mild change observed only in those animals that had mononuclear cell leukemia in the liver and was most likely a manifestation of anoxia due to large numbers of mononuclear leukemic cells infiltrating the centrilobular sinusoids.
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A minimal to mild increase in platelet counts occurred in all exposed groups of males and in 1000 and 3000 ppm females. There was evidence of a minimal decrease in the erythron of the female mice. This was demonstrated by minimal decreases in the erythrocyte counts in 1000 and 3000 ppm females and a minimal decrease in hematocrit values in the 3000 ppm group. The red cell indices (mean cell volume, hemoglobin, and hemoglobin concentration) for the affected female mice demonstrated minimal increases. In general, the altered values for the erythron and red cell indices were within physiological ranges and the severity of these alterations were so minimal that they were not considered biologically significant (data not shown).
Liver weights of male and female mice exposed to 300 ppm or greater were significantly increased compared to the controls (Table 7).
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Based on lower mean body weights, increased liver weights, as well as incidences and severity of hepatocellular lesions in mice exposed to 1000 or 3000 ppm, DDS exposure concentrations selected for the 2-year feed study in mice were 30, 100, and 300 ppm.
Two-year carcinogenicity studies.
Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weight of 300 ppm mice was less than in the controls throughout most of the study. The mean body weight of mice in the 30 and 100 ppm groups was generally similar to that of the controls. Feed consumption did not differ from that of the controls throughout the study. Dietary concentrations of 30, 100, and 300 ppm delivered average daily exposure of approximately 3.8, 13, and 40 mg/kg/day to males and approximately 2.8, 10, and 33 mg/kg/day to females. There were no clinical findings attributed to DDS exposure.
The incidence of centrilobular hepatocyte hypertrophy in all exposed groups of males and in 100 and 300 ppm females was significantly greater than that in the controls, and the severity increased with increasing exposure concentration (Table 8). Hepatocyte hypertrophy in mice was morphologically similar to that observed in rats. The incidence of eosinophilic foci in 300 ppm females was significantly increased.
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DISCUSSION |
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In the 14-week toxicity studies, there were no exposure-related deaths or clinical signs of toxicity related to DDS in rats or mice. Although some exposure concentrations appeared unpalatable during the first week, feed consumption was similar to controls during the remainder of the studies.
The liver was the primary organ affected by exposure to DDS in rats and mice. Rats exposed to 100 ppm or greater had exposure concentration-dependent increases in liver weights, up to twice that of the control groups. Also, groups exposed to 100 ppm or greater generally had centrilobular hypertrophy. The severity of this lesion increased in an exposure-related manner. Changes in sorbitol dehydrogenase activity and bile acid concentrations were consistent with the liver lesions observed histopathologically in rats. There were species and gender differences in the susceptibility of animals to DDS-induced liver effects. The liver effects in female rats were seen at greater exposure concentrations and were less severe than those in males. Although the patterns of liver toxicity, expressed as increases in liver weights accompanied by centrilobular hypertrophy, were similar in rats and mice, mice were less sensitive to these effects. Mice required higher exposure concentrations on a body weight basis to display liver effects similar to those in rats (6 to 200 mg/kg in rats versus 15 to 480 mg/kg in male mice and 165 to 480 mg/kg in female mice). These variations could be due to sex and species differences in the metabolism and disposition of DDS. For example, mice have a higher rate of chemical metabolism by the mixed-function oxidase system than rats (Parke and Ioannides, 1990).
