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There has been much concern recently about possible adverse health effects related to exposure to toxic chemicals among residents of Kanawha County in southern West Virginia. An epidemiological study of trends in cancer mortality from 1950-1984 among the general population of Kanawha County in southern West Virginia was mounted. Cabell County, West Virginia was chosen to be a comparison county for Kanawha in addition to West Virginia and the total United States. The cancer mortality rates for white males and females were calculated using NCHS mortality data and Census Bureau population data available on the Mortality and Population Data System (MPDS) at the University of Pittsburgh. Mortality rates for cancer in Kanawha and Cabell Counties were evaluated over the time period 1950-1984 with an age-period-cohort (APC) analysis. In this analysis, poisson regression models were fit using the statistical program GLIM (Generalized Linear Models) to determine the separate effects of age, period of death, and birth cohort on the specific cancers of interest (lung, liver, bladder, CNS, leukemia, lympho-reticulosarcoma, all cancers). There were no significant county differences for cancer death rates between Kanawha and Cabell Counties except for leukemia among white males [O.R. = 1.27, 95% (C.I. = 1.03-1.6)], and for lympho-reticulosarcoma [O.R. = 1.66(1.24-2.07)], suggesting a possible occupational exposure. For leukemia, aleukemia, the effect observed seems to have declined. In contrast, the elevation of lympho-reticulosarcoma rates has remained in recent years (1970-1984).

We describe 2 Caucasian men with rheumatoid arthritis (RA) who developed non-Hodgkin's lymphoma of identical histological type during treatment with low dose oral weekly methotrexate (MTX). Both patients had longstanding RA and had been treated with MTX for over 2 years at time of tumor diagnosis; neither had secondary Sjögren's syndrome. The oncogenic potential of MTX and RA arthritis is reviewed.

A 20-year-old man with heavy exposure to upholsterers' glue presented with life-threatening acute myocarditis, and then rapidly developed acute hepatic necrosis and acute renal failure. He made a rapid and complete recovery from this florid acute illness, only to present three months later with supradiaphragmatic non-Hodgkin's lymphoma. These illnesses have all been described in association with solvent exposure. The unique feature of this case is the occurrence of multiple manifestations which might be attributed to solvent exposure, both acute and chronic, in the same individual.

2,6-Dichlorobenzonitrile (Dichlobenil) is the active principle of a commercial herbicide that was previously shown to be carcinogenic for animals. Dichlobenil was administered to male Swiss albino mice in order to assess the possible oncogenic properties of the active principle alone. The substance at 2 ppm concentration was injected (0.0005 mg/injection) either by subcutaneous or intraperitoneal route to 2 randomized groups of 30 animals each every third day for 13 times. Dichlobenil induced a significant increase of malignant tumors (lymphoma, mesothelioma, hepatocellular carcinoma, and pulmonary alveologenic carcinoma) with respect to the controls (p less than 0.01 in both treated groups). As for tumor histotypes, only lymphoma incidence was significantly increased in the intraperitoneally treated animals (p less than 0.05). Dichlobenil can be suspected of being a possible carcinogen in Swiss mice but the mechanism of its action is not precisely known.

Oil lumps collected on the beaches of Israel in 1970, 1971 and 1973 were extracted with pure acetone and the extracts were used to paint the skin of mice twice weekly for 12 months. The oil lumps originated from crude oil spilled from tankers. The less recently collected oils induced papillomata and lymphomata in some animals. They were also more active than the recent oil in the induction of generalized amyloidosis. Mice painted for 12 months with acetone alone developed amyloidosis to a similar extent as those painted with the oldest oil. In previously reported experiments, however, acetone was much less active than the oil in producing amyloidosis after 5 months of painting. The possibility that acetone and oil might act both synergistically or to be antagonistic at different phases of amyloidogenesis is discussed.