The increased incidences of hepatocellular hypertrophy and increased liver weights seen in the current studies were most likely due to induction of drug metabolizing enzymes by DDS. In a 4-week study using male Sprague-Dawley rats, DDS increased the hepatic microsomal activities of benzyloxyresorufin-O-dealkylase (BROD) and pentoxyresorufin-O-dealkylase (PROD) that were induced by DDS 67- and 25-fold, respectively, when compared to controls. These changes were accompanied by hepatomegaly. Hepatic UDP-glucuronyltransferase and glutathione S-transferase activities were also induced (Poon et al., 1999). BROD and PROD are markers for cytochrome P4502B catalytic activity (Lubet et al., 1989
). The characteristics of hepatic microsomal enzyme and cytochrome P450 induction by DDS resemble phenobarbitone-type inducers, including organohalogen pesticides such as DDT. Treatment of animals with phenobarbitone-type inducers results in marked hepatic hypertrophy, increased concentration of microsomal protein, and proliferation of the smooth endoplasmic reticulum. These changes which predominantly occur in the centrilobular region of the liver are accompanied by increases in protein and phospholipid synthesis and selected cytochrome P450 isozymes. The net effect of these changes is increased biotransformation of foreign and endogenous substances. Induction of specific cytochrome P450 isozymes by phenobarbitone-type compounds is most likely regulated at the transcriptional level and involves an increase in the mRNAs encoding these enzymes (Sipes and Gandolfi, 1986
). Many hepatic cytochrome P450 inducers of the phenobarbitone type (CYP2B1) have been shown to act as nongenotoxic rodent hepatocarcinogens and/or tumor promoters. The phenobarbitone-type inducers include a diverse group of chemical classes such as chlorinated hydrocarbon pesticides, polyhalogenated biphenyls, hypolipidemic peroxisome proliferating agents, and certain steroids (Lubet et al., 1989
).
DDT and its metabolites are lipid soluble. Once absorbed, they are readily distributed to all the tissues and stored preferentially in tissues with a high lipid content. The central nervous system, liver, and reproductive systems are major sites of DDT toxicity. Acute oral exposure to DDT has been associated with tremors, hyperexcitability, and convulsions in several species. Oral administration of DDT causes liver cell tumors including carcinomas in rodents. According to the International Agency for Research on Cancer (IARC), DDT is possibly carcinogenic in humans. DDT impairs reproduction and/or development in mice, rats, rabbits, dogs, and avian species, is nonmutagenic in bacterial or mammalian test systems, and inhibits cellcell communication (ATSDR, 1994; Flodström et al., 1990
; IARC, 1991
).
DDS, like DDT, is highly lipid-soluble, slowly metabolized, and distributed mainly throughout the adipose tissue as the parent compound with an estimated half-life of 12 days in this compartment (Mathews et al., 1996). Although some DDS is eliminated unchanged in the feces and urine, most of its elimination is via metabolism. Mathematical modeling of the toxicokinetics supports the view that DDS induces enzymes involved in its metabolism (NTP 2000
). Unlike DDT, DDS is minimally toxic to the liver and central nervous system. Specifically, the liver effects seen in the current studies were limited to hypertrophy (possibly a secondary response to induction of the drug metabolizing enzymes); and central nervous system toxicity was not observed (because neither clinical signs of toxicity nor neurobehavioral alterations were seen).
In the current 2-year studies, there were no increases in the incidences of neoplasms in the liver or any other organ in rats or mice, that was related to DDS exposure, nor were there any liver changes indicative of overt toxicity in exposed animals. As seen in the 14-week studies, liver effects were mostly limited to hepatocyte hypertrophy. Increased incidences of hepatocyte hypertrophy were seen in 30 ppm male rats, 300 ppm female rats, 100 ppm rats, and 100 and 300 ppm mice. Hepatocyte hypertrophy was a minimal to mild change, characterized by increased size of centrilobular hepatocytes compared to those of the controls and to the affected animal's midzonal or periportal hepatocytes. In contrast, centrilobular degenerative changes were seen only in 100 and 300 ppm female rats. Overall, these results suggest that even though DDS is structurally related to DDT and has some common physical and biochemical properties, it is minimally toxic to rodents. This dissimilarity in toxicity could be attributed to the structural differences between the compounds. Bridged diphenyl acaricides, which are structurally similar to DDT, are generally several-fold less toxic than DDT (March, 1976). The sulfonyl compound, tetradifon (2,4,5,4-tetrachlorodiphenyl sulfone), used as an acaricide, has a similar pattern of minimal liver effects to that seen for DDS (WHO, 1986
). Furthermore, the sulfonated derivatives of DDT were much less toxic to Mallard ducks during egg production when compared to the parent compound, suggesting sulfonation reduces the toxicity of DDT (Kolaja, 1977
). Accordingly, it seems the sulfone moiety in the DDS structure mitigates the expected toxic effects of this organohalogen compound.