Human myeloid leukemia cell lines ML-1, ML-2, ML-3, promyelocytic leukemia cell line HL-60 and histiocytic lymphoma cell line U-937 were induced to differentiate by 0.5-10 ng/ml (0.8-16 nM) 12-O-tetradecanoylphorbol-13-acetate (TPA). After 48-72 h of induction, changes of the morphology, cytochemistry and of the antigenic phenotype of induced and control cells were studied using a panel of monoclonal antibodies against granulocytic, monocytic, HLA-ABC and HLA-DR antigens in indirect immunofluorescence. Cells of the TPA-treated cultures acquired morphological, cytochemical and antigenic markers of monocytes/macrophages, as surface adherence, alpha-naphthyl acetate esterase (alpha-NE) and acid phosphatase activity and the expression of monocytic antigens detected with monoclonal antibodies 63D3, FMC 17, B 44.1, B 52.1 and anti-Mol. During differentiation in vitro induced by TPA, also loss of HLA-DR antigens and diminution of antigen of cell activation were detected with antibodies L 243 and 4F2. The expression of granulocytic antigens was only slightly diminished and the expression of HLA-ABC antigens was not changed by TPA-treatment. There were differences in the percentage of cells induced to differentiate among the lines of different origin and even among the lines ML-1, ML-2 and ML-3, established from a single patient with acute myeloid leukemia. After treatment of cultures with 5 ng/ml TPA for 72 h DNA synthesis was inhibited to 60-80%.

The enhancement or delay in the appearance of spontaneous reticulum cell neoplasms (RCN-B) in SJL/J mice was tested. Immunosuppressive treatment with antithymocyte serum and prolonged antigenic stimulation by repeated injections of sheep erythrocytes, leukemogenic cell-free centrifugates, and multichain synthetic polypeptides had no effect on the incidence or latency of spontaneous tumor appearance. Treatment with mineral oil or incomplete Freund adjuvant markedly enhanced tumor appearance (though the abundance of plasma cells induced by these treatments did not evoke the development of plasmacytomas, nor did it affect the incidence of serum paraproteinemia among mice with spontaneous tumors). Treatment with cortisone acetate, however, markedly retarded spontaneous tumor development. Tumors occurring early due to mineral oil and adjuvant treatment all had the characteristics of "RCN-B plasma cell type," and tumors occurring late due to cortisone treatment were all of the "RCN-B reticulum cell type." The possible involvement of the stem cell pool size in the enhancement or delay of spontaneous tumor development was discussed.

Although benzidine is recognized as a bladder carcinogen in humans and a liver carcinogen in laboratory animals, its toxicological effects appear to be extended to several other endpoints. This economically important chemical is the base for over 200 dyes and is used extensively in manufacturing. In a chronic lifespan study lasting 33 months, both sexes of F1 hybrid (genetically homogeneous) and monohybrid cross (genetically heterogeneous) mice from BALB/c male and C57BL/6 female crosses were exposed to benzidine dihydrochloride in their drinking water at concentrations of 0, 20, 30, 40, 60, 80, and 120 ppm for the females, and 0, 30, 40, 60, 80, 120, and 160 ppm for males. Animals were removed from the study when they were dead or moribund. In addition to hepatocellular carcinomas, there were several other toxicological end-points identified that appeared to be related to the administration of benzidine. Dose-response trends were noted for pigmentation of the spleen, hepatic cytological alterations, hyperplasia of the bile ducts, megakaryocytosis of the bone marrow, vacuolization of the brain, adenoma of the Harderian gland, atrophy of the ovaries, and angioma of the uterus. Also, dose-related effects were noted with respect to time to lung tumor and time to mortality due to reticulum-cell sarcomas.

We report a case of isolated malignant lymphoma of the jejunum occurring 18 18 months after continuous diphenylhydantoin therapy for epilepsy. Although this association may be purely coincidental, we suggest a possible causal relationship between the two in light of current knowledge about the immunological aberrations that may be caused by prolonged administration of diphenylhydantoin in man.

A comparative study was done in mice on the effects of silica and olivine inhalation. The exposure periods in the dust chambers were for periods of 150, 300, and 570 days, with the longest time period covering a large portion of the predicted life span of the Balb/c mouse. Detailed necropsies including histology were done at the end of the exposures and at 30 and 150 days following removal of animals from the 150- and 300-day dust exposures. The results indicate that silica causes considerably more tissue damage in lungs and mediastinal lymph nodes, leading to granulomas.

Prolonged immunosuppressive therapy with cyclophosphamide increases the prevalence of neoplasms in NZB/NZW mice, an animal model of systemic lupus erythematosus. The current study was designed to compare the oncogenic properties of high dose cyclophosphamide with a low dose therapeutic regimen. Female NZB/NZW mice received life-long therapy with "high dose" cyclophosphamide, 16 mg/kg/day, or "low-dose" cyclophosphamide, 5.7 mg/kg/day; control mice received saline. High dose therapy clearly accelerated appearance of neoplasms. Seventeen of 19 mice treated with high-dose cyclophosphamide developed neoplasms at the mean age of 61 weeks. Fifty-seven percent of these tumors were mammary carcinomas. Neoplasms appeared in all mice treated with low dose; mean longevity in this treatment group was 80 weeks (compared to high dose treated mice, P less than 0.001). Carcinomas, pulmonary adenomas, and lymphomas were the most common tumors in mice receiving low dose therapy. Positive tests for ANA were suppressed in high dose treated mice. AntiDNA antibody levels and glomerulonephritis were decreased significantly in both groups of cyclophosphamide-treated mice compared to controls. It was concluded that the high daily dose of immunosuppressive drug was related to early oncogenesis in autoimmune NZB/NZW mice.

A middle-aged woman was treated for breast carcinoma with postoperative adjuvant chest wall irradiation, followed four and seven years later with therapy to spinal ports for palliation of metastatic disease. For the next three and a half years, she received oral cyclophosphamide on a daily basis to a total of more than 110 g. Twelve years after diagnosis and five years after the start of chemotherapy, an aggressive, large cell lymphoma of the ileum developed, with poor response to conventional therapy. This may represent the first patient with breast carcinoma in whom a treatment-induced non-Hodgkin's lymphoma has developed.

To assess the mortality experience of a cohort of chemical workers in the Kanawha Valley of West Virginia, 29,139 males who worked at any one of three facilities over a 39-year period were followed-up for vital status. The facilities include two chemical manufacturing plants and a research and development center. From this cohort, 5,785 men were found to have died as of the study end, December 31, 1978. This was less than the 6,148.5 men expected to have died, based upon the United States white male population (standardized mortality ratio (SMR) = 94, 95% confidence interval (CI) = 92-96). Eighty-six specific causes of death were examined. Statistically significant increased deaths were observed for two causes; cancers of the liver (not specified as primary or secondary) (SMR = 174; CI = 102-280) and lympho- and reticulosarcoma (SMR = 140; CI = 104-187). When all biliary and liver cancer was examined by duration and time since initial employment, the SMR for those who worked at least 25 years and whose deaths occurred 30 years or more after first employment was 301 (95% confidence limit = 168-497). The identification and follow-up of this complete cohort provides the basis for future study of subcohorts with specific chemical and process exposures and case control studies of specific causes of death.

Diffuse histiocytic lymphoma developed in a 48-year-old man with Wegener's granulomatosis after nine years of therapy with cyclophosphamide. He died despite aggressive surgical and medical therapy for the lymphoma. This may be the first report of diffuse histiocytic lymphoma following treatment of Wegener's granulomatosis with cyclophosphamide. Recommendations for the approach towards extended therapy of smoldering Wegener's granulomatosis are discussed.

Histiocytic lymphoma of the ileocecal region developed in a patient with multiple myeloma following successful long-term alkylating agent therapy. Five and one-half years after the diagnosis of myeloma, while in remission on cyclophosphamide therapy, the patient experienced severe abdominal right lower quadrant pain due to a large cecal lymphoma. A right hemicolectomy was performed with relief of symptoms. However, 9 months later, while still asymptomatic, routine physical examination revealed a recurrent right lower quadrant tumor. Radiation therapy decreased the size of the mass, but five months later partial small bowel obstruction occurred because of recurrent lymphomatous infiltration. The patient died 7 years after the diagnosis of myeloma with extensive abdominal lymphoma. There was no evidence of recurrent myeloma after the initial remission on cyclophosphamide therapy. This patient adds to the growing literature of a second malignancy occurring after prolonged successful chemotherapy of a primary neoplasm.