Induction of drug metabolizing enzymes is a reversible event, and withdrawal of an inducing agent returns enzymatic activity to basal levels (Sipes and Gandolfi, 1986). However, highly lipophilic-inducing agents such as DDT and DDS may be retained in the body and lead to prolonged induction because of their continued presence. In most instances, liver enlargement in the absence of pathological changes (such as degenerative lesions, cell proliferation, and necrosis) is considered to be an adaptation to increased function load and thus a physiological rather than toxicological response (Amacher et al., 1998
). However, adverse effects may possibly arise from increased mixed-function oxidase activities that cause altered sensitivities toward hepatotoxins or carcinogens (Parke and Ioannides, 1990
; Schulte-Hermann, 1974
). Based on the results of the current 14-week and 2-year studies, a no-observed-adverse-effect level (NOAEL) of 30 ppm (1.5 mg/kg) in rats is suggested for both short- and long-term exposures.
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NOTES |
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REFERENCES |
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Amacher, D. E., Schomaker, S. J., and Burkhardt, J. E. (1998). The relationship among microsomal enzyme induction, liver weight, and histological change in rat toxicology studies. Food Chem. Toxicol. 36, 831839.[ISI][Medline]
Bailer, A. J., and Portier, C. J. (1988). Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples. Biometrics 44, 417431.[ISI][Medline]
Cox, D. R. (1972). Regression models and life-tables. J. R. Stat. Soc. B34, 187220.[ISI]
Dunnett, C. W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Am. Stat. Assoc. 50, 10961121.[ISI]
Ellerichmann, T., Bergman, Å., Franke, S., Hühnerfuss, H., Jakobsson, E., König, W.A., and Larsson, C. (1998). Gas chromatographic enantiomer separations of chiral PCB methyl sulfons and identification of selectively retained enantiomers in human liver. Fresenius Environ. Bull. 7, 244257.[ISI]
U.S. EPA (1991). Twenty-seventh report of the interagency testing committee to the administrator; receipt of report and request for comments regarding priority list of chemicals. Fed. Regist. 56, pp. 95349572.
Flodström, S., Hemming, H., Wärngård, L., and Ahlborg, U. G. (1990). Promotion of altered hepatic foci development in rat liver, cytochrome P450 enzyme induction, and inhibition of cellcell communication by DDT and some structurally related organhalogen pesticides. Carcinogenesis 11, 14131417.[Abstract]
Garty, O. M., Lewis, J. W., and Brydia, L. E. (1974). Characterization of 4,4'-dichlorodiphenyl sulfate impurities by gas chromatography and mass spectrometry. Anal. Chem. 46, 815820.[ISI]
Guzzella, L., and Sora, S. (1998). Mutagenic activity of lake-water samples used as drinking water resources in northern Italy. Water Res. 32, 17331742.[ISI]
Haglund, P., Leander, O., and Zook, D. (1998). Analysis of the recently detected environmental contaminant bis-(4-chlorophenyl) sulfone in temperature-resistant polymers. Organohal. Compounds 35, 427429.
Harnagea, F., and Badilescu, S. (1965). Infrared spectrophotometric determination of N, N-di-n-butyl-p-chlorobenzenesulfonamide and p-chlorobenzenesulfonyl chloride in the presence of bis (p-chlorophenyl) sulfone. Rev. Chim. 16, 599600.
IARC (1991). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Occupational Exposure in Insecticide Application and Some Pesticides, Vol. 53, pp. 179250. International Agency for Research on Cancer, Lyon, France.