Data from a chronic feeding study with 2-acetylaminofluorene [(2-AAF) CAS: 53-96-3; N-fluoren-2-yl-acetamide] done on 20,880 female BALB/c mice were analyzed for associations between cage shelf level and occurrence of induced and spontaneous neoplasms. Each cage was maintained on a rack at a given shelf level throughout the experiment, allowing analysis of data by shelf level. Differences in the crude incidence of 2-AAF-induced liver and bladder neoplasms appeared to be shelf related, but these differences were small and disappeared when shelf-level analyses of time-to-tumor onset distributions were performed. There was evidence for a shelf-level influence on 5 of the 6 major spontaneous neoplasms noted. Time to onset of uterine polyps and reticulum cell sarcomas was significantly delayed on the top shelf of five of six animal rooms. Also, there was a significant delay in onset of lymphomas, adrenocortical adenomas, and lung alveolar cell tumors on the top shelf when data were combined from all six animal rooms, but these delays on the top shelf were significant in no more than two of six animal rooms when rooms were analyzed separately. There was no indication of any shelf-level influence on the development of harderian gland adenomas. In conclusion, shelf level is an environmental factor that should be considered in the design and analysis of carcinogenesis studies.

Groups of inbred C57BL/6Os female mice were subjected to one of the following -reatments: 1) subamyloidogenic administration of sodium caseinate (C group); 2) four intragastric intubations of 0.25 mg 3-methylcholanthrene (MCA) (MCA group); 3) a sodium caseinate injection followed by MCA (C-MCA group); or 4) MCA followed by a soidum caseinate injection (MCA-C group). During their life-spans, mice of the C group developed a significantly high incidence of neoplasms, especially histiocytic lymphomas, No myelogenous leukemia was observed in the C group, but it was seen in the MCA, C-MCA, and MCA-C groups. The occurrence rate of other neoplasms was significantly high in the C, MCA, and MCA-C groups, but it was not significantly high in the C-MCA group compared with the untreated group. Results suggested that sodium caseinate treatment shifts target organs in MCA carcinogenesis. In all treated groups, amyloidosis of a secondary type was observed at a significantly high rate in the following order of severity by treatment group: MCA, MCA-C, C-MCA, and C groups, MCA was obviously amyloidogenic with or without sodium caseinate adjuvant treatment; although the sodium caseinate treatment was subamyloidogenic, it elicited neoplasms, including neoplasms of lymphoreticular tissue.

By means of application of methyl-, ethyl-, n-propyl-, iso-propyl- and n-butylurea together with sodium nitrite the formation of corresponding carcinogenic N-nitroso compounds is demonstrated. The transplacental action of endogenously formed ethylnitrosourea led to a characteristic spectrum of tumours in the offspring comprising mainly neurogenic neoplasms of the brain and Nn. trigemini. The tumour incidence is especially high after application of precursors (ethylurea and nitrite) with the food. In postnatal experiments with methylurea and nitrite, there were induced mostly neurogenic tumours and reticulum cell sarcomas of the paracoecal region. A similar spectrum of tumours was found after postnatal application of iso-propylurea and nitrite by gastric tube. After a single dose of iso-propylurea and nitrite at day 21 of pregnancy there seems to be a slight carcinogenic effect in a small group of animals. The application of n-propylurea and n-butylurea, resp., together with nitrite led mainly to reticulum cell sarcomas of the paracoecal region after formation of corresponding alkylnitrosoureas. The spectrum of tumours is compared with that after the action of complete carcinogen and with the results obtained by other authors.

The occurrence of malignant histiocytic lymphomas (MHLT) after an intrapleural inoculation of silica and the presence of a hyperplastic or granulomatous reaction to the silica were confirmed in cesarean-derived barrier-maintained inbred W rats. A specific hyperplastic reaction in the silica granulomas preceded the appearance of MHLT. Hyperplastic changes were observed when the absolute monocyte count at weeks 25-30 was slightly higher than that seen in the controls. Silica injected intrapleurally penetrated the thymus tissue but the carbon and coal dusts and the silica, which was administered by other routes, did not involve the thymus. Also, silica was the sole dust, when introduced into the coelomic cavities that produced MHLT, which grew rapidly on entering the thymus. Rats that died with MHLT had widespread dissemination with malignant foci situated most consistently above the diaphragm.

The effects of splenectomy on carcinogenesis by a single 10-mg dose of 7,12-dimethylbenz[alpha]anthracene (DMBA) given in olive oil by gavage was tested on BTOs, C57BL/60s, C3H/HeOs, and BALB/cOs mice. The splenectomy, performed a week before the DMBA was given, did not affect physical status or the incidence of acute toxic death of animals. DMBA-treated animals developed neoplasms at a significantly higher rate than did untreated mice. Splenectomy did not influence the overall incidence of neoplasms. Observed tumors in DMBA-treated groups were those of skin, forestomach, colon, liver, lung, adrenal, ovary, breast, hematopoietic-lymphoreticular system, and vascular system, depending on the strain. Types of DMBA-treated neoplasms were affected by prior splenectomy, depending on the strain: Splenectomy inhibited lung adenomas in BALB/cOs females and hepatomas in C57BL/60s females; splenectomy enhanced skin neoplasms in C57BL/60s and squamous cell carcinoma of the forestomach in BTOs males. The most significant change was in the incidence of the group of lymphomas. Myelogenous leukemia was increased in DMBA-treated groups of all strains, but splenectomy inhibited the development of this type of lymphoma.

3- or 14-month-old female rats were intravenously injected N-nitroso-N-methylurea (MNU), 50 mg/kg body weight, 2 or 4 times weekly. There was a direct correlation between the incidence of mammary carcinomas and MNU doses. Kidney tumors occurred inversely proportional to the dose of the carcinogen. Mammary adenocarcinomas were only observed in young MNU-treated rats. Cervicovaginal malignant tumors were only observed in old MNU-treated rats. The incidence of hematopoietic system tumors was the same in animals of both age groups. Rats treated with MNU showed acceleration of benign spontaneous tumor development. The effect of aging on the initial stage of MNU-induced carcinogenesis is believed to be determined by age-associated changes in the proliferative activity of target tissues. The effect of aging on the further development of carcinogenesis may be caused by age-associated hormonal, metabolic, and immunological shifts.

Inbred Swiss mice were treated with technical BHC (1) orally with the diet or by intubation and (2) by skin painting. The total duration of the experiment was 80 weeks. There was no difference in body growth and mortality between the experimental and control groups. Symptoms of intoxication in the form of convulsions and tendency of circling in one direction with drooping ears were observed alongwith corneal opacity 40 weeks after the experiment. Oral BHC treatment resulted in a significant increase in the incidence of liver tumours and tumours of lymphoreticular tissue. Males and females were equally susceptible. Skin painting of mice did not significantly increase the incidence of tumour.

A 45-year-old White man presented with multiple aneurysm formation and severe constitutional symptoms, the control of which entailed long-term corticosteroid therapy. Early in the patient's clinical course, two aneurysms were resected, and at subsequent postmortem examination the vascular lesions were found to be inactive and fibrosed, which suggested that the corticosteroids had been effective in controlling the inflammatory reaction. Of special interest was the development of diffuse lymphoma of the large cell type (histiocytic lymphoma) late in the course of the disease. This report emphasises the association between immunosuppressive therapy and subsequent neoplasia, and stresses the need for caution in the administration of these agents to patients whose condition is benign.

There was a significant excess of deaths caused by major lymphomas in men employed in occupations where benzene and/or coal tar fractions are used. The increase in risk was limited to those who were 45 years of age and older at death, an observation which is consistent with the possibility that chronic exposure might be important. Evidence from other studies suggests that benzene may adversely affect the immunological system.

Inbred strains BALB/c and CBA and noninbred Swiss mice were used for transplanting skin autografts exposed before transplantation for approximately 48 h to (a) culturing in room air and (b) culturing in 45--48% CO2 in air. These pre-transplantation manipulations of skin autografts led to malignant lymphomas in the hosts. The lymphoma incidence was highest in the recipients of the CO2 -treated grafts; moreover, it was greater than the spontaneous incidence even in the recipients of grafts exposed to culturing in air alone, in some types of mice. The following abnormalities of the reticuloendothelial system were noted: (1) proliferation of lymph follicles into irregular masses of pleomorphic cells, (2) hyperplasia with concomitant atrophy of the lymphoid tissue (o) replacement of the lymph follicles by malignant lymphoid cells. Renal lesions resembling membranes glomerulitis occurred occasionally. The occurrence varied in different strains.