Kaplan, E. L., and Meier, P. (1958). Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457481.[ISI]
Kolaja, G. J. (1977). The effects of DDT, DDE, and their sulfonated derivatives on eggshell formation in the Mallard duck. Bull. Environ. Contam. Toxicol. 17, 697701.[ISI][Medline]
Lubet, R. A., Nims, R. W., Ward, J. M., Rice, J. M., and Diwan, B. A. (1989). Induction of cytochrome P450b and its relationship to liver tumor promotion. J. Am. Coll. Toxicol. 8, 259268.[ISI]
March, R. B. (1976). Properties and actions of bridged diphenyl acaricides. Environ. Health Perspect. 14, 8391.[ISI][Medline]
Mathews, J. M., Black, S. L., and Matthews, H. B. (1996). p, p'-Dichlorodiphenyl sulfone metabolism and disposition in rats. Drug Metab. Dispos. 24, 579587.[Abstract]
Misra, G. S., and Asthana, R. S. (1957). Substituted sulphones and sulphonamides and their cyanoethylation products as insecticides. J. Prakt. Chem. 4, 270277.[ISI]
Moser, V. C., Tilson, H. A., MacPhail, R. C., Becking, G. C., Cuomo, V., Frantík, E., Kulig, B. M., and Winneke, G. (1997). The IPCS collaborative study on neurobehavioral screening methods: II. Protocol design and testing procedures. Neurotoxicology 18, 929938.[ISI][Medline]
Müller, S., Efer, J., and Engewald, W. (1997). Water pollution screening by large-volume injection of aqueous samples and application to GC/MS analysis of a river Elbe sample. Fresenius J. Anal. Chem. 357, 558560.[ISI]
NTP (2000). Toxicology and Carcinogenesis Studies of p, p'-Dichlorodiphenyl Sulfone in F344/N Rats and B6C3F1 Mice. National Toxicology Program, NTP TR 501, NIH Publication No. 004435, DHHS.
Olsson, A., and Bergman, Å. (1995). A new persistent contaminant detected in Baltic wildlife: Bis (4-chlorophenyl) sulfone. Ambio 24, 119123.[ISI]
Parke, D. V., and Ioannides, C. (1990). Role of cytochromes P-450 in mouse liver tumor production. Prog. Clin. Biol. Res. 331, 215230.[Medline]
Poon, R., Lecavalier, P., Chu, I., Yagminas, A., Nadeau, B., Bergman, Å., and Larsson, C. (1999). Effects of bis (4-chlorophenyl) on rats following 28-day dietary exposure. J. Toxicol. Environ. Health 56, 185198.
Portier, C. J., and Bailer, A. J. (1989). Testing for increased carcinogenicity using a survival-adjusted quantal response test. Fundam. Appl. Toxicol. 12, 731737.[ISI][Medline]
Schulte-Hermann, R. (1974). Induction of liver growth by xenobiotic compounds and other stimuli. CRC Rev. Toxicol. 3, 97158.
Sipes, I. G., and Gandolfi, A. J. (1986). Biotransformation of toxicants. In Casarett and Doull's Toxicology (L. J. Casarett, Jr., J. Doull, C. D. Klaassen, and M. O. Amdur, Eds.), 3rd ed., pp. 6498. Macmillan, New York.
Swindlehurst, R. J., Johnston, P. A., Tröndle, S., Stringer, R. L., Stephenson, A. D., and Stone, I. M. (1995). Regulation of toxic chemicals in the Mediterranean: The need for an adequate strategy. Sci. Total Environ. 171, 243264.[ISI]
Tarone, R. E. (1975). Tests for trend in life table analysis. Biometrika 62, 679682.[ISI]
Valters, K., Olsson, A., Vitinsh, M., and Bergman, Å. (1999). Contamination sources in Latvia: Levels of organochlorines in perch (Perca fluviatilis) from rivers Daugava and Lielupe. Ambio 28, 335340.[ISI]
Williams, D. A. (1972). The comparison of several dose levels with a zero dose control. Biometrics 28, 519531.[ISI][Medline]
WHO (1986). Tetradifon. Environmental Health Criteria 67. World Health Organization, Geneva.