Benzidine, recognized as a bladder carcinogen in man and as a liver carcinogen in experimental animals, is the chemical basis of as many as 200 commercial dyes. Physiological processes can metabolize these dyes to release benzidine, thereby creating a potential exposure hazard. To assess this hazard, both sexes of F1 hybrid (genetically homogeneous) and monohybrid (genetically heterogeneous) mice from a BALB/c male and C57BL/6 female cross were exposed for their respective lifespans to benzidine dihydrochloride in their drinking water at concentrations of 0, 30, 40, 60, 80, 120, and 160 ppm for males, and 0, 20, 30, 40, 60, 80, and 120 ppm for females. Animals were removed from the study when they were dead or moribund. This study was terminated after 33 months of exposure. Using the endpoint of hepatocellular adenomas and carcinomas, the Armitage Doll multistage model was used to describe the tumor rates in the experimental dose range and to obtain the upper confidence level on tumor rates. Linear interpolation was used between zero dose and the upper confidence level of the lowest experimental dosage for predicting potential low dose tumor rates. Dose-response effects on body weight, survival, and liver neoplasms were noted in both stocks. For each of the endpoints, the females were more susceptible than males and the F1 (homogeneous) stock was more susceptible than the monohybrid cross (heterogeneous). The calculated virtually "safe" dose predicted to produce less than one per million F1 female mice with a liver tumor is 0.045 ppb. One part per billion of benzidine dihydrochloride in the drinking water of these mice is estimated to produce liver tumors in less than 2.23 mice per 100,000 population.

Six patients are described with chronic liver disease, 3 with primary biliary cirrhosis and 3 with chronic active hepatitis, all of whom developed malignant disease in organs other than the liver. Two malignancies were mixed histiocytic-lymphocytic lymphomas. All patients had received corticosteroid or azathioprine therapy. Specific lymphocyte counts and immunoglobulin and antibody determinations failed to reveal a consistent pattern of abnormality to recognize the patient at risk. Several diseases in which the immune responsiveness is disturbed seem to have this potentiality in common, especially if therapy that further alters immunological reactivity is given.

Groups of F344 rats of each sex were exposed to either ethylene oxide (ETO) vapor (concentrations of 100, 33 or 10 ppm) or to room air for 6 hours daily, 5 days per week, for up to 2 years. Three representative sections of the brain from each rat were evaluated. Twenty-three primary brain tumors were found, two of which were in control animals. Increased numbers of brain tumors were seen in 100 ppm and 33 ppm ETO exposed male and female rats. Significant trend analyses were found for both males and females, indicating that, under the conditions of this study, ETO exposure above 10 ppm was related to the development of these brain tumors.

The response of lymphoreticular tissues to a single i.p. injection of benzo(a)pyrene was studied in the first generation of C57BL/6J X C3HeB/FeJ F1 and C3HeB/FeJ X A/J F1 mice. Groups of 1-, 15-, and 42-day-old animals of both sexes received 75 or 150 mug of the carcinogen per g body weight. After a period of approximately 90 weeks, a high incidence (up to 43%) of reticulum cell sarcomas was observed in C57BL/6J X C3HeB/FeJ F1 mice treated with benzo(a)pyrene at 40 days of age. Animals treated with carcinogen at younger ages had a lower incidence of reticulum cell sarcomas. These sarcomas showed marked cellular pleomorphism and were classified into histiocytic, epitheloid-nodular, reticulocytic, and fibrocytic forms according to the predominant cell type. Lymphomas of thymic and extrathymic lymphoid origin and leukemia of granulocytic type were seen in a descending order of frequency. Control animals of either strain that were killed at 90 weeks of age were basically free of lymphoreticular tumors, while those kept under observation up to 170 weeks developed these tumors in 24% (C57BL X C3H F1) and 10% (C3H X A/J F1), respectively. Studies revealed that the augmentation and/or acceleration of development of the lymphoreticular neoplasms and specifically reticulum cell sarcomas by benzo(a)pyrene was dependent upon the strain and sex of mice used and the age at which the animals were exposed to carcinogen.

0,0-Dimethyl(1-hydroxy-2,2,2-trichloroethyl)-phosphonate (Trichlorfon; TCP) was tested for carcinogenic activity in male and female mice derived from strain AB/Jena by oral (oesophageal-gastric intubation), intraperitoneal and dermal administration. The maximum period of treatment was 73 (oral), 73 (intraperitoneal) or 75 (dermal) weeks. During this period the following maximum mean total doses of TCP per animal had been administered: 157.5 mg(male, oral), 154 mg (female, oral), 160.8 mg (male, intraperitoneal), 149.7 mg (female, intraperitoneal). The dermally treated male and female mice had received a maximum total dose of 375 mg per animal. The study was terminated at 80 weeks. There is no statistic significant difference when compared the total tumour incidence of TCP-treated animals and control mice or the incidence of the different corresponding groups of mice separated by the route of administration or the incidence of malignant and benign tumours separated for the different groups. These findings were independent from whether the groups of TCP-treated animals and solvent control animals were combined or divided by sex for comparison.

The importance of cause-of-death determination in an animal carcinogenesis study with respect to estimation of time-to-tumor distributions of internally occurring (occult) tumors is discussed. A nontechnical description of time-to-tumor estimation is presented. The information obtained from time-to-tumor estimation when cause-of-death designation was used is illustrated for liver tumors in female mice of the inbred strain BALB/cStCrlfC3Hf/Nctr from the ED01 study with N-2-fluorenylacetamide done at the National Center for Toxicological Research. A time-to-tumor analysis of reticulum cell sarcoma data from the same study has provided insight into some difficulties involved in routine case-by-case determination of cause of death. A more flexible system for assigning of cause of death to dead animals and cause of morbidity to moribund animals is described as a way to improve cause-of-death assignment.

Two patients with primary chronic cold hemagglutinin disease (CHAD) were treated with chlorambucil for ten and 7 1/2 years, with cumulative doses of 14 and 6.6 g, respectively. Both responded favorably, and malignant lymphoma eventually developed in both of them. An attempt to assess the incidence of lymphoma as part of the natural course of untreated CHAD failed for want of proof. Literature since 1970 reported no chlorambucil-associated lymphoma. Of 77 responses to a questionnaire mailed to 135 US hematology-oncology programs, 76 reported no examples of chlorambucil-associated lymphoma. One response, however, did relate that diffuse histiocytic lymphoma developed in three of 141 patients receiving prolonged chlorambucil therapy for polycythemia vera. Alkylating-agent therapy for CHAD might be associated with development of lymphoma.

Toxaphene is highly carcinogenic in rats and mice. Toxaphene induced malignant neoplasms of the liver in rats. Neoplasms at all sites, as well as malignant neoplasms, were increased in male and female rats ingesting toxaphene. Sarcomas were found more often in male rats and carcinomas in female rats. Neoplasms of the endocrine organs were also increased in male and female toxaphene-treated rats. The incidence of neoplasms of the reproductive system was increased in female rats, as was the incidence of mammary gland neoplasms in male rats. Toxic changes in male rats given toxaphene included interstitial fibrosis of the kidney and atrophy of the testes. Toxaphene induced malignant neoplasms of the liver in male and female mice. The incidence of malignant neoplasms at all sites was also increased. In addition to hepatic neoplasms, male mice had leukemia or lymphosarcoma and females had sarcomas of the uterus.

During experiments to study the evolution of hepatocellular carcinoma in adult male Wistar rats by exposing regenerating livers to the action of small doses of dimethylnitrosamine (DMN) or N-2-acetylaminofluorene (AAF), several primary sarcomas of the liver were incidentally observed. The morphology and behavior of the tumors suggest their origin from Kupffer's cells. Kupffer cell sarcomas occurred more frequently when 70% hepatectomy was used as the regenerative stimulus. None of the 36 animals treated with AAF alone and 2 of the 38 rats given DMN only had this tumor.

Phorbol, the unesterified parent alcohol of the skin promoter TPA, was administered i.p., twice weekly, throughout the lifetime of mice of 7 inbred strains: males and females of AKR/J, C3Heb and BALB/c, and females of SJL/J, DBA/2, SWR and C57BL. A striking difference in strain response was observed, with a pronounced leukaemogenic effect in SWR, a signficiant shortening of the latent period for spontaneous reticulum cell sarcomas (RCNB) in SJL/J, and no demonstrable effect in the other strains. When mice of 3 of the above-mentioned strains (SWR, SJL/J and AKR/J) were thymectomized prior to the beginning of phorbol treatment, different patterns of response were again observed. Thymectomy did not influence the leukaemia incidence in SWR mice, slightly inhibited RCNB development in SJL/J mice and converted phorbol into a leukaemogenic agent for AKR/J mice.

Three patients with multiple myeloma who developed a plasma cell sarcoma during apparently successful chemothapy are described. It is postulated that the chemotherapy induced the sarcomatous change